RHINOSINUSITIS (J MULLOL SECTION EDITOR)

Clinical Evidence and Biomarkers Linking Allergy and Acuteor Chronic Rhinosinusitis in Children a Systematic Review

Eugenio De Corso12amp Daniela Lucidi3 amp Elena Cantone4

amp Giancarlo Ottaviano5amp Tiziana Di Cesare1 amp

Veronica Seccia6 amp Gaetano Paludetti1 amp Jacopo Galli1

Accepted 20 August 2020 Springer Science+Business Media LLC part of Springer Nature 2020

AbstractPurpose of the Review We provide a systematic review of experimental and clinical evidences linking allergy to acute includingcommon cold and chronic rhinosinusitis in children Furthermore we questioned if anti-allergy treatment may prevent theoccurrence of rhinosinusitis or improve outcomes of its specific managementRecent Findings Allergic rhinitis is a common childhood disease in industrialized countries that is responsible for a major impacton quality of life and healthcare resources Over the years many authors tried to correlate allergy with comorbidities and inparticular to the onset of rhinosinusitis including common cold even though conflicting results are frequently reached Weperformed a systematic review in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis(PRISMA) process Our search yielded 7103 that were finally screened This resulted in 25 publications of which the full textswere assessed and included in a qualitative analysis per different phenotypes of rhinosinusitisSummary The evidence suggests that allergy may lead to overall impairment of mechanical and immunological defense functionof the nasal mucosa against viruses and that anti-allergy treatment may significantly decrease the number and severity of upperrespiratory tract infections including common colds in children It was not possible to perform the analysis for allergy and post-viral acute rhinosinusitis bacterial acute rhinosinusitis and recurrent acute rhinosinusitis because of paucity and heterogeneity ofdata Although there is no definitive proof of causation linking allergy to chronic rhinosinusitis studies lead to suppose that anti-allergy treatment may improve outcomes of specific CRS treatments

Keywords Allergy Rhinovirus Coronavirus Common cold Acute rhinosinusitis Chronic rhinosinusitis Children

Introduction

Allergic rhinitis (AR) in children has a significant impact onglobal quality of life including school performance sleepdisorders and emotional health [1] AR is a nasal mucosa

inflammatory condition caused by environmental allergensinteracting with immunoglobulin (Ig) E in sensitized subjectsRepeated exposure may lead to long-term changes in systemicand local inflammation including upregulation of nasal eosin-ophils and allergen-specific IgE increased levels of adhesion

This article is part of the Topical Collection on Rhinosinusitis

Eugenio De Corsoeugeniodecorsopoliclinicogemelliit

1 Department of Head and Neck Surgery ndash OtorhinolaryngologyFondazione policlinico Universitario A Gemelli IRCCS UniversitagraveCattolica del Sacro Cuore Rome Italy

2 Department of Head and Neck Surgery ldquoA Gemellirdquo HospitalDivision of rhinology - Institute of Otorhinolaryngology CatholicUniversity School of Medicine and Surgery Largo A Gemelli n100168 Rome Italy

3 Department of Otolaryngology-Head and Neck Surgery UniversityHospital of Modena Modena Italy

4 Department of Neuroscience Reproductive andOdontostomatological Sciences ENT section University ldquoFedericoIIrdquo Naples Italy

5 Department of Neurosciences Otolaryngology Section Universityof Padova Padova Italy

6 Otolaryngology Audiology and Phoniatric Operative UnitDepartment of Surgical Medical Molecular Pathology and CriticalCare Medicine Azienda Ospedaliero Universitaria PisanaUniversity of Pisa Pisa Italy

httpsdoiorg101007s11882-020-00967-9

Published online 5 September 2020

Current Allergy and Asthma Reports (2020) 20 68

molecules in airway mucosa and enhanced systemic responseto allergen challenge [2] Consequently it is not surprisingthat AR has been historically associated with comorbid upperairway diseases [3] Herein we review clinical and laboratoryevidence linking allergy to rhinosinusitis in children Weaimed to investigate allergy not only as etiologic but also asa worsening factor in fact poorly controlled AR might con-tribute to exacerbations and as such its adequate treatmentmight improve outcomes [4]

Material and Methods

Search Strategy

This systematic review was conducted in accordance with thePreferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) process to identify published experimen-tal and clinical articles about allergy and rhinosinusitis includ-ing common cold in children Manuscript were screened pri-marily by Ovid Medline and EMBASE and from othersources (PubMed Central Cochrane review Web ofScience and Google Scholar) and published from January2000 to April 2020 Only 3 articles before this date wereincluded because they were considered particularly relevantfor this systematic review Literature searches were performedin April 2020

We performed two different searches using MeSH termsOne group of authors focused on experimental studiesmatching the term as fol lows [( rhinovirus) OR(coronavirus) OR (epithelial barrier) OR (epithelial cells)OR (barrier function) OR (nasal epithelial cells) OR (viralinfections)] AND [(allergy) OR (allergic rhinitis) OR (atopy)OR (atopic) OR (allergic children) OR (non-allergic children)OR (immunoglobulin E)] AND [(children) OR (childhood)OR (pediatric)] The second group of authors focused on clin-ical studies matching the term as follows [(respiratory infec-tions) OR (acute rhinosinusitis) OR (chronic rhinosinusitis)OR (sinusitis) OR (rhinosinusitis) OR (recurrent sinusitis)OR (endoscopic sinus surgery) OR (URTI) OR (upper recur-rent respiratory infection) OR (common cold)] AND [(allergy)OR (allergic rhinitis) OR (atopy) OR (atopic) OR (allergicchildren) OR (non-allergic children) OR (immunoglobulinE) OR (immunotherapy) OR (antihistamine)) AND ((chil-dren) OR (childhood) OR (pediatric)]

Study Selection

In the first screening authors read the title and abstract of thearticles selecting those being as inclusive as possible Theabstracts were screened independently by reviewers of thetwo groups Any disagreements were resolved by consensusInclusion and exclusion criteria were established before the

selection of relevant studies The inclusion criteria were pri-mary research (including descriptive studies observationalstudies randomized trials and basic science articles) pub-lished after January 2000 addressing allergy andrhinosinusitis in children including common coldFurthermore we questioned if anti-allergy treatment may pre-vent the occurrence of rhinosinusitis or improve its specificmanagement

We excluded secondary research studies (eg review arti-cles or systematic review) case studies newspaper articlelecture letter comment personal narrative consensus confer-ence and editorial Only articles with full text available wereincluded Additional studies were manually identified fromthe reference lists of retrieved literature We excluded all thearticle that did not meet the inclusion criteria or deal directlywith the issue investigated Based on our review it was notpossible to differentiate between atopy or sensitization andallergy We included only English-language peer-reviewedpapers

Results and Discussion

The details of the systematic search performed are shown inFig 1 In total our search yielded 9870 articles after dupli-cates removal We excluded 2767 articles due to time of pub-lication and type of article and then 7103 were finallyscreened This resulted in 25 publications of which the fulltexts were assessed and included in a qualitative analysis Wesummarized in tables the included studies per phenotype clas-sifying evidence using GRADE methodology No studieswere included in a quantitative synthesis (meta-analysis)

Allergy and Acute Rhinosinusitis in Children

According to the EPOS2020 guidelines [5] acuterhinosinusitis (ARS) in children is defined as a sudden onsetof two or more of the following symptoms nasal blockageobstructioncongestion discolored nasal discharge and cough(daytime and night time) for lt 12 weeks ARS in children cantheoretically be divided into viral acute rhinosinusitis (iecommon cold) post-viral rhinosinusitis and acute bacterialrhinosinusitis (ABRS) Acute viral rhinosinusitis has usuallya duration of symptoms of le 10 days Post-viral one is definedif symptoms increase after 5 days or are persistent for gt10 days with less than 12 weeks duration only small sub-groups of these are of bacterial origin Discolored mucoussevere pain fever gt 38 degC and ldquodouble sickeningrdquo lead tothe suspicious of bacterial supra infection Recurrent ARS(RARS) is defined as ge 4 episodes of rhinosinusitis per yearwith symptom-free intervals

68 Page 2 of 13 Curr Allergy Asthma Rep (2020) 20 68

Allergy and Acute Viral Rhinosinusitis in Children (ieCommon Cold) Including Viral Upper RespiratoryTract Infections (URTIs)

Viral acute rhinosinusitis (ie common cold) may be inducedin children by a wide variety of viruses such rhinoviruses(RV) and coronaviruses (CoV) as well as respiratory

syncytial virus (RSV) parainfluenza viruses and adenovi-ruses The common cold is the most frequent upper respiratorytract infection (URTI) which is the most commonly treatedacute problem in primary pediatric care [6] URTI are causedmainly by viruses and may involve not only the nose andsinuses but also the pharynx larynx and large airwaysClinical expression of URTIs is variable and it is influenced

Fig 1 Flowchart of article searchand selection

Page 3 of 13 68Curr Allergy Asthma Rep (2020) 20 68

by the nature of the infecting virus by the age and by phys-iological state and immunological experience of the host Sinonasal clinical features of common cold or URTI commonlyoverlap and are characterized by self-limiting irritation of theupper airways with associated cough with no proof of pneu-monia [7] Based on our review of the literature we observedthat authors for research purpose include common colds inURTI for this reason we included both papers about allergyand common cold or URTI

Laboratory Evidences and Biomarkers Linking Allergyto Increased Risk of Viral Acute Rhinosinusitis

Allergy may induce inflammation of the nasal mucosa leadingto impairment of epithelial barrier function and secondarydeficiency of early local immune reaction Several studiesdemonstrated in fact that the upper airway epithelium repre-sents not only a mechanical wall against pathogens bymucociliary clearance but also an immunological barrier mod-ulating the innate immune response through cytokine produc-tion [8 9]

Interestingly authors [10 11] demonstrated impairment ofthe overall mechanical function of the epithelium and in par-ticular decreased expression of tight-junction proteinsoccludin and zonula occludens-1 in cultured epithelial nasalcells from allergic patients Steelant et al [12] demonstratedthat nasal secretions from allergic subjects rapidly decreasethe trans-tissue resistance of epithelial cell cultures in vitroThey also showed that anti-IL-4 treatment in mice preventedepithelial barrier disruption Finally several authors havedemonstrated [13 14] that allergy may expedite viral over-come of mechanical barriers because Th2-polarized cytokinessuch as IL-4 IL-5 and IL-13 can upregulate endothelial andepithelial expression of adhesion molecules like intercellularadhesionmolecule-1 (ICAM-1) which is the receptor for 90of rhinoviruses

On the other hand several authors demonstrated that aller-gy may modify the immunological functions of the epitheliaMany studies showed the deficiency of the innate immuneresponse in allergic mucosa of upper and lower respiratoryepithelia cells Furthermore it has been demonstrated in thelab that interferon production may be defective in allergicpatients Interferons are crucial for induction of apoptosis invirus-infected host cells because they prevent establishment ofviral replication and promote phagocytosis of infected cells[15ndash17]

The majority of experimental studies about this topic usedcultured epithelial cells obtained from adults and for this rea-son they were not included in the qualitative analyses Theonly article included was of Teach et al [18] reporting thatperipheral blood mononuclear cells cultured from a subset ofatopic children treated with anti-IgE improved INF-α produc-tion after incubation with rhinovirus (Table 1)

Clinical Evidence Linking Allergy to Risk of Viral UpperRespiratory Infection

From a clinical point of view the results are more controver-sial than those from the laboratory Studies in the literaturecomparing the incidence of upper respiratory infections be-tween allergic and non-allergic subjects are relatively few innumber We found 3 retrospective and 1 prospective articlethat were included in the qualitative analyses (Table 2)

In two manuscripts it has been demonstrated that atopicallergic patients had increased susceptibility to upper respira-tory infections In 2006 in a large cross-sectional surveyKarevold et al [19] demonstrated that atopy increases the riskof developing upper and lower respiratory tract infections inchildren In particular atopy was the strongest risk factor suchas in the home environment (dampness) AccordinglyCiprandi et al [20] in a prospective study observed that aller-gic children have a significantly higher number of upper re-spiratory infections more serious in duration and severitycompared with non-allergic children

Other authors disagree Kvaeligrner et al [21] reported thatcorrelation between upper respiratory infection and atopic dis-eases from a population-based sample of 7992 Norwegiantwins was weak even though results were inconclusiveSuumltccediluuml et al [22] confirmed that the number of episodes peryear was not significantly different between atopic andhealthy children even though atopic ones had longer episodesof recurrent URTI compared to controls

Interestingly all clinical studies included in the qualitativeanalyses about therapy (Table 2) supported the hypothesis thatanti-allergy-specific or non-specific treatments may preventviral infections of the upper airways Antihistamine therapycan act by reducing the expression of adhesion viral receptorsto modulate the production of Th2-related interleukins [20]Authors [14 23] demonstrated that children treated withcetirizine had a significant reduction in ICAM-I expressionon epithelial cells thus preventing possible relapse of rhino-virus infections and diminishing both the number and severityof recurrent respiratory infections in children Barberi et al[24bullbull 25] demonstrated that children treated with sublingualimmunotherapy (SLIT) had significantly fewer respiratory in-fections (RI) than symptomatically treated children In addi-tion SLIT-treated children had less fever episodes per yearand took fewer medications vs symptomatically treatedchildren

Allergy and Post-Viral Acute Rhinosinusitis and AcuteBacterial Rhinosinusitis (ABRS) in Children

In the articles reviewed we did not find manuscript inwhich authors distinguished between post-viral ARS andABRS Authors focused the attention particularly on therisks of bacterial superinfection Recent evidence suggests

68 Page 4 of 13 Curr Allergy Asthma Rep (2020) 20 68

in fact that damage or disruption of mucociliary functiondue to viral infection is probably a major cause of superor secondary bacterial infection Allergy is a conditionthat potentially can exacerbate an inflammatory sinonasalresponse although very limited data are available to con-firm this hypothesis in children [26] Based on paucityand heterogeneity of the studies it was not possible toperform a qualitative analysis linking allergy to ABRSor to post-viral ARS [5] For this reason herewith wereport available data by a narrative description

Lin et al [27] demonstrated that the prevalence of col-onization by methicillin-resistant S aureus was higher inatopic children than healthy ones and that atopic childrenwere more likely to develop ARS than non-atopic onesInterestingly other authors [28] observed that AR washighly prevalent in orbital ARS complications in childrenand specifically it was found in 643 of children withpre-septal cellulitis in 25 with periostitis and in 765with subperiosteal abscess Furthermore the prevalence ofAR was significantly higher in patients presenting in pol-len season from February to August than in patients pre-senting between September and January The authors sug-gested that allergy may be a cofactor in the pathogenesisof orbital complication of ARS In addition Alho et al[29] observed that subjects with allergic IgE-mediatedrhinitis had more severe paranasal sinus changes in CTscans than non-allergic subjects during viral colds Theauthors suggested that these changes were signs of moreseverely impaired sinus function increasing the risk ofbacterial sinusitis

Shi-Wei Lin et al [30] recently evaluated the risk ofincident ARS among children with allergic rhinitis using a

nationwide population-based health claims research databaseand including a large number of patients The authors ob-served that the risk of ARS was significantly higher in pedi-atric patients with allergic rhinitis compared with those with-out the condition (adjusted hazard ratio = 303 95 confi-dence interval = 289ndash318) Caution is advised wheninterpreting the findings of the authors due to limitations ofthe study retrospective design and diagnosis of ARS based onclinical history (authors could not confirm bacterial etiologyof sinusitis)

On the other hand Leo et al [31] demonstrated thatchildren with grass pollen-induced rhinitis during expo-sure to pollen had an incidence of endoscopic confirmedARS comparable with non-allergic children they conse-quently suggested that AR was a negligible risk factor forARS and that the most common risk factor was instead aprevious acute viral infection Accordingly EPOS 2020concluded that there appears to be small evidence to sup-port the presence of AR as a risk factor for developingARS in children recognizing a central role for previousviral infection

Allergy and Recurrent Acute Rhinosinusitis (RARS) inChildren

We found very limited and heterogeneous data linking allergyto RARS and it was not possible to perform a qualitativeanalysis Choi et al [32] evaluated the predisposing factorsthat may be associated with chronic and recurrent RS exam-ining 296 patients with RS younger than 13 years of age Theprevalence of allergic rhinitis atopy and asthma was signifi-cantly higher in patients with chronic and recurrent RS than

Table 1 Laboratory evidence linking allergy to allergy to increased risk of viral acute rhinosinusitis

Evidence from the lab linking allergy to allergy to increased risk of viral acute rhinosinusitis

AuthorYear (ref)

No of cases age Experimental models Methods Relevant results Association( L e v e l o fevidence)

Teach et al 2015[20]

N = 478 children(102 plusmn 293 years)

Peripheral bloodmononuclearcell culturesincubatedex-vivo withrhinovirus

Measuring IFN-α insupernatants ofPBMCscultures obtainedfrom asubset of subjects(n = 87)incubated ex vivowithrhinovirusin patientstreatedor not withomalizumab

The group treated with anti-IgEhad improved IFN-αproductionafter virus infection suggestingrestoring of the impairedinterferonresponse and increasingantiviralimmunity and suggesting thatanti-IgEmay prevent upper and lowerrespiratoryinfections and asthmaexacerbations

Yes(Level V)

PBMC peripheral blood mononuclear cell INF-α interferon alpha

Page 5 of 13 68Curr Allergy Asthma Rep (2020) 20 68

those with acute and subacute RS Veskitkul et al [33] eval-uated the clinical characteristics and predisposing factors ofRARS in children as well as the preventive therapy The au-thors detected allergy in 351 of cases and suggested thatchildren with RARS should be always evaluated for the pres-ence of underlying predisposing conditions including allergicdisease Nevertheless no comparison with a control group

was performed and for this reason data are not definitelysupporting a link between allergy and RARS

Allergy and Chronic Rhinosinusitis (CRS) in Children

Chronic rhinosinusitis (with or without nasal polyps) in chil-dren is defined as presence of two or more symptoms one of

Table 2 Articles investigating clinical association between allergy and upper respiratory infections

Clinical evidence linking allergy to risk of upper respiratory tract infections

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Karevoldet al2006[19]

Cross-sectionalsurvey

N = 5125(10 years)

Assess co-morbidity and risk factors forrecurrent upper and lower respiratoryinfections

Atopic disease was a constitutional riskfactor for upper and lower airwayinfections

Yes(Level IV)

Ciprandiet al2009[20]

Prospective study N = 117(402 plusmn10 years) 46allergic

Evaluate the number and duration of RIin allergic and non-allergic children

Allergic children showed a significantlyhigher number (mean 126 plusmn 073)and longer duration of RI (892 days)in comparison with non-allergicgroup (094 plusmn 137 and 485 days)

Yes(Level II)

Kvaeligrneret al1996[21]

Retrospectiveanalysis

N = 7992 (meanage not known)

Estimate comorbidity between earinfections tonsillitis sinusitis andrelated childhood diseases

The correlation between the infectiousand atopic diseases was weak

Inconclusive(Level IV)

Suumltccediluumlet al2016[22]

Retrospectiveanalysis

N = 507 children(46 range4ndash190 months)

Evaluate children presenting with thecomplaint of recurrent infections andto determine the possible predictivefactors

Atopic children had longer episodes ofrecurrent URTI compared to controlshowever the number of episodes peryear was not significantly different

No(Level IV)

Role of anti-allergy treatment in preventing upper respiratory infections

Ciprandi1999[20]

Double-blind andplacebo--controlled study

N = 20 childrenwith allergy

10 terfenadinegroup(85 plusmn 3 years)10 placebo

(79 plusmn 27 years)

Continuous terfenadine (1 mgkg perbody weight per day) vs placebo for1 year Outcome Symptomsinflammatory cells and ICAM-1measured by nasal scraping

Terfenadine treatment reduces ICAM-1expression on nasal epithelial cellschildren treated with terfenadine hadsignificantly fewer extra visits andschool absences than the placebogroup

Yes(Level I)

Fasce1996[14]

Double-blindplacebocontrolledrandomizedstudy

N = 20 children(5ndash14 yearsold) with miteallergy

Cetirizine vs placebo for 15 days Nasalscrapings were performed to evaluateinflammatory cell infiltration andICAM-I expression on epithelial cells

Cetirizine-treated children showed asignificant reduction (or even totalabsence) of ICAM-I expression onepithelial cells (p = 0002) and areduction trend in inflammatory cellcounts compared with placebo

Yes(Level I)

Barebri2015[25]

Prospective casecontrolobservationalstudy notrandomized

N = 40 HDMallergic children(93 years)

Patients were subdivided in 2 groups 20treated by symptomatic drugs and 20by high-dose HDM-SLIT

SLIT-treated children had significantly(p = 001) less RI episodes (35) thancontrol group (545)

Yes(Level II)

Barberi2018[24]

Retrospectiveanalysis

N = 33 HDMallergic children(93 years)

Investigate whether 3 year high-doseHDM-SLIT affects respiratoryinfections in children with allergicrhinitis

SLIT-treated children had significantlyfewer RI episodes thansymptomatically treated children Inaddition they had less fever and tookfewer medications such as antibioticsand antipyretics

Yes(Level IV)

HDM house dust mites SLIT sub-lingual immunotherapy URTI upper respiratory tract infections RI respiratory infections ICAM intercellularadhesion molecule

68 Page 6 of 13 Curr Allergy Asthma Rep (2020) 20 68

which should be either nasal blockageobstructioncongestionor nasal discharge (anteriorposterior nasal drip) with or with-out facial painpressure andor cough for ge 12 weeks associat-ed with pathognomonic endoscopic signs or CT changes [5]The prevalence of CRS in children is lower than in adults (2ndash4) nevertheless the negative impact on quality of life seemsto be similar to that observed in adults Studies on CRS inchildren are less common and it is more difficult to investi-gate the relationship with allergy [5] Several factors contrib-ute to complicate the analyses including incomplete evalua-tion (nasal endoscopy andor imaging are rarely performed inmany children) and the difficulty to differentiate CRS fromadenoid hypertrophy adenoiditis and (allergic) rhinitis Infact nasal blockage may occur in AR children due to edem-atous mucosa neurogenic and vascular responses over-production of secretions and impaired mucociliary clearanceleading to congestion of the ostia and symptoms simulatingrhinosinusitis On the other hand the blockage leads to stag-nant debris and acidotic environment that might stimulatebacteria overgrowth [34 35]

Histopathological analysis [36 37] demonstrated that pe-diatric CRS is quite different from the adult form showinggreater inflammatory cellularity higher density of submucosallymphocytes less eosinophilic inflammation basement mem-brane thickening and mucous gland hyperplasia suggesting adifferent pathway compared with the adult CRS patternwhich is predominantly characterized by a Th2-oriented re-sponse with polypoid changes The presence of nasal polypsin a pediatric patient should suggest the hypothesis of cysticfibrosis that has not been included in this paper More specif-ically some evidence supports the hypothesis that CRS inchildren over the age of 13 seems to be based more on eosin-ophilic inflammation while under this age CRS seems to bebased more on neutrophilic inflammation thus justifying thelower prevalence of nasal polyps in children than in adult [3637]

Several manuscripts support the hypothesis that AR andCRS could be different faces of the same disease AR in factis typically characterized by a Th2 immune response involv-ing IL-4 IL-5 and IL-13 which drives IgE production andrecruitment of eosinophil granulocytes It has been suggested[38ndash42] that eosinophils by generating potent toxic agents(cationic proteins oxygen-free radicals and proinflammatorycytokines) may play a major role in initiating and perpetuat-ing inflammation of sinonasal mucosa in patients with AR

Evidence from the Lab and Biomarkers Linking AllergicInflammation to Increased Risk of Chronic Rhinosinusitisin Children

All studies included in a qualitative analysis support a specificlink between CRS and AR in children (Table 3) Chawes [43]studied nasal eosinophilia and nasal airway patency (assessed

by acoustic rhinometry) in children with AR non-allergic rhi-nitis and healthy controls Nasal eosinophilia and irreversiblenasal airway obstruction were significantly associated withAR while there was no such association with non-allergicrhinitis The authors suggested that chronic inflammationand structural remodeling of the sinonasal mucosa may occurin allergic children even at 6 years of age

Some authors suggested that allergic sinonasal inflamma-tion may support bacterial infection Blair et al [44] in ananimal model showed that allergic inflammatory reactionmay obstruct sinus drainage encouraging bacterial infectioninto the maxillary sinus Shin et al [45] demonstrated thattotal IgE total eosinophil count and serum eosinophil cationicprotein levels were significantly higher in CRS childrenwhose symptoms and radiologic abnormalities did not resolveafter 12 weeks despite appropriate antibiotic therapy (non-responder) compared with responders and healthy controlsMoreover AR in children may affect the efficiency ofmucociliary clearance which is one of the most importantprotective functions of the respiratory epitheliumDeterioration of mucociliary system appears to be related tomore severe rhinitis with a higher intensity of local nasal in-flammation reflected in nasal smear eosinophilia [46bullbull]

Brożek-Mądry and co-workers [47] evaluated the relationbetween bacterial strains and cytological examination of nasalmucosa in children with CRS they found that the most com-mon strains of bacteria observed in CRS (Hemophilusinfluenzae Moraxella catarrhalis and Staphylococcusaureus) were associated with a higher prevalence of atopyand percentage of eosinophils in cytology It must be notedthat S aureus enterotoxins are able to induce increased sever-ity of the disease amplifying eosinophilic inflammation inatopic patients [48]

Clinical Evidences Linking Allergic Inflammation to IncreasedRisk of Chronic Rhinosinusitis

The association between allergy and CRS in adults has beendiscussed for years and a strong association has been observedwith particular subtypes of CRS with nasal polyps(CRSwNP) such as central compartment atopic disease andallergic fungal rhinosinusitis (AFRS) [49 50] Manuscripts onpediatric CRS are less common predominantly because ofethical issues regarding administration of X-rays in the pedi-atric population The publications included in the qualitativeanalyses are summarized in Table 4 Conclusions of the stud-ies included in the qualitative analyses were not unanimouslylinking allergy to chronic rhinosinusitis

Several manuscripts seem to support a positive clinical as-sociation between AR and CRS describing a prevalence vary-ing between 27 and 59 of patients [51ndash53] Brietzke et al[54] in an expert panel consensus suggested that there is aclinically relevant association between AR and pediatric

Page 7 of 13 68Curr Allergy Asthma Rep (2020) 20 68

CRS particularly in older children Sedaghat et al[55] analyzing a large series of 4044 pediatric cases observedAR in 269 children with CRS but their results were incon-clusive because no comparison with control group wasprovided Choi et al [32] showed that age atopy AR andasthma may be predisposing factors for pediatric CRS andrecurrent RS The authors proposed that specific evaluationfor allergic diseases should be considered when managingchronic or recurrent RS More recently Anamika et al [56bull]demonstrated a positive skin prick test in 53 of the cases in acohort of 110 children with CRS moreover those with atopyhad higher mean Lund-Mackay endoscopic score and sinusand nasal quality of life survey score than non-atopic patients

Huang et al [57] attempted discrimination among differentallergies and reported that mold allergy represents a significant

risk factor for development of sinusitis compared with non-mold allergy in a case series of 413 children followed for5 years These data suggest that perennial allergy may be astronger risk factor for CRS compared with seasonal allergy

On the other hand some studies suggested a lack of corre-lation between allergic disease and pediatric CRS Leo et al[58] in a report on 351 children affected by CRS demonstrat-ed that the prevalence of sensitization to aeroallergens wascomparable with that of the general pediatric population Noclinical evidence could account for a higher rate of nasal con-gestion nor a harsher clinical course in allergic children [59]Sedaghat et al [51 60] observed that pediatric patients withAR and CRS seem to have the same aeroallergen sensitivityprofile compared with the general pediatric population withAR Furthermore the authors did not find a positive

Table 3 Evidence of inflammatory cells and mediators linking allergy to chronic rhinosinusitis in children

Biomarkers linking allergy to risk of CRS

AuthorYear() ref

No of cases Experimentalmodels

Methods Relevant results Association(Level ofevidence)

Chawes 2011[43]

N = 411 children withAR non-AR andhealthy controls(6 years)

Nasal airwaypatency wasassessed byacousticrhinometry

Acoustic rhinometry was performedtwice in the childrsquos 6th year of lifewith or without allergy Nasaleosinophilia was assessed by nasalscraping

Nasal eosinophilia correlated withirreversible nasal airwayobstruction in allergic childrenalready at age 6 years No changein nasal airway patency wereobserved in non-allergic rhinitis

Yes(Level III)

Blair et al2001 [44]

NA Mousesensitized toovalbuminbyintraperito-nealinjection

Sinuses of the mouse were infected byS pneumoniae with or withoutconcomitant administration ofovalbumin to induce or not allergicinflammation

Mice with allergic sinonasalinflammation had significantlymore bacteria and significantlymore inflammation (as indicated byneutrophil eosinophil andmononuclear influx) into the sinuswith respect to the non-allergicones

Yes(Level V)

Shin et al2015 [45]

N = 36 CRSresponders vs 22CRS

non-responders 22healthy controls

(age lt 15 years)

Serumanalyses

Skin prick tests were performed alongwith serum total IgE TEC serumECP level and ImmunoCAPanalysis for common allergens

TEC ECP and total IgE levels weresignificantly higher in thenon-responder group than in theresponder and control groups

Yes(Level III)

Mikolajczyket al 2019[46bullbull]

N = 842 AR childrenand 96 controls

EOSnsMCT

All patients underwent saccharin andskin prick tests nasal smeareosinophilia total and specific IgEserum concentration and MCTmeasurement

Nasal MCT was significantly longerin AR patients than controlsEOSns were significantly higherin patients than controls A weakbut significant correlation wasobserved between EOSns andMCT

Yes(Level III)

Brożek-Mądryet al 2012[47]

N = 64 patients withchronicrhinosinusitiswithout polyps and30 controls (age5ndash18 years)

Epithelialcultures(middlemeatal cells)

Middle meatus culture and cytologicalexamination from the inferior nasalconcha and middle meatus

The most common strains of bacteriafound in patients with CRS wereassociated with a higher percentageof eosinophils in cytology and highprevalence in atopic patients

Yes(Level V)

AR allergic rhinitis CRS chronic rhinosinusitis MCT mucociliary transport time EOSns percentage of eosinophils in nasal smear TEC totaleosinophil count ECP serum eosinophil cationic protein

68 Page 8 of 13 Curr Allergy Asthma Rep (2020) 20 68

association between the number of aeroallergen sensitivitiesand the presence of atopic comorbidities with the subsequent

development of CRS suggesting that the severity of atopyalone may not be positively predictive of CRS development

Table 4 Clinical evidences linking allergy to chronic rhinosinusitis in children

Clinical evidences linking allergy to risk of CRS in children

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Sedaghatet al2014[55]

Retrospectiveanalysis

N = 4044 childrenwith CRS(89 years)

Retrospective review of childrendiagnosed as uncomplicated CRSby an otolaryngology or allergyoffice evaluation

Comorbidities observed in CRS childrenwere primary ciliary dyskinesia (02)cystic fibrosis (41) immunologicdisorder (123) and AR (269)

Inconclusive(Level IV)

Choi et al2012[32]

Prospectivestudy

N = 296(lt 13 years)with recurrentRS

To evaluate predisposing factors forchronic and recurrent RS

The prevalence of AR atopy and asthmawas significantly higher in patients withCRS and recurrent RS than those withacute and subacute RS

Yes(Level II)

Anamikaet al2019[56bull]

Cross-sectionalstudy

N = 110 childrenwith CRS(7-18 years)

To determine atopic profile ofchildren with CRS and impact ofatopic status on disease severity andquality of life

Positive skin prick test was present in 527of patients Atopic CRS had a significanthigher mean Lund-Mackay endoscopicscore and symptoms scores thannon-atopic ones

Yes(Level IV)

Huang2000[57]

Prospectiveobservationalstudy

N = 413 RAchildren

(3ndash15 years)

To evaluate mold allergy as risk factorfor sinusitis

The authors compared 215 PAR with198 SAR

The prevalence of sinusitis was significantlyhigher among patients with PAR thanamong those with SAR regardless of ageor season patients with mold allergy PARhad a higher risk than those with non-moldallergy

Yes(Level II)

Leo et al2007[58]

Cross-sectionalstudy

N = 351 childrenwith CRS(523 plusmn211 years)

CRS underwent allergen sensitizationwork-up by skin prick test withcommon inhalant allergens andtotal IgE measurement

Prevalence of sensitization to aeroallergens inchildren with CRS is comparable with thatof the general pediatric population

No(Level IV)

Nathanet al2004[62]

Prospectiveobservationalstudy

N = 114 RA andCRS (childrenand adult)

Patients were surveyed for globalsymptoms and specific symptomsrelated to the nose sinuses eyesand chest with the SOQ

Immunotherapy is an effective treatment forpatients with sinus disease and allergicrhinitis

Yes(Level II)

RamadanampHiner-man2006[61]

Prospectiveobservationalstudy

N = 141 patientswho underwentESS (7 years)

To evaluate outcome of ESS at 1 yearafter the operation

Children with AR who were on treatmentbefore surgery had an 84 success ratecompared with 62 for those childrenwith non-treated AR by immunotherapy

Yes(Level II)

Kim et al2005[63]

Retrospectiveobservationalstudy

N = 97 patients(age range

5ndash15 years)

Retrospective analysis of long-termsuccess rates of ESS with respect toseveral predisposing factors

Multivariate logistic regression analysisallergy was not correlated to pooroutcomes after pediatric ESS

No(Level IV)

ElSharka-wy2012[64]

Prospectiveobservationalstudy

N = 87 children(45 with nasalallergy)(age le 14)

To assess predictive factors ofoutcome after ESS

The success rate in CRS with nasal allergywas 875 and in CRS without nasalallergy was 857

No(Level II)

Lee et al2009[66]

Retrospectiveanalysis

N = 53 childrenwho underwentFESS(age lt 18 years)

To investigate factors leading toprotracted nasal discharge afterpediatric endoscopic sinus surgery

Blood eosinophil count did not differsignificantly between the ldquoprotractedrdquo andthe ldquoresolvedrdquo groups On the other handhistory of allergic rhinitis was morefrequently observed in the ldquoprotractedrdquogroup

Yes(Level IV)

Wu et al2019[67bull]

Retrospectiveanalysis

N = 188 childrenESS for CRS

To evaluate prognostic factors relatedto revision surgery after ESS

Patients with positive aeroallergen tests hadhigher rates of CRS recurrence after ESSand required revision surgery

Yes(Level IV)

CRS chronic rhinosinusitis RS rhinosinusitis AR allergic rhinitis PAR perennial allergic rhinitis SAR seasonal allergic rhinitis SOQ sinusitisoutcome questionnaire ESS endoscopic sinus surgery FESS functional endoscopic sinus surgery

Page 9 of 13 68Curr Allergy Asthma Rep (2020) 20 68

These articles were not included in the qualitative analysesdue to the type of article

Impact of Allergy on Outcome of Chronic RhinosinusitisTreatment

Ramadan and Hinerman [61] in a retrospective study notedthat children with AR underwent to endoscopic sinus surgery(ESS) do not have a poorer outcome respect non-allergic oneNevertheless children with AR who were on immunotherapybefore surgery had an 84 success rate compared with 62for those children with AR who were not treated (p = 0022)Accordingly Nathan et al [62] using the sinusitis outcomesquestionnaire (SOQ) demonstrated that immunotherapy wasan effective treatment for patients with sinus disease and ARin both children and adults

About surgery outcomes Kim et al [63] and El Sharkawyet al [64] observed that functional endoscopic sinus surgery inchildren with CRS and AR does not provide significantlydifferent results compared with children without AR whichis similar to what has been reported in adults [65] On thecontrary in a study by Lee et al [66] a significantly greaterchance of protracted mucopurulent discharge after FESS wasregistered in patients with AR The authors assumed that theinflammatory process of nasal allergy which led to the devel-opment of CRS probably impaired the postoperative woundhealing by mucosal congestion poor-functioning mucociliaryclearance and recurrent sneezing that placed pressure on the

denuded mucosa An analogous conclusion was made by Wuet al [67bull] who demonstrated that pediatric patients with pos-itive aeroallergen tests had higher rates of CRS recurrenceafter ESS and required revision surgery

Allergic Fungal Rhinosinusitis (AFRS) in Children

AFRS is also present in the pediatric age group and it shouldbe considered a differential in children presenting with nasalpolyposis along with the other causes like ciliary dysmotilitydisorders and cystic fibrosis [68] There is paucity of data inliterature regarding nature clinical course and its recurrencein children and it was not possible to perform a qualitativeanalysis Patro et al [69] in a single center prospective studycompared features of AFRS in children with adults The au-thors concluded that AFRS was more aggressive in childrenwith increased fungal load when compared with adults Theserum IgE levels were also found to be significantly higher inpediatric group suggesting a higher fungal load with in-creased sensitivity to fungal antigen in children TypicallyAFRS in children was less responsive to treatment with in-creased recurrence rates

Conclusions

AR is a common disease in childhood in industrialized coun-tries and it has a major impact on quality of life and healthcare

Fig 2 Practical algorithm based on different phenotypes of rhinosinusitisin children Abbreviations ARS acute rhinosinusitis CRS chronicrhinosinusitis URTI upper respiratory tract infections ABRS acute

bacterial rhinosinusitis RARS recurrent acute rhinosinusitis AFRSallergic fungal rhinosinusitis

68 Page 10 of 13 Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

1 Meltzer EO Hamilos DL Rhinosinusitis diagnosis and manage-ment for the clinician a synopsis of recent consensus guidelinesMayo Clin Proc 201186(5)427ndash43 httpsdoiorg104065mcp20100392

2 Wood RA Pediatric asthma JAMA 2002288(6)745ndash7 httpsdoiorg101001jama2886745

3 Bousquet J Van Cauwenberge P KhaltaevN et al Allergic rhinitisand its impact on asthma JAMA 2001108(5)S147ndash334 httpsdoiorg101034j1398-9995200223625

4 Borish L Allergic rhinitis systemic inflammation and implicationsfor management J Allergy Clin Immunol 2003112(6)1021ndash31httpsdoiorg101016jjaci200309015

5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

6 Tan YSL Hong CY Chong PN Tan ESL Lew YJ Lin RTPKnowledge that upper respiratory tract infection resolves on itsown is associated with more appropriate health-seeking behaviorand antibiotic cognition Singap Med J 200647(6)518ndash24

7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

9 Parker D Prince A Innate immunity in the respiratory epitheliumAm J Respir Cell Mol Biol 201145(2)189ndash201 httpsdoiorg101165rcmb2011-0011RT

Page 11 of 13 68Curr Allergy Asthma Rep (2020) 20 68

Allergy and Acute Viral Rhinosinusitis in Children (ieCommon Cold) Including Viral Upper RespiratoryTract Infections (URTIs)

Viral acute rhinosinusitis (ie common cold) may be inducedin children by a wide variety of viruses such rhinoviruses(RV) and coronaviruses (CoV) as well as respiratory

syncytial virus (RSV) parainfluenza viruses and adenovi-ruses The common cold is the most frequent upper respiratorytract infection (URTI) which is the most commonly treatedacute problem in primary pediatric care [6] URTI are causedmainly by viruses and may involve not only the nose andsinuses but also the pharynx larynx and large airwaysClinical expression of URTIs is variable and it is influenced

Fig 1 Flowchart of article searchand selection

Page 3 of 13 68Curr Allergy Asthma Rep (2020) 20 68

by the nature of the infecting virus by the age and by phys-iological state and immunological experience of the host Sinonasal clinical features of common cold or URTI commonlyoverlap and are characterized by self-limiting irritation of theupper airways with associated cough with no proof of pneu-monia [7] Based on our review of the literature we observedthat authors for research purpose include common colds inURTI for this reason we included both papers about allergyand common cold or URTI

Laboratory Evidences and Biomarkers Linking Allergyto Increased Risk of Viral Acute Rhinosinusitis

Allergy may induce inflammation of the nasal mucosa leadingto impairment of epithelial barrier function and secondarydeficiency of early local immune reaction Several studiesdemonstrated in fact that the upper airway epithelium repre-sents not only a mechanical wall against pathogens bymucociliary clearance but also an immunological barrier mod-ulating the innate immune response through cytokine produc-tion [8 9]

Interestingly authors [10 11] demonstrated impairment ofthe overall mechanical function of the epithelium and in par-ticular decreased expression of tight-junction proteinsoccludin and zonula occludens-1 in cultured epithelial nasalcells from allergic patients Steelant et al [12] demonstratedthat nasal secretions from allergic subjects rapidly decreasethe trans-tissue resistance of epithelial cell cultures in vitroThey also showed that anti-IL-4 treatment in mice preventedepithelial barrier disruption Finally several authors havedemonstrated [13 14] that allergy may expedite viral over-come of mechanical barriers because Th2-polarized cytokinessuch as IL-4 IL-5 and IL-13 can upregulate endothelial andepithelial expression of adhesion molecules like intercellularadhesionmolecule-1 (ICAM-1) which is the receptor for 90of rhinoviruses

On the other hand several authors demonstrated that aller-gy may modify the immunological functions of the epitheliaMany studies showed the deficiency of the innate immuneresponse in allergic mucosa of upper and lower respiratoryepithelia cells Furthermore it has been demonstrated in thelab that interferon production may be defective in allergicpatients Interferons are crucial for induction of apoptosis invirus-infected host cells because they prevent establishment ofviral replication and promote phagocytosis of infected cells[15ndash17]

The majority of experimental studies about this topic usedcultured epithelial cells obtained from adults and for this rea-son they were not included in the qualitative analyses Theonly article included was of Teach et al [18] reporting thatperipheral blood mononuclear cells cultured from a subset ofatopic children treated with anti-IgE improved INF-α produc-tion after incubation with rhinovirus (Table 1)

Clinical Evidence Linking Allergy to Risk of Viral UpperRespiratory Infection

From a clinical point of view the results are more controver-sial than those from the laboratory Studies in the literaturecomparing the incidence of upper respiratory infections be-tween allergic and non-allergic subjects are relatively few innumber We found 3 retrospective and 1 prospective articlethat were included in the qualitative analyses (Table 2)

In two manuscripts it has been demonstrated that atopicallergic patients had increased susceptibility to upper respira-tory infections In 2006 in a large cross-sectional surveyKarevold et al [19] demonstrated that atopy increases the riskof developing upper and lower respiratory tract infections inchildren In particular atopy was the strongest risk factor suchas in the home environment (dampness) AccordinglyCiprandi et al [20] in a prospective study observed that aller-gic children have a significantly higher number of upper re-spiratory infections more serious in duration and severitycompared with non-allergic children

Other authors disagree Kvaeligrner et al [21] reported thatcorrelation between upper respiratory infection and atopic dis-eases from a population-based sample of 7992 Norwegiantwins was weak even though results were inconclusiveSuumltccediluuml et al [22] confirmed that the number of episodes peryear was not significantly different between atopic andhealthy children even though atopic ones had longer episodesof recurrent URTI compared to controls

Interestingly all clinical studies included in the qualitativeanalyses about therapy (Table 2) supported the hypothesis thatanti-allergy-specific or non-specific treatments may preventviral infections of the upper airways Antihistamine therapycan act by reducing the expression of adhesion viral receptorsto modulate the production of Th2-related interleukins [20]Authors [14 23] demonstrated that children treated withcetirizine had a significant reduction in ICAM-I expressionon epithelial cells thus preventing possible relapse of rhino-virus infections and diminishing both the number and severityof recurrent respiratory infections in children Barberi et al[24bullbull 25] demonstrated that children treated with sublingualimmunotherapy (SLIT) had significantly fewer respiratory in-fections (RI) than symptomatically treated children In addi-tion SLIT-treated children had less fever episodes per yearand took fewer medications vs symptomatically treatedchildren

Allergy and Post-Viral Acute Rhinosinusitis and AcuteBacterial Rhinosinusitis (ABRS) in Children

In the articles reviewed we did not find manuscript inwhich authors distinguished between post-viral ARS andABRS Authors focused the attention particularly on therisks of bacterial superinfection Recent evidence suggests

68 Page 4 of 13 Curr Allergy Asthma Rep (2020) 20 68

in fact that damage or disruption of mucociliary functiondue to viral infection is probably a major cause of superor secondary bacterial infection Allergy is a conditionthat potentially can exacerbate an inflammatory sinonasalresponse although very limited data are available to con-firm this hypothesis in children [26] Based on paucityand heterogeneity of the studies it was not possible toperform a qualitative analysis linking allergy to ABRSor to post-viral ARS [5] For this reason herewith wereport available data by a narrative description

Lin et al [27] demonstrated that the prevalence of col-onization by methicillin-resistant S aureus was higher inatopic children than healthy ones and that atopic childrenwere more likely to develop ARS than non-atopic onesInterestingly other authors [28] observed that AR washighly prevalent in orbital ARS complications in childrenand specifically it was found in 643 of children withpre-septal cellulitis in 25 with periostitis and in 765with subperiosteal abscess Furthermore the prevalence ofAR was significantly higher in patients presenting in pol-len season from February to August than in patients pre-senting between September and January The authors sug-gested that allergy may be a cofactor in the pathogenesisof orbital complication of ARS In addition Alho et al[29] observed that subjects with allergic IgE-mediatedrhinitis had more severe paranasal sinus changes in CTscans than non-allergic subjects during viral colds Theauthors suggested that these changes were signs of moreseverely impaired sinus function increasing the risk ofbacterial sinusitis

Shi-Wei Lin et al [30] recently evaluated the risk ofincident ARS among children with allergic rhinitis using a

nationwide population-based health claims research databaseand including a large number of patients The authors ob-served that the risk of ARS was significantly higher in pedi-atric patients with allergic rhinitis compared with those with-out the condition (adjusted hazard ratio = 303 95 confi-dence interval = 289ndash318) Caution is advised wheninterpreting the findings of the authors due to limitations ofthe study retrospective design and diagnosis of ARS based onclinical history (authors could not confirm bacterial etiologyof sinusitis)

On the other hand Leo et al [31] demonstrated thatchildren with grass pollen-induced rhinitis during expo-sure to pollen had an incidence of endoscopic confirmedARS comparable with non-allergic children they conse-quently suggested that AR was a negligible risk factor forARS and that the most common risk factor was instead aprevious acute viral infection Accordingly EPOS 2020concluded that there appears to be small evidence to sup-port the presence of AR as a risk factor for developingARS in children recognizing a central role for previousviral infection

Allergy and Recurrent Acute Rhinosinusitis (RARS) inChildren

We found very limited and heterogeneous data linking allergyto RARS and it was not possible to perform a qualitativeanalysis Choi et al [32] evaluated the predisposing factorsthat may be associated with chronic and recurrent RS exam-ining 296 patients with RS younger than 13 years of age Theprevalence of allergic rhinitis atopy and asthma was signifi-cantly higher in patients with chronic and recurrent RS than

Table 1 Laboratory evidence linking allergy to allergy to increased risk of viral acute rhinosinusitis

Evidence from the lab linking allergy to allergy to increased risk of viral acute rhinosinusitis

AuthorYear (ref)

No of cases age Experimental models Methods Relevant results Association( L e v e l o fevidence)

Teach et al 2015[20]

N = 478 children(102 plusmn 293 years)

Peripheral bloodmononuclearcell culturesincubatedex-vivo withrhinovirus

Measuring IFN-α insupernatants ofPBMCscultures obtainedfrom asubset of subjects(n = 87)incubated ex vivowithrhinovirusin patientstreatedor not withomalizumab

The group treated with anti-IgEhad improved IFN-αproductionafter virus infection suggestingrestoring of the impairedinterferonresponse and increasingantiviralimmunity and suggesting thatanti-IgEmay prevent upper and lowerrespiratoryinfections and asthmaexacerbations

Yes(Level V)

PBMC peripheral blood mononuclear cell INF-α interferon alpha

Page 5 of 13 68Curr Allergy Asthma Rep (2020) 20 68

those with acute and subacute RS Veskitkul et al [33] eval-uated the clinical characteristics and predisposing factors ofRARS in children as well as the preventive therapy The au-thors detected allergy in 351 of cases and suggested thatchildren with RARS should be always evaluated for the pres-ence of underlying predisposing conditions including allergicdisease Nevertheless no comparison with a control group

was performed and for this reason data are not definitelysupporting a link between allergy and RARS

Allergy and Chronic Rhinosinusitis (CRS) in Children

Chronic rhinosinusitis (with or without nasal polyps) in chil-dren is defined as presence of two or more symptoms one of

Table 2 Articles investigating clinical association between allergy and upper respiratory infections

Clinical evidence linking allergy to risk of upper respiratory tract infections

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Karevoldet al2006[19]

Cross-sectionalsurvey

N = 5125(10 years)

Assess co-morbidity and risk factors forrecurrent upper and lower respiratoryinfections

Atopic disease was a constitutional riskfactor for upper and lower airwayinfections

Yes(Level IV)

Ciprandiet al2009[20]

Prospective study N = 117(402 plusmn10 years) 46allergic

Evaluate the number and duration of RIin allergic and non-allergic children

Allergic children showed a significantlyhigher number (mean 126 plusmn 073)and longer duration of RI (892 days)in comparison with non-allergicgroup (094 plusmn 137 and 485 days)

Yes(Level II)

Kvaeligrneret al1996[21]

Retrospectiveanalysis

N = 7992 (meanage not known)

Estimate comorbidity between earinfections tonsillitis sinusitis andrelated childhood diseases

The correlation between the infectiousand atopic diseases was weak

Inconclusive(Level IV)

Suumltccediluumlet al2016[22]

Retrospectiveanalysis

N = 507 children(46 range4ndash190 months)

Evaluate children presenting with thecomplaint of recurrent infections andto determine the possible predictivefactors

Atopic children had longer episodes ofrecurrent URTI compared to controlshowever the number of episodes peryear was not significantly different

No(Level IV)

Role of anti-allergy treatment in preventing upper respiratory infections

Ciprandi1999[20]

Double-blind andplacebo--controlled study

N = 20 childrenwith allergy

10 terfenadinegroup(85 plusmn 3 years)10 placebo

(79 plusmn 27 years)

Continuous terfenadine (1 mgkg perbody weight per day) vs placebo for1 year Outcome Symptomsinflammatory cells and ICAM-1measured by nasal scraping

Terfenadine treatment reduces ICAM-1expression on nasal epithelial cellschildren treated with terfenadine hadsignificantly fewer extra visits andschool absences than the placebogroup

Yes(Level I)

Fasce1996[14]

Double-blindplacebocontrolledrandomizedstudy

N = 20 children(5ndash14 yearsold) with miteallergy

Cetirizine vs placebo for 15 days Nasalscrapings were performed to evaluateinflammatory cell infiltration andICAM-I expression on epithelial cells

Cetirizine-treated children showed asignificant reduction (or even totalabsence) of ICAM-I expression onepithelial cells (p = 0002) and areduction trend in inflammatory cellcounts compared with placebo

Yes(Level I)

Barebri2015[25]

Prospective casecontrolobservationalstudy notrandomized

N = 40 HDMallergic children(93 years)

Patients were subdivided in 2 groups 20treated by symptomatic drugs and 20by high-dose HDM-SLIT

SLIT-treated children had significantly(p = 001) less RI episodes (35) thancontrol group (545)

Yes(Level II)

Barberi2018[24]

Retrospectiveanalysis

N = 33 HDMallergic children(93 years)

Investigate whether 3 year high-doseHDM-SLIT affects respiratoryinfections in children with allergicrhinitis

SLIT-treated children had significantlyfewer RI episodes thansymptomatically treated children Inaddition they had less fever and tookfewer medications such as antibioticsand antipyretics

Yes(Level IV)

HDM house dust mites SLIT sub-lingual immunotherapy URTI upper respiratory tract infections RI respiratory infections ICAM intercellularadhesion molecule

68 Page 6 of 13 Curr Allergy Asthma Rep (2020) 20 68

which should be either nasal blockageobstructioncongestionor nasal discharge (anteriorposterior nasal drip) with or with-out facial painpressure andor cough for ge 12 weeks associat-ed with pathognomonic endoscopic signs or CT changes [5]The prevalence of CRS in children is lower than in adults (2ndash4) nevertheless the negative impact on quality of life seemsto be similar to that observed in adults Studies on CRS inchildren are less common and it is more difficult to investi-gate the relationship with allergy [5] Several factors contrib-ute to complicate the analyses including incomplete evalua-tion (nasal endoscopy andor imaging are rarely performed inmany children) and the difficulty to differentiate CRS fromadenoid hypertrophy adenoiditis and (allergic) rhinitis Infact nasal blockage may occur in AR children due to edem-atous mucosa neurogenic and vascular responses over-production of secretions and impaired mucociliary clearanceleading to congestion of the ostia and symptoms simulatingrhinosinusitis On the other hand the blockage leads to stag-nant debris and acidotic environment that might stimulatebacteria overgrowth [34 35]

Histopathological analysis [36 37] demonstrated that pe-diatric CRS is quite different from the adult form showinggreater inflammatory cellularity higher density of submucosallymphocytes less eosinophilic inflammation basement mem-brane thickening and mucous gland hyperplasia suggesting adifferent pathway compared with the adult CRS patternwhich is predominantly characterized by a Th2-oriented re-sponse with polypoid changes The presence of nasal polypsin a pediatric patient should suggest the hypothesis of cysticfibrosis that has not been included in this paper More specif-ically some evidence supports the hypothesis that CRS inchildren over the age of 13 seems to be based more on eosin-ophilic inflammation while under this age CRS seems to bebased more on neutrophilic inflammation thus justifying thelower prevalence of nasal polyps in children than in adult [3637]

Several manuscripts support the hypothesis that AR andCRS could be different faces of the same disease AR in factis typically characterized by a Th2 immune response involv-ing IL-4 IL-5 and IL-13 which drives IgE production andrecruitment of eosinophil granulocytes It has been suggested[38ndash42] that eosinophils by generating potent toxic agents(cationic proteins oxygen-free radicals and proinflammatorycytokines) may play a major role in initiating and perpetuat-ing inflammation of sinonasal mucosa in patients with AR

Evidence from the Lab and Biomarkers Linking AllergicInflammation to Increased Risk of Chronic Rhinosinusitisin Children

All studies included in a qualitative analysis support a specificlink between CRS and AR in children (Table 3) Chawes [43]studied nasal eosinophilia and nasal airway patency (assessed

by acoustic rhinometry) in children with AR non-allergic rhi-nitis and healthy controls Nasal eosinophilia and irreversiblenasal airway obstruction were significantly associated withAR while there was no such association with non-allergicrhinitis The authors suggested that chronic inflammationand structural remodeling of the sinonasal mucosa may occurin allergic children even at 6 years of age

Some authors suggested that allergic sinonasal inflamma-tion may support bacterial infection Blair et al [44] in ananimal model showed that allergic inflammatory reactionmay obstruct sinus drainage encouraging bacterial infectioninto the maxillary sinus Shin et al [45] demonstrated thattotal IgE total eosinophil count and serum eosinophil cationicprotein levels were significantly higher in CRS childrenwhose symptoms and radiologic abnormalities did not resolveafter 12 weeks despite appropriate antibiotic therapy (non-responder) compared with responders and healthy controlsMoreover AR in children may affect the efficiency ofmucociliary clearance which is one of the most importantprotective functions of the respiratory epitheliumDeterioration of mucociliary system appears to be related tomore severe rhinitis with a higher intensity of local nasal in-flammation reflected in nasal smear eosinophilia [46bullbull]

Brożek-Mądry and co-workers [47] evaluated the relationbetween bacterial strains and cytological examination of nasalmucosa in children with CRS they found that the most com-mon strains of bacteria observed in CRS (Hemophilusinfluenzae Moraxella catarrhalis and Staphylococcusaureus) were associated with a higher prevalence of atopyand percentage of eosinophils in cytology It must be notedthat S aureus enterotoxins are able to induce increased sever-ity of the disease amplifying eosinophilic inflammation inatopic patients [48]

Clinical Evidences Linking Allergic Inflammation to IncreasedRisk of Chronic Rhinosinusitis

The association between allergy and CRS in adults has beendiscussed for years and a strong association has been observedwith particular subtypes of CRS with nasal polyps(CRSwNP) such as central compartment atopic disease andallergic fungal rhinosinusitis (AFRS) [49 50] Manuscripts onpediatric CRS are less common predominantly because ofethical issues regarding administration of X-rays in the pedi-atric population The publications included in the qualitativeanalyses are summarized in Table 4 Conclusions of the stud-ies included in the qualitative analyses were not unanimouslylinking allergy to chronic rhinosinusitis

Several manuscripts seem to support a positive clinical as-sociation between AR and CRS describing a prevalence vary-ing between 27 and 59 of patients [51ndash53] Brietzke et al[54] in an expert panel consensus suggested that there is aclinically relevant association between AR and pediatric

Page 7 of 13 68Curr Allergy Asthma Rep (2020) 20 68

CRS particularly in older children Sedaghat et al[55] analyzing a large series of 4044 pediatric cases observedAR in 269 children with CRS but their results were incon-clusive because no comparison with control group wasprovided Choi et al [32] showed that age atopy AR andasthma may be predisposing factors for pediatric CRS andrecurrent RS The authors proposed that specific evaluationfor allergic diseases should be considered when managingchronic or recurrent RS More recently Anamika et al [56bull]demonstrated a positive skin prick test in 53 of the cases in acohort of 110 children with CRS moreover those with atopyhad higher mean Lund-Mackay endoscopic score and sinusand nasal quality of life survey score than non-atopic patients

Huang et al [57] attempted discrimination among differentallergies and reported that mold allergy represents a significant

risk factor for development of sinusitis compared with non-mold allergy in a case series of 413 children followed for5 years These data suggest that perennial allergy may be astronger risk factor for CRS compared with seasonal allergy

On the other hand some studies suggested a lack of corre-lation between allergic disease and pediatric CRS Leo et al[58] in a report on 351 children affected by CRS demonstrat-ed that the prevalence of sensitization to aeroallergens wascomparable with that of the general pediatric population Noclinical evidence could account for a higher rate of nasal con-gestion nor a harsher clinical course in allergic children [59]Sedaghat et al [51 60] observed that pediatric patients withAR and CRS seem to have the same aeroallergen sensitivityprofile compared with the general pediatric population withAR Furthermore the authors did not find a positive

Table 3 Evidence of inflammatory cells and mediators linking allergy to chronic rhinosinusitis in children

Biomarkers linking allergy to risk of CRS

AuthorYear() ref

No of cases Experimentalmodels

Methods Relevant results Association(Level ofevidence)

Chawes 2011[43]

N = 411 children withAR non-AR andhealthy controls(6 years)

Nasal airwaypatency wasassessed byacousticrhinometry

Acoustic rhinometry was performedtwice in the childrsquos 6th year of lifewith or without allergy Nasaleosinophilia was assessed by nasalscraping

Nasal eosinophilia correlated withirreversible nasal airwayobstruction in allergic childrenalready at age 6 years No changein nasal airway patency wereobserved in non-allergic rhinitis

Yes(Level III)

Blair et al2001 [44]

NA Mousesensitized toovalbuminbyintraperito-nealinjection

Sinuses of the mouse were infected byS pneumoniae with or withoutconcomitant administration ofovalbumin to induce or not allergicinflammation

Mice with allergic sinonasalinflammation had significantlymore bacteria and significantlymore inflammation (as indicated byneutrophil eosinophil andmononuclear influx) into the sinuswith respect to the non-allergicones

Yes(Level V)

Shin et al2015 [45]

N = 36 CRSresponders vs 22CRS

non-responders 22healthy controls

(age lt 15 years)

Serumanalyses

Skin prick tests were performed alongwith serum total IgE TEC serumECP level and ImmunoCAPanalysis for common allergens

TEC ECP and total IgE levels weresignificantly higher in thenon-responder group than in theresponder and control groups

Yes(Level III)

Mikolajczyket al 2019[46bullbull]

N = 842 AR childrenand 96 controls

EOSnsMCT

All patients underwent saccharin andskin prick tests nasal smeareosinophilia total and specific IgEserum concentration and MCTmeasurement

Nasal MCT was significantly longerin AR patients than controlsEOSns were significantly higherin patients than controls A weakbut significant correlation wasobserved between EOSns andMCT

Yes(Level III)

Brożek-Mądryet al 2012[47]

N = 64 patients withchronicrhinosinusitiswithout polyps and30 controls (age5ndash18 years)

Epithelialcultures(middlemeatal cells)

Middle meatus culture and cytologicalexamination from the inferior nasalconcha and middle meatus

The most common strains of bacteriafound in patients with CRS wereassociated with a higher percentageof eosinophils in cytology and highprevalence in atopic patients

Yes(Level V)

AR allergic rhinitis CRS chronic rhinosinusitis MCT mucociliary transport time EOSns percentage of eosinophils in nasal smear TEC totaleosinophil count ECP serum eosinophil cationic protein

68 Page 8 of 13 Curr Allergy Asthma Rep (2020) 20 68

association between the number of aeroallergen sensitivitiesand the presence of atopic comorbidities with the subsequent

development of CRS suggesting that the severity of atopyalone may not be positively predictive of CRS development

Table 4 Clinical evidences linking allergy to chronic rhinosinusitis in children

Clinical evidences linking allergy to risk of CRS in children

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Sedaghatet al2014[55]

Retrospectiveanalysis

N = 4044 childrenwith CRS(89 years)

Retrospective review of childrendiagnosed as uncomplicated CRSby an otolaryngology or allergyoffice evaluation

Comorbidities observed in CRS childrenwere primary ciliary dyskinesia (02)cystic fibrosis (41) immunologicdisorder (123) and AR (269)

Inconclusive(Level IV)

Choi et al2012[32]

Prospectivestudy

N = 296(lt 13 years)with recurrentRS

To evaluate predisposing factors forchronic and recurrent RS

The prevalence of AR atopy and asthmawas significantly higher in patients withCRS and recurrent RS than those withacute and subacute RS

Yes(Level II)

Anamikaet al2019[56bull]

Cross-sectionalstudy

N = 110 childrenwith CRS(7-18 years)

To determine atopic profile ofchildren with CRS and impact ofatopic status on disease severity andquality of life

Positive skin prick test was present in 527of patients Atopic CRS had a significanthigher mean Lund-Mackay endoscopicscore and symptoms scores thannon-atopic ones

Yes(Level IV)

Huang2000[57]

Prospectiveobservationalstudy

N = 413 RAchildren

(3ndash15 years)

To evaluate mold allergy as risk factorfor sinusitis

The authors compared 215 PAR with198 SAR

The prevalence of sinusitis was significantlyhigher among patients with PAR thanamong those with SAR regardless of ageor season patients with mold allergy PARhad a higher risk than those with non-moldallergy

Yes(Level II)

Leo et al2007[58]

Cross-sectionalstudy

N = 351 childrenwith CRS(523 plusmn211 years)

CRS underwent allergen sensitizationwork-up by skin prick test withcommon inhalant allergens andtotal IgE measurement

Prevalence of sensitization to aeroallergens inchildren with CRS is comparable with thatof the general pediatric population

No(Level IV)

Nathanet al2004[62]

Prospectiveobservationalstudy

N = 114 RA andCRS (childrenand adult)

Patients were surveyed for globalsymptoms and specific symptomsrelated to the nose sinuses eyesand chest with the SOQ

Immunotherapy is an effective treatment forpatients with sinus disease and allergicrhinitis

Yes(Level II)

RamadanampHiner-man2006[61]

Prospectiveobservationalstudy

N = 141 patientswho underwentESS (7 years)

To evaluate outcome of ESS at 1 yearafter the operation

Children with AR who were on treatmentbefore surgery had an 84 success ratecompared with 62 for those childrenwith non-treated AR by immunotherapy

Yes(Level II)

Kim et al2005[63]

Retrospectiveobservationalstudy

N = 97 patients(age range

5ndash15 years)

Retrospective analysis of long-termsuccess rates of ESS with respect toseveral predisposing factors

Multivariate logistic regression analysisallergy was not correlated to pooroutcomes after pediatric ESS

No(Level IV)

ElSharka-wy2012[64]

Prospectiveobservationalstudy

N = 87 children(45 with nasalallergy)(age le 14)

To assess predictive factors ofoutcome after ESS

The success rate in CRS with nasal allergywas 875 and in CRS without nasalallergy was 857

No(Level II)

Lee et al2009[66]

Retrospectiveanalysis

N = 53 childrenwho underwentFESS(age lt 18 years)

To investigate factors leading toprotracted nasal discharge afterpediatric endoscopic sinus surgery

Blood eosinophil count did not differsignificantly between the ldquoprotractedrdquo andthe ldquoresolvedrdquo groups On the other handhistory of allergic rhinitis was morefrequently observed in the ldquoprotractedrdquogroup

Yes(Level IV)

Wu et al2019[67bull]

Retrospectiveanalysis

N = 188 childrenESS for CRS

To evaluate prognostic factors relatedto revision surgery after ESS

Patients with positive aeroallergen tests hadhigher rates of CRS recurrence after ESSand required revision surgery

Yes(Level IV)

CRS chronic rhinosinusitis RS rhinosinusitis AR allergic rhinitis PAR perennial allergic rhinitis SAR seasonal allergic rhinitis SOQ sinusitisoutcome questionnaire ESS endoscopic sinus surgery FESS functional endoscopic sinus surgery

Page 9 of 13 68Curr Allergy Asthma Rep (2020) 20 68

These articles were not included in the qualitative analysesdue to the type of article

Impact of Allergy on Outcome of Chronic RhinosinusitisTreatment

Ramadan and Hinerman [61] in a retrospective study notedthat children with AR underwent to endoscopic sinus surgery(ESS) do not have a poorer outcome respect non-allergic oneNevertheless children with AR who were on immunotherapybefore surgery had an 84 success rate compared with 62for those children with AR who were not treated (p = 0022)Accordingly Nathan et al [62] using the sinusitis outcomesquestionnaire (SOQ) demonstrated that immunotherapy wasan effective treatment for patients with sinus disease and ARin both children and adults

About surgery outcomes Kim et al [63] and El Sharkawyet al [64] observed that functional endoscopic sinus surgery inchildren with CRS and AR does not provide significantlydifferent results compared with children without AR whichis similar to what has been reported in adults [65] On thecontrary in a study by Lee et al [66] a significantly greaterchance of protracted mucopurulent discharge after FESS wasregistered in patients with AR The authors assumed that theinflammatory process of nasal allergy which led to the devel-opment of CRS probably impaired the postoperative woundhealing by mucosal congestion poor-functioning mucociliaryclearance and recurrent sneezing that placed pressure on the

denuded mucosa An analogous conclusion was made by Wuet al [67bull] who demonstrated that pediatric patients with pos-itive aeroallergen tests had higher rates of CRS recurrenceafter ESS and required revision surgery

Allergic Fungal Rhinosinusitis (AFRS) in Children

AFRS is also present in the pediatric age group and it shouldbe considered a differential in children presenting with nasalpolyposis along with the other causes like ciliary dysmotilitydisorders and cystic fibrosis [68] There is paucity of data inliterature regarding nature clinical course and its recurrencein children and it was not possible to perform a qualitativeanalysis Patro et al [69] in a single center prospective studycompared features of AFRS in children with adults The au-thors concluded that AFRS was more aggressive in childrenwith increased fungal load when compared with adults Theserum IgE levels were also found to be significantly higher inpediatric group suggesting a higher fungal load with in-creased sensitivity to fungal antigen in children TypicallyAFRS in children was less responsive to treatment with in-creased recurrence rates

Conclusions

AR is a common disease in childhood in industrialized coun-tries and it has a major impact on quality of life and healthcare

Fig 2 Practical algorithm based on different phenotypes of rhinosinusitisin children Abbreviations ARS acute rhinosinusitis CRS chronicrhinosinusitis URTI upper respiratory tract infections ABRS acute

bacterial rhinosinusitis RARS recurrent acute rhinosinusitis AFRSallergic fungal rhinosinusitis

68 Page 10 of 13 Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

1 Meltzer EO Hamilos DL Rhinosinusitis diagnosis and manage-ment for the clinician a synopsis of recent consensus guidelinesMayo Clin Proc 201186(5)427ndash43 httpsdoiorg104065mcp20100392

2 Wood RA Pediatric asthma JAMA 2002288(6)745ndash7 httpsdoiorg101001jama2886745

3 Bousquet J Van Cauwenberge P KhaltaevN et al Allergic rhinitisand its impact on asthma JAMA 2001108(5)S147ndash334 httpsdoiorg101034j1398-9995200223625

4 Borish L Allergic rhinitis systemic inflammation and implicationsfor management J Allergy Clin Immunol 2003112(6)1021ndash31httpsdoiorg101016jjaci200309015

5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

6 Tan YSL Hong CY Chong PN Tan ESL Lew YJ Lin RTPKnowledge that upper respiratory tract infection resolves on itsown is associated with more appropriate health-seeking behaviorand antibiotic cognition Singap Med J 200647(6)518ndash24

7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

9 Parker D Prince A Innate immunity in the respiratory epitheliumAm J Respir Cell Mol Biol 201145(2)189ndash201 httpsdoiorg101165rcmb2011-0011RT

Page 11 of 13 68Curr Allergy Asthma Rep (2020) 20 68

by the nature of the infecting virus by the age and by phys-iological state and immunological experience of the host Sinonasal clinical features of common cold or URTI commonlyoverlap and are characterized by self-limiting irritation of theupper airways with associated cough with no proof of pneu-monia [7] Based on our review of the literature we observedthat authors for research purpose include common colds inURTI for this reason we included both papers about allergyand common cold or URTI

Laboratory Evidences and Biomarkers Linking Allergyto Increased Risk of Viral Acute Rhinosinusitis

Allergy may induce inflammation of the nasal mucosa leadingto impairment of epithelial barrier function and secondarydeficiency of early local immune reaction Several studiesdemonstrated in fact that the upper airway epithelium repre-sents not only a mechanical wall against pathogens bymucociliary clearance but also an immunological barrier mod-ulating the innate immune response through cytokine produc-tion [8 9]

Interestingly authors [10 11] demonstrated impairment ofthe overall mechanical function of the epithelium and in par-ticular decreased expression of tight-junction proteinsoccludin and zonula occludens-1 in cultured epithelial nasalcells from allergic patients Steelant et al [12] demonstratedthat nasal secretions from allergic subjects rapidly decreasethe trans-tissue resistance of epithelial cell cultures in vitroThey also showed that anti-IL-4 treatment in mice preventedepithelial barrier disruption Finally several authors havedemonstrated [13 14] that allergy may expedite viral over-come of mechanical barriers because Th2-polarized cytokinessuch as IL-4 IL-5 and IL-13 can upregulate endothelial andepithelial expression of adhesion molecules like intercellularadhesionmolecule-1 (ICAM-1) which is the receptor for 90of rhinoviruses

On the other hand several authors demonstrated that aller-gy may modify the immunological functions of the epitheliaMany studies showed the deficiency of the innate immuneresponse in allergic mucosa of upper and lower respiratoryepithelia cells Furthermore it has been demonstrated in thelab that interferon production may be defective in allergicpatients Interferons are crucial for induction of apoptosis invirus-infected host cells because they prevent establishment ofviral replication and promote phagocytosis of infected cells[15ndash17]

The majority of experimental studies about this topic usedcultured epithelial cells obtained from adults and for this rea-son they were not included in the qualitative analyses Theonly article included was of Teach et al [18] reporting thatperipheral blood mononuclear cells cultured from a subset ofatopic children treated with anti-IgE improved INF-α produc-tion after incubation with rhinovirus (Table 1)

Clinical Evidence Linking Allergy to Risk of Viral UpperRespiratory Infection

From a clinical point of view the results are more controver-sial than those from the laboratory Studies in the literaturecomparing the incidence of upper respiratory infections be-tween allergic and non-allergic subjects are relatively few innumber We found 3 retrospective and 1 prospective articlethat were included in the qualitative analyses (Table 2)

In two manuscripts it has been demonstrated that atopicallergic patients had increased susceptibility to upper respira-tory infections In 2006 in a large cross-sectional surveyKarevold et al [19] demonstrated that atopy increases the riskof developing upper and lower respiratory tract infections inchildren In particular atopy was the strongest risk factor suchas in the home environment (dampness) AccordinglyCiprandi et al [20] in a prospective study observed that aller-gic children have a significantly higher number of upper re-spiratory infections more serious in duration and severitycompared with non-allergic children

Other authors disagree Kvaeligrner et al [21] reported thatcorrelation between upper respiratory infection and atopic dis-eases from a population-based sample of 7992 Norwegiantwins was weak even though results were inconclusiveSuumltccediluuml et al [22] confirmed that the number of episodes peryear was not significantly different between atopic andhealthy children even though atopic ones had longer episodesof recurrent URTI compared to controls

Interestingly all clinical studies included in the qualitativeanalyses about therapy (Table 2) supported the hypothesis thatanti-allergy-specific or non-specific treatments may preventviral infections of the upper airways Antihistamine therapycan act by reducing the expression of adhesion viral receptorsto modulate the production of Th2-related interleukins [20]Authors [14 23] demonstrated that children treated withcetirizine had a significant reduction in ICAM-I expressionon epithelial cells thus preventing possible relapse of rhino-virus infections and diminishing both the number and severityof recurrent respiratory infections in children Barberi et al[24bullbull 25] demonstrated that children treated with sublingualimmunotherapy (SLIT) had significantly fewer respiratory in-fections (RI) than symptomatically treated children In addi-tion SLIT-treated children had less fever episodes per yearand took fewer medications vs symptomatically treatedchildren

Allergy and Post-Viral Acute Rhinosinusitis and AcuteBacterial Rhinosinusitis (ABRS) in Children

In the articles reviewed we did not find manuscript inwhich authors distinguished between post-viral ARS andABRS Authors focused the attention particularly on therisks of bacterial superinfection Recent evidence suggests

68 Page 4 of 13 Curr Allergy Asthma Rep (2020) 20 68

in fact that damage or disruption of mucociliary functiondue to viral infection is probably a major cause of superor secondary bacterial infection Allergy is a conditionthat potentially can exacerbate an inflammatory sinonasalresponse although very limited data are available to con-firm this hypothesis in children [26] Based on paucityand heterogeneity of the studies it was not possible toperform a qualitative analysis linking allergy to ABRSor to post-viral ARS [5] For this reason herewith wereport available data by a narrative description

Lin et al [27] demonstrated that the prevalence of col-onization by methicillin-resistant S aureus was higher inatopic children than healthy ones and that atopic childrenwere more likely to develop ARS than non-atopic onesInterestingly other authors [28] observed that AR washighly prevalent in orbital ARS complications in childrenand specifically it was found in 643 of children withpre-septal cellulitis in 25 with periostitis and in 765with subperiosteal abscess Furthermore the prevalence ofAR was significantly higher in patients presenting in pol-len season from February to August than in patients pre-senting between September and January The authors sug-gested that allergy may be a cofactor in the pathogenesisof orbital complication of ARS In addition Alho et al[29] observed that subjects with allergic IgE-mediatedrhinitis had more severe paranasal sinus changes in CTscans than non-allergic subjects during viral colds Theauthors suggested that these changes were signs of moreseverely impaired sinus function increasing the risk ofbacterial sinusitis

Shi-Wei Lin et al [30] recently evaluated the risk ofincident ARS among children with allergic rhinitis using a

nationwide population-based health claims research databaseand including a large number of patients The authors ob-served that the risk of ARS was significantly higher in pedi-atric patients with allergic rhinitis compared with those with-out the condition (adjusted hazard ratio = 303 95 confi-dence interval = 289ndash318) Caution is advised wheninterpreting the findings of the authors due to limitations ofthe study retrospective design and diagnosis of ARS based onclinical history (authors could not confirm bacterial etiologyof sinusitis)

On the other hand Leo et al [31] demonstrated thatchildren with grass pollen-induced rhinitis during expo-sure to pollen had an incidence of endoscopic confirmedARS comparable with non-allergic children they conse-quently suggested that AR was a negligible risk factor forARS and that the most common risk factor was instead aprevious acute viral infection Accordingly EPOS 2020concluded that there appears to be small evidence to sup-port the presence of AR as a risk factor for developingARS in children recognizing a central role for previousviral infection

Allergy and Recurrent Acute Rhinosinusitis (RARS) inChildren

We found very limited and heterogeneous data linking allergyto RARS and it was not possible to perform a qualitativeanalysis Choi et al [32] evaluated the predisposing factorsthat may be associated with chronic and recurrent RS exam-ining 296 patients with RS younger than 13 years of age Theprevalence of allergic rhinitis atopy and asthma was signifi-cantly higher in patients with chronic and recurrent RS than

Table 1 Laboratory evidence linking allergy to allergy to increased risk of viral acute rhinosinusitis

Evidence from the lab linking allergy to allergy to increased risk of viral acute rhinosinusitis

AuthorYear (ref)

No of cases age Experimental models Methods Relevant results Association( L e v e l o fevidence)

Teach et al 2015[20]

N = 478 children(102 plusmn 293 years)

Peripheral bloodmononuclearcell culturesincubatedex-vivo withrhinovirus

Measuring IFN-α insupernatants ofPBMCscultures obtainedfrom asubset of subjects(n = 87)incubated ex vivowithrhinovirusin patientstreatedor not withomalizumab

The group treated with anti-IgEhad improved IFN-αproductionafter virus infection suggestingrestoring of the impairedinterferonresponse and increasingantiviralimmunity and suggesting thatanti-IgEmay prevent upper and lowerrespiratoryinfections and asthmaexacerbations

Yes(Level V)

PBMC peripheral blood mononuclear cell INF-α interferon alpha

Page 5 of 13 68Curr Allergy Asthma Rep (2020) 20 68

those with acute and subacute RS Veskitkul et al [33] eval-uated the clinical characteristics and predisposing factors ofRARS in children as well as the preventive therapy The au-thors detected allergy in 351 of cases and suggested thatchildren with RARS should be always evaluated for the pres-ence of underlying predisposing conditions including allergicdisease Nevertheless no comparison with a control group

was performed and for this reason data are not definitelysupporting a link between allergy and RARS

Allergy and Chronic Rhinosinusitis (CRS) in Children

Chronic rhinosinusitis (with or without nasal polyps) in chil-dren is defined as presence of two or more symptoms one of

Table 2 Articles investigating clinical association between allergy and upper respiratory infections

Clinical evidence linking allergy to risk of upper respiratory tract infections

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Karevoldet al2006[19]

Cross-sectionalsurvey

N = 5125(10 years)

Assess co-morbidity and risk factors forrecurrent upper and lower respiratoryinfections

Atopic disease was a constitutional riskfactor for upper and lower airwayinfections

Yes(Level IV)

Ciprandiet al2009[20]

Prospective study N = 117(402 plusmn10 years) 46allergic

Evaluate the number and duration of RIin allergic and non-allergic children

Allergic children showed a significantlyhigher number (mean 126 plusmn 073)and longer duration of RI (892 days)in comparison with non-allergicgroup (094 plusmn 137 and 485 days)

Yes(Level II)

Kvaeligrneret al1996[21]

Retrospectiveanalysis

N = 7992 (meanage not known)

Estimate comorbidity between earinfections tonsillitis sinusitis andrelated childhood diseases

The correlation between the infectiousand atopic diseases was weak

Inconclusive(Level IV)

Suumltccediluumlet al2016[22]

Retrospectiveanalysis

N = 507 children(46 range4ndash190 months)

Evaluate children presenting with thecomplaint of recurrent infections andto determine the possible predictivefactors

Atopic children had longer episodes ofrecurrent URTI compared to controlshowever the number of episodes peryear was not significantly different

No(Level IV)

Role of anti-allergy treatment in preventing upper respiratory infections

Ciprandi1999[20]

Double-blind andplacebo--controlled study

N = 20 childrenwith allergy

10 terfenadinegroup(85 plusmn 3 years)10 placebo

(79 plusmn 27 years)

Continuous terfenadine (1 mgkg perbody weight per day) vs placebo for1 year Outcome Symptomsinflammatory cells and ICAM-1measured by nasal scraping

Terfenadine treatment reduces ICAM-1expression on nasal epithelial cellschildren treated with terfenadine hadsignificantly fewer extra visits andschool absences than the placebogroup

Yes(Level I)

Fasce1996[14]

Double-blindplacebocontrolledrandomizedstudy

N = 20 children(5ndash14 yearsold) with miteallergy

Cetirizine vs placebo for 15 days Nasalscrapings were performed to evaluateinflammatory cell infiltration andICAM-I expression on epithelial cells

Cetirizine-treated children showed asignificant reduction (or even totalabsence) of ICAM-I expression onepithelial cells (p = 0002) and areduction trend in inflammatory cellcounts compared with placebo

Yes(Level I)

Barebri2015[25]

Prospective casecontrolobservationalstudy notrandomized

N = 40 HDMallergic children(93 years)

Patients were subdivided in 2 groups 20treated by symptomatic drugs and 20by high-dose HDM-SLIT

SLIT-treated children had significantly(p = 001) less RI episodes (35) thancontrol group (545)

Yes(Level II)

Barberi2018[24]

Retrospectiveanalysis

N = 33 HDMallergic children(93 years)

Investigate whether 3 year high-doseHDM-SLIT affects respiratoryinfections in children with allergicrhinitis

SLIT-treated children had significantlyfewer RI episodes thansymptomatically treated children Inaddition they had less fever and tookfewer medications such as antibioticsand antipyretics

Yes(Level IV)

HDM house dust mites SLIT sub-lingual immunotherapy URTI upper respiratory tract infections RI respiratory infections ICAM intercellularadhesion molecule

68 Page 6 of 13 Curr Allergy Asthma Rep (2020) 20 68

which should be either nasal blockageobstructioncongestionor nasal discharge (anteriorposterior nasal drip) with or with-out facial painpressure andor cough for ge 12 weeks associat-ed with pathognomonic endoscopic signs or CT changes [5]The prevalence of CRS in children is lower than in adults (2ndash4) nevertheless the negative impact on quality of life seemsto be similar to that observed in adults Studies on CRS inchildren are less common and it is more difficult to investi-gate the relationship with allergy [5] Several factors contrib-ute to complicate the analyses including incomplete evalua-tion (nasal endoscopy andor imaging are rarely performed inmany children) and the difficulty to differentiate CRS fromadenoid hypertrophy adenoiditis and (allergic) rhinitis Infact nasal blockage may occur in AR children due to edem-atous mucosa neurogenic and vascular responses over-production of secretions and impaired mucociliary clearanceleading to congestion of the ostia and symptoms simulatingrhinosinusitis On the other hand the blockage leads to stag-nant debris and acidotic environment that might stimulatebacteria overgrowth [34 35]

Histopathological analysis [36 37] demonstrated that pe-diatric CRS is quite different from the adult form showinggreater inflammatory cellularity higher density of submucosallymphocytes less eosinophilic inflammation basement mem-brane thickening and mucous gland hyperplasia suggesting adifferent pathway compared with the adult CRS patternwhich is predominantly characterized by a Th2-oriented re-sponse with polypoid changes The presence of nasal polypsin a pediatric patient should suggest the hypothesis of cysticfibrosis that has not been included in this paper More specif-ically some evidence supports the hypothesis that CRS inchildren over the age of 13 seems to be based more on eosin-ophilic inflammation while under this age CRS seems to bebased more on neutrophilic inflammation thus justifying thelower prevalence of nasal polyps in children than in adult [3637]

Several manuscripts support the hypothesis that AR andCRS could be different faces of the same disease AR in factis typically characterized by a Th2 immune response involv-ing IL-4 IL-5 and IL-13 which drives IgE production andrecruitment of eosinophil granulocytes It has been suggested[38ndash42] that eosinophils by generating potent toxic agents(cationic proteins oxygen-free radicals and proinflammatorycytokines) may play a major role in initiating and perpetuat-ing inflammation of sinonasal mucosa in patients with AR

Evidence from the Lab and Biomarkers Linking AllergicInflammation to Increased Risk of Chronic Rhinosinusitisin Children

All studies included in a qualitative analysis support a specificlink between CRS and AR in children (Table 3) Chawes [43]studied nasal eosinophilia and nasal airway patency (assessed

by acoustic rhinometry) in children with AR non-allergic rhi-nitis and healthy controls Nasal eosinophilia and irreversiblenasal airway obstruction were significantly associated withAR while there was no such association with non-allergicrhinitis The authors suggested that chronic inflammationand structural remodeling of the sinonasal mucosa may occurin allergic children even at 6 years of age

Some authors suggested that allergic sinonasal inflamma-tion may support bacterial infection Blair et al [44] in ananimal model showed that allergic inflammatory reactionmay obstruct sinus drainage encouraging bacterial infectioninto the maxillary sinus Shin et al [45] demonstrated thattotal IgE total eosinophil count and serum eosinophil cationicprotein levels were significantly higher in CRS childrenwhose symptoms and radiologic abnormalities did not resolveafter 12 weeks despite appropriate antibiotic therapy (non-responder) compared with responders and healthy controlsMoreover AR in children may affect the efficiency ofmucociliary clearance which is one of the most importantprotective functions of the respiratory epitheliumDeterioration of mucociliary system appears to be related tomore severe rhinitis with a higher intensity of local nasal in-flammation reflected in nasal smear eosinophilia [46bullbull]

Brożek-Mądry and co-workers [47] evaluated the relationbetween bacterial strains and cytological examination of nasalmucosa in children with CRS they found that the most com-mon strains of bacteria observed in CRS (Hemophilusinfluenzae Moraxella catarrhalis and Staphylococcusaureus) were associated with a higher prevalence of atopyand percentage of eosinophils in cytology It must be notedthat S aureus enterotoxins are able to induce increased sever-ity of the disease amplifying eosinophilic inflammation inatopic patients [48]

Clinical Evidences Linking Allergic Inflammation to IncreasedRisk of Chronic Rhinosinusitis

The association between allergy and CRS in adults has beendiscussed for years and a strong association has been observedwith particular subtypes of CRS with nasal polyps(CRSwNP) such as central compartment atopic disease andallergic fungal rhinosinusitis (AFRS) [49 50] Manuscripts onpediatric CRS are less common predominantly because ofethical issues regarding administration of X-rays in the pedi-atric population The publications included in the qualitativeanalyses are summarized in Table 4 Conclusions of the stud-ies included in the qualitative analyses were not unanimouslylinking allergy to chronic rhinosinusitis

Several manuscripts seem to support a positive clinical as-sociation between AR and CRS describing a prevalence vary-ing between 27 and 59 of patients [51ndash53] Brietzke et al[54] in an expert panel consensus suggested that there is aclinically relevant association between AR and pediatric

Page 7 of 13 68Curr Allergy Asthma Rep (2020) 20 68

CRS particularly in older children Sedaghat et al[55] analyzing a large series of 4044 pediatric cases observedAR in 269 children with CRS but their results were incon-clusive because no comparison with control group wasprovided Choi et al [32] showed that age atopy AR andasthma may be predisposing factors for pediatric CRS andrecurrent RS The authors proposed that specific evaluationfor allergic diseases should be considered when managingchronic or recurrent RS More recently Anamika et al [56bull]demonstrated a positive skin prick test in 53 of the cases in acohort of 110 children with CRS moreover those with atopyhad higher mean Lund-Mackay endoscopic score and sinusand nasal quality of life survey score than non-atopic patients

Huang et al [57] attempted discrimination among differentallergies and reported that mold allergy represents a significant

risk factor for development of sinusitis compared with non-mold allergy in a case series of 413 children followed for5 years These data suggest that perennial allergy may be astronger risk factor for CRS compared with seasonal allergy

On the other hand some studies suggested a lack of corre-lation between allergic disease and pediatric CRS Leo et al[58] in a report on 351 children affected by CRS demonstrat-ed that the prevalence of sensitization to aeroallergens wascomparable with that of the general pediatric population Noclinical evidence could account for a higher rate of nasal con-gestion nor a harsher clinical course in allergic children [59]Sedaghat et al [51 60] observed that pediatric patients withAR and CRS seem to have the same aeroallergen sensitivityprofile compared with the general pediatric population withAR Furthermore the authors did not find a positive

Table 3 Evidence of inflammatory cells and mediators linking allergy to chronic rhinosinusitis in children

Biomarkers linking allergy to risk of CRS

AuthorYear() ref

No of cases Experimentalmodels

Methods Relevant results Association(Level ofevidence)

Chawes 2011[43]

N = 411 children withAR non-AR andhealthy controls(6 years)

Nasal airwaypatency wasassessed byacousticrhinometry

Acoustic rhinometry was performedtwice in the childrsquos 6th year of lifewith or without allergy Nasaleosinophilia was assessed by nasalscraping

Nasal eosinophilia correlated withirreversible nasal airwayobstruction in allergic childrenalready at age 6 years No changein nasal airway patency wereobserved in non-allergic rhinitis

Yes(Level III)

Blair et al2001 [44]

NA Mousesensitized toovalbuminbyintraperito-nealinjection

Sinuses of the mouse were infected byS pneumoniae with or withoutconcomitant administration ofovalbumin to induce or not allergicinflammation

Mice with allergic sinonasalinflammation had significantlymore bacteria and significantlymore inflammation (as indicated byneutrophil eosinophil andmononuclear influx) into the sinuswith respect to the non-allergicones

Yes(Level V)

Shin et al2015 [45]

N = 36 CRSresponders vs 22CRS

non-responders 22healthy controls

(age lt 15 years)

Serumanalyses

Skin prick tests were performed alongwith serum total IgE TEC serumECP level and ImmunoCAPanalysis for common allergens

TEC ECP and total IgE levels weresignificantly higher in thenon-responder group than in theresponder and control groups

Yes(Level III)

Mikolajczyket al 2019[46bullbull]

N = 842 AR childrenand 96 controls

EOSnsMCT

All patients underwent saccharin andskin prick tests nasal smeareosinophilia total and specific IgEserum concentration and MCTmeasurement

Nasal MCT was significantly longerin AR patients than controlsEOSns were significantly higherin patients than controls A weakbut significant correlation wasobserved between EOSns andMCT

Yes(Level III)

Brożek-Mądryet al 2012[47]

N = 64 patients withchronicrhinosinusitiswithout polyps and30 controls (age5ndash18 years)

Epithelialcultures(middlemeatal cells)

Middle meatus culture and cytologicalexamination from the inferior nasalconcha and middle meatus

The most common strains of bacteriafound in patients with CRS wereassociated with a higher percentageof eosinophils in cytology and highprevalence in atopic patients

Yes(Level V)

AR allergic rhinitis CRS chronic rhinosinusitis MCT mucociliary transport time EOSns percentage of eosinophils in nasal smear TEC totaleosinophil count ECP serum eosinophil cationic protein

68 Page 8 of 13 Curr Allergy Asthma Rep (2020) 20 68

association between the number of aeroallergen sensitivitiesand the presence of atopic comorbidities with the subsequent

development of CRS suggesting that the severity of atopyalone may not be positively predictive of CRS development

Table 4 Clinical evidences linking allergy to chronic rhinosinusitis in children

Clinical evidences linking allergy to risk of CRS in children

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Sedaghatet al2014[55]

Retrospectiveanalysis

N = 4044 childrenwith CRS(89 years)

Retrospective review of childrendiagnosed as uncomplicated CRSby an otolaryngology or allergyoffice evaluation

Comorbidities observed in CRS childrenwere primary ciliary dyskinesia (02)cystic fibrosis (41) immunologicdisorder (123) and AR (269)

Inconclusive(Level IV)

Choi et al2012[32]

Prospectivestudy

N = 296(lt 13 years)with recurrentRS

To evaluate predisposing factors forchronic and recurrent RS

The prevalence of AR atopy and asthmawas significantly higher in patients withCRS and recurrent RS than those withacute and subacute RS

Yes(Level II)

Anamikaet al2019[56bull]

Cross-sectionalstudy

N = 110 childrenwith CRS(7-18 years)

To determine atopic profile ofchildren with CRS and impact ofatopic status on disease severity andquality of life

Positive skin prick test was present in 527of patients Atopic CRS had a significanthigher mean Lund-Mackay endoscopicscore and symptoms scores thannon-atopic ones

Yes(Level IV)

Huang2000[57]

Prospectiveobservationalstudy

N = 413 RAchildren

(3ndash15 years)

To evaluate mold allergy as risk factorfor sinusitis

The authors compared 215 PAR with198 SAR

The prevalence of sinusitis was significantlyhigher among patients with PAR thanamong those with SAR regardless of ageor season patients with mold allergy PARhad a higher risk than those with non-moldallergy

Yes(Level II)

Leo et al2007[58]

Cross-sectionalstudy

N = 351 childrenwith CRS(523 plusmn211 years)

CRS underwent allergen sensitizationwork-up by skin prick test withcommon inhalant allergens andtotal IgE measurement

Prevalence of sensitization to aeroallergens inchildren with CRS is comparable with thatof the general pediatric population

No(Level IV)

Nathanet al2004[62]

Prospectiveobservationalstudy

N = 114 RA andCRS (childrenand adult)

Patients were surveyed for globalsymptoms and specific symptomsrelated to the nose sinuses eyesand chest with the SOQ

Immunotherapy is an effective treatment forpatients with sinus disease and allergicrhinitis

Yes(Level II)

RamadanampHiner-man2006[61]

Prospectiveobservationalstudy

N = 141 patientswho underwentESS (7 years)

To evaluate outcome of ESS at 1 yearafter the operation

Children with AR who were on treatmentbefore surgery had an 84 success ratecompared with 62 for those childrenwith non-treated AR by immunotherapy

Yes(Level II)

Kim et al2005[63]

Retrospectiveobservationalstudy

N = 97 patients(age range

5ndash15 years)

Retrospective analysis of long-termsuccess rates of ESS with respect toseveral predisposing factors

Multivariate logistic regression analysisallergy was not correlated to pooroutcomes after pediatric ESS

No(Level IV)

ElSharka-wy2012[64]

Prospectiveobservationalstudy

N = 87 children(45 with nasalallergy)(age le 14)

To assess predictive factors ofoutcome after ESS

The success rate in CRS with nasal allergywas 875 and in CRS without nasalallergy was 857

No(Level II)

Lee et al2009[66]

Retrospectiveanalysis

N = 53 childrenwho underwentFESS(age lt 18 years)

To investigate factors leading toprotracted nasal discharge afterpediatric endoscopic sinus surgery

Blood eosinophil count did not differsignificantly between the ldquoprotractedrdquo andthe ldquoresolvedrdquo groups On the other handhistory of allergic rhinitis was morefrequently observed in the ldquoprotractedrdquogroup

Yes(Level IV)

Wu et al2019[67bull]

Retrospectiveanalysis

N = 188 childrenESS for CRS

To evaluate prognostic factors relatedto revision surgery after ESS

Patients with positive aeroallergen tests hadhigher rates of CRS recurrence after ESSand required revision surgery

Yes(Level IV)

CRS chronic rhinosinusitis RS rhinosinusitis AR allergic rhinitis PAR perennial allergic rhinitis SAR seasonal allergic rhinitis SOQ sinusitisoutcome questionnaire ESS endoscopic sinus surgery FESS functional endoscopic sinus surgery

Page 9 of 13 68Curr Allergy Asthma Rep (2020) 20 68

These articles were not included in the qualitative analysesdue to the type of article

Impact of Allergy on Outcome of Chronic RhinosinusitisTreatment

Ramadan and Hinerman [61] in a retrospective study notedthat children with AR underwent to endoscopic sinus surgery(ESS) do not have a poorer outcome respect non-allergic oneNevertheless children with AR who were on immunotherapybefore surgery had an 84 success rate compared with 62for those children with AR who were not treated (p = 0022)Accordingly Nathan et al [62] using the sinusitis outcomesquestionnaire (SOQ) demonstrated that immunotherapy wasan effective treatment for patients with sinus disease and ARin both children and adults

About surgery outcomes Kim et al [63] and El Sharkawyet al [64] observed that functional endoscopic sinus surgery inchildren with CRS and AR does not provide significantlydifferent results compared with children without AR whichis similar to what has been reported in adults [65] On thecontrary in a study by Lee et al [66] a significantly greaterchance of protracted mucopurulent discharge after FESS wasregistered in patients with AR The authors assumed that theinflammatory process of nasal allergy which led to the devel-opment of CRS probably impaired the postoperative woundhealing by mucosal congestion poor-functioning mucociliaryclearance and recurrent sneezing that placed pressure on the

denuded mucosa An analogous conclusion was made by Wuet al [67bull] who demonstrated that pediatric patients with pos-itive aeroallergen tests had higher rates of CRS recurrenceafter ESS and required revision surgery

Allergic Fungal Rhinosinusitis (AFRS) in Children

AFRS is also present in the pediatric age group and it shouldbe considered a differential in children presenting with nasalpolyposis along with the other causes like ciliary dysmotilitydisorders and cystic fibrosis [68] There is paucity of data inliterature regarding nature clinical course and its recurrencein children and it was not possible to perform a qualitativeanalysis Patro et al [69] in a single center prospective studycompared features of AFRS in children with adults The au-thors concluded that AFRS was more aggressive in childrenwith increased fungal load when compared with adults Theserum IgE levels were also found to be significantly higher inpediatric group suggesting a higher fungal load with in-creased sensitivity to fungal antigen in children TypicallyAFRS in children was less responsive to treatment with in-creased recurrence rates

Conclusions

AR is a common disease in childhood in industrialized coun-tries and it has a major impact on quality of life and healthcare

Fig 2 Practical algorithm based on different phenotypes of rhinosinusitisin children Abbreviations ARS acute rhinosinusitis CRS chronicrhinosinusitis URTI upper respiratory tract infections ABRS acute

bacterial rhinosinusitis RARS recurrent acute rhinosinusitis AFRSallergic fungal rhinosinusitis

68 Page 10 of 13 Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

1 Meltzer EO Hamilos DL Rhinosinusitis diagnosis and manage-ment for the clinician a synopsis of recent consensus guidelinesMayo Clin Proc 201186(5)427ndash43 httpsdoiorg104065mcp20100392

2 Wood RA Pediatric asthma JAMA 2002288(6)745ndash7 httpsdoiorg101001jama2886745

3 Bousquet J Van Cauwenberge P KhaltaevN et al Allergic rhinitisand its impact on asthma JAMA 2001108(5)S147ndash334 httpsdoiorg101034j1398-9995200223625

4 Borish L Allergic rhinitis systemic inflammation and implicationsfor management J Allergy Clin Immunol 2003112(6)1021ndash31httpsdoiorg101016jjaci200309015

5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

6 Tan YSL Hong CY Chong PN Tan ESL Lew YJ Lin RTPKnowledge that upper respiratory tract infection resolves on itsown is associated with more appropriate health-seeking behaviorand antibiotic cognition Singap Med J 200647(6)518ndash24

7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

9 Parker D Prince A Innate immunity in the respiratory epitheliumAm J Respir Cell Mol Biol 201145(2)189ndash201 httpsdoiorg101165rcmb2011-0011RT

Page 11 of 13 68Curr Allergy Asthma Rep (2020) 20 68

in fact that damage or disruption of mucociliary functiondue to viral infection is probably a major cause of superor secondary bacterial infection Allergy is a conditionthat potentially can exacerbate an inflammatory sinonasalresponse although very limited data are available to con-firm this hypothesis in children [26] Based on paucityand heterogeneity of the studies it was not possible toperform a qualitative analysis linking allergy to ABRSor to post-viral ARS [5] For this reason herewith wereport available data by a narrative description

Lin et al [27] demonstrated that the prevalence of col-onization by methicillin-resistant S aureus was higher inatopic children than healthy ones and that atopic childrenwere more likely to develop ARS than non-atopic onesInterestingly other authors [28] observed that AR washighly prevalent in orbital ARS complications in childrenand specifically it was found in 643 of children withpre-septal cellulitis in 25 with periostitis and in 765with subperiosteal abscess Furthermore the prevalence ofAR was significantly higher in patients presenting in pol-len season from February to August than in patients pre-senting between September and January The authors sug-gested that allergy may be a cofactor in the pathogenesisof orbital complication of ARS In addition Alho et al[29] observed that subjects with allergic IgE-mediatedrhinitis had more severe paranasal sinus changes in CTscans than non-allergic subjects during viral colds Theauthors suggested that these changes were signs of moreseverely impaired sinus function increasing the risk ofbacterial sinusitis

Shi-Wei Lin et al [30] recently evaluated the risk ofincident ARS among children with allergic rhinitis using a

nationwide population-based health claims research databaseand including a large number of patients The authors ob-served that the risk of ARS was significantly higher in pedi-atric patients with allergic rhinitis compared with those with-out the condition (adjusted hazard ratio = 303 95 confi-dence interval = 289ndash318) Caution is advised wheninterpreting the findings of the authors due to limitations ofthe study retrospective design and diagnosis of ARS based onclinical history (authors could not confirm bacterial etiologyof sinusitis)

On the other hand Leo et al [31] demonstrated thatchildren with grass pollen-induced rhinitis during expo-sure to pollen had an incidence of endoscopic confirmedARS comparable with non-allergic children they conse-quently suggested that AR was a negligible risk factor forARS and that the most common risk factor was instead aprevious acute viral infection Accordingly EPOS 2020concluded that there appears to be small evidence to sup-port the presence of AR as a risk factor for developingARS in children recognizing a central role for previousviral infection

Allergy and Recurrent Acute Rhinosinusitis (RARS) inChildren

We found very limited and heterogeneous data linking allergyto RARS and it was not possible to perform a qualitativeanalysis Choi et al [32] evaluated the predisposing factorsthat may be associated with chronic and recurrent RS exam-ining 296 patients with RS younger than 13 years of age Theprevalence of allergic rhinitis atopy and asthma was signifi-cantly higher in patients with chronic and recurrent RS than

Table 1 Laboratory evidence linking allergy to allergy to increased risk of viral acute rhinosinusitis

Evidence from the lab linking allergy to allergy to increased risk of viral acute rhinosinusitis

AuthorYear (ref)

No of cases age Experimental models Methods Relevant results Association( L e v e l o fevidence)

Teach et al 2015[20]

N = 478 children(102 plusmn 293 years)

Peripheral bloodmononuclearcell culturesincubatedex-vivo withrhinovirus

Measuring IFN-α insupernatants ofPBMCscultures obtainedfrom asubset of subjects(n = 87)incubated ex vivowithrhinovirusin patientstreatedor not withomalizumab

The group treated with anti-IgEhad improved IFN-αproductionafter virus infection suggestingrestoring of the impairedinterferonresponse and increasingantiviralimmunity and suggesting thatanti-IgEmay prevent upper and lowerrespiratoryinfections and asthmaexacerbations

Yes(Level V)

PBMC peripheral blood mononuclear cell INF-α interferon alpha

Page 5 of 13 68Curr Allergy Asthma Rep (2020) 20 68

those with acute and subacute RS Veskitkul et al [33] eval-uated the clinical characteristics and predisposing factors ofRARS in children as well as the preventive therapy The au-thors detected allergy in 351 of cases and suggested thatchildren with RARS should be always evaluated for the pres-ence of underlying predisposing conditions including allergicdisease Nevertheless no comparison with a control group

was performed and for this reason data are not definitelysupporting a link between allergy and RARS

Allergy and Chronic Rhinosinusitis (CRS) in Children

Chronic rhinosinusitis (with or without nasal polyps) in chil-dren is defined as presence of two or more symptoms one of

Table 2 Articles investigating clinical association between allergy and upper respiratory infections

Clinical evidence linking allergy to risk of upper respiratory tract infections

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Karevoldet al2006[19]

Cross-sectionalsurvey

N = 5125(10 years)

Assess co-morbidity and risk factors forrecurrent upper and lower respiratoryinfections

Atopic disease was a constitutional riskfactor for upper and lower airwayinfections

Yes(Level IV)

Ciprandiet al2009[20]

Prospective study N = 117(402 plusmn10 years) 46allergic

Evaluate the number and duration of RIin allergic and non-allergic children

Allergic children showed a significantlyhigher number (mean 126 plusmn 073)and longer duration of RI (892 days)in comparison with non-allergicgroup (094 plusmn 137 and 485 days)

Yes(Level II)

Kvaeligrneret al1996[21]

Retrospectiveanalysis

N = 7992 (meanage not known)

Estimate comorbidity between earinfections tonsillitis sinusitis andrelated childhood diseases

The correlation between the infectiousand atopic diseases was weak

Inconclusive(Level IV)

Suumltccediluumlet al2016[22]

Retrospectiveanalysis

N = 507 children(46 range4ndash190 months)

Evaluate children presenting with thecomplaint of recurrent infections andto determine the possible predictivefactors

Atopic children had longer episodes ofrecurrent URTI compared to controlshowever the number of episodes peryear was not significantly different

No(Level IV)

Role of anti-allergy treatment in preventing upper respiratory infections

Ciprandi1999[20]

Double-blind andplacebo--controlled study

N = 20 childrenwith allergy

10 terfenadinegroup(85 plusmn 3 years)10 placebo

(79 plusmn 27 years)

Continuous terfenadine (1 mgkg perbody weight per day) vs placebo for1 year Outcome Symptomsinflammatory cells and ICAM-1measured by nasal scraping

Terfenadine treatment reduces ICAM-1expression on nasal epithelial cellschildren treated with terfenadine hadsignificantly fewer extra visits andschool absences than the placebogroup

Yes(Level I)

Fasce1996[14]

Double-blindplacebocontrolledrandomizedstudy

N = 20 children(5ndash14 yearsold) with miteallergy

Cetirizine vs placebo for 15 days Nasalscrapings were performed to evaluateinflammatory cell infiltration andICAM-I expression on epithelial cells

Cetirizine-treated children showed asignificant reduction (or even totalabsence) of ICAM-I expression onepithelial cells (p = 0002) and areduction trend in inflammatory cellcounts compared with placebo

Yes(Level I)

Barebri2015[25]

Prospective casecontrolobservationalstudy notrandomized

N = 40 HDMallergic children(93 years)

Patients were subdivided in 2 groups 20treated by symptomatic drugs and 20by high-dose HDM-SLIT

SLIT-treated children had significantly(p = 001) less RI episodes (35) thancontrol group (545)

Yes(Level II)

Barberi2018[24]

Retrospectiveanalysis

N = 33 HDMallergic children(93 years)

Investigate whether 3 year high-doseHDM-SLIT affects respiratoryinfections in children with allergicrhinitis

SLIT-treated children had significantlyfewer RI episodes thansymptomatically treated children Inaddition they had less fever and tookfewer medications such as antibioticsand antipyretics

Yes(Level IV)

HDM house dust mites SLIT sub-lingual immunotherapy URTI upper respiratory tract infections RI respiratory infections ICAM intercellularadhesion molecule

68 Page 6 of 13 Curr Allergy Asthma Rep (2020) 20 68

which should be either nasal blockageobstructioncongestionor nasal discharge (anteriorposterior nasal drip) with or with-out facial painpressure andor cough for ge 12 weeks associat-ed with pathognomonic endoscopic signs or CT changes [5]The prevalence of CRS in children is lower than in adults (2ndash4) nevertheless the negative impact on quality of life seemsto be similar to that observed in adults Studies on CRS inchildren are less common and it is more difficult to investi-gate the relationship with allergy [5] Several factors contrib-ute to complicate the analyses including incomplete evalua-tion (nasal endoscopy andor imaging are rarely performed inmany children) and the difficulty to differentiate CRS fromadenoid hypertrophy adenoiditis and (allergic) rhinitis Infact nasal blockage may occur in AR children due to edem-atous mucosa neurogenic and vascular responses over-production of secretions and impaired mucociliary clearanceleading to congestion of the ostia and symptoms simulatingrhinosinusitis On the other hand the blockage leads to stag-nant debris and acidotic environment that might stimulatebacteria overgrowth [34 35]

Histopathological analysis [36 37] demonstrated that pe-diatric CRS is quite different from the adult form showinggreater inflammatory cellularity higher density of submucosallymphocytes less eosinophilic inflammation basement mem-brane thickening and mucous gland hyperplasia suggesting adifferent pathway compared with the adult CRS patternwhich is predominantly characterized by a Th2-oriented re-sponse with polypoid changes The presence of nasal polypsin a pediatric patient should suggest the hypothesis of cysticfibrosis that has not been included in this paper More specif-ically some evidence supports the hypothesis that CRS inchildren over the age of 13 seems to be based more on eosin-ophilic inflammation while under this age CRS seems to bebased more on neutrophilic inflammation thus justifying thelower prevalence of nasal polyps in children than in adult [3637]

Several manuscripts support the hypothesis that AR andCRS could be different faces of the same disease AR in factis typically characterized by a Th2 immune response involv-ing IL-4 IL-5 and IL-13 which drives IgE production andrecruitment of eosinophil granulocytes It has been suggested[38ndash42] that eosinophils by generating potent toxic agents(cationic proteins oxygen-free radicals and proinflammatorycytokines) may play a major role in initiating and perpetuat-ing inflammation of sinonasal mucosa in patients with AR

Evidence from the Lab and Biomarkers Linking AllergicInflammation to Increased Risk of Chronic Rhinosinusitisin Children

All studies included in a qualitative analysis support a specificlink between CRS and AR in children (Table 3) Chawes [43]studied nasal eosinophilia and nasal airway patency (assessed

by acoustic rhinometry) in children with AR non-allergic rhi-nitis and healthy controls Nasal eosinophilia and irreversiblenasal airway obstruction were significantly associated withAR while there was no such association with non-allergicrhinitis The authors suggested that chronic inflammationand structural remodeling of the sinonasal mucosa may occurin allergic children even at 6 years of age

Some authors suggested that allergic sinonasal inflamma-tion may support bacterial infection Blair et al [44] in ananimal model showed that allergic inflammatory reactionmay obstruct sinus drainage encouraging bacterial infectioninto the maxillary sinus Shin et al [45] demonstrated thattotal IgE total eosinophil count and serum eosinophil cationicprotein levels were significantly higher in CRS childrenwhose symptoms and radiologic abnormalities did not resolveafter 12 weeks despite appropriate antibiotic therapy (non-responder) compared with responders and healthy controlsMoreover AR in children may affect the efficiency ofmucociliary clearance which is one of the most importantprotective functions of the respiratory epitheliumDeterioration of mucociliary system appears to be related tomore severe rhinitis with a higher intensity of local nasal in-flammation reflected in nasal smear eosinophilia [46bullbull]

Brożek-Mądry and co-workers [47] evaluated the relationbetween bacterial strains and cytological examination of nasalmucosa in children with CRS they found that the most com-mon strains of bacteria observed in CRS (Hemophilusinfluenzae Moraxella catarrhalis and Staphylococcusaureus) were associated with a higher prevalence of atopyand percentage of eosinophils in cytology It must be notedthat S aureus enterotoxins are able to induce increased sever-ity of the disease amplifying eosinophilic inflammation inatopic patients [48]

Clinical Evidences Linking Allergic Inflammation to IncreasedRisk of Chronic Rhinosinusitis

The association between allergy and CRS in adults has beendiscussed for years and a strong association has been observedwith particular subtypes of CRS with nasal polyps(CRSwNP) such as central compartment atopic disease andallergic fungal rhinosinusitis (AFRS) [49 50] Manuscripts onpediatric CRS are less common predominantly because ofethical issues regarding administration of X-rays in the pedi-atric population The publications included in the qualitativeanalyses are summarized in Table 4 Conclusions of the stud-ies included in the qualitative analyses were not unanimouslylinking allergy to chronic rhinosinusitis

Several manuscripts seem to support a positive clinical as-sociation between AR and CRS describing a prevalence vary-ing between 27 and 59 of patients [51ndash53] Brietzke et al[54] in an expert panel consensus suggested that there is aclinically relevant association between AR and pediatric

Page 7 of 13 68Curr Allergy Asthma Rep (2020) 20 68

CRS particularly in older children Sedaghat et al[55] analyzing a large series of 4044 pediatric cases observedAR in 269 children with CRS but their results were incon-clusive because no comparison with control group wasprovided Choi et al [32] showed that age atopy AR andasthma may be predisposing factors for pediatric CRS andrecurrent RS The authors proposed that specific evaluationfor allergic diseases should be considered when managingchronic or recurrent RS More recently Anamika et al [56bull]demonstrated a positive skin prick test in 53 of the cases in acohort of 110 children with CRS moreover those with atopyhad higher mean Lund-Mackay endoscopic score and sinusand nasal quality of life survey score than non-atopic patients

Huang et al [57] attempted discrimination among differentallergies and reported that mold allergy represents a significant

risk factor for development of sinusitis compared with non-mold allergy in a case series of 413 children followed for5 years These data suggest that perennial allergy may be astronger risk factor for CRS compared with seasonal allergy

On the other hand some studies suggested a lack of corre-lation between allergic disease and pediatric CRS Leo et al[58] in a report on 351 children affected by CRS demonstrat-ed that the prevalence of sensitization to aeroallergens wascomparable with that of the general pediatric population Noclinical evidence could account for a higher rate of nasal con-gestion nor a harsher clinical course in allergic children [59]Sedaghat et al [51 60] observed that pediatric patients withAR and CRS seem to have the same aeroallergen sensitivityprofile compared with the general pediatric population withAR Furthermore the authors did not find a positive

Table 3 Evidence of inflammatory cells and mediators linking allergy to chronic rhinosinusitis in children

Biomarkers linking allergy to risk of CRS

AuthorYear() ref

No of cases Experimentalmodels

Methods Relevant results Association(Level ofevidence)

Chawes 2011[43]

N = 411 children withAR non-AR andhealthy controls(6 years)

Nasal airwaypatency wasassessed byacousticrhinometry

Acoustic rhinometry was performedtwice in the childrsquos 6th year of lifewith or without allergy Nasaleosinophilia was assessed by nasalscraping

Nasal eosinophilia correlated withirreversible nasal airwayobstruction in allergic childrenalready at age 6 years No changein nasal airway patency wereobserved in non-allergic rhinitis

Yes(Level III)

Blair et al2001 [44]

NA Mousesensitized toovalbuminbyintraperito-nealinjection

Sinuses of the mouse were infected byS pneumoniae with or withoutconcomitant administration ofovalbumin to induce or not allergicinflammation

Mice with allergic sinonasalinflammation had significantlymore bacteria and significantlymore inflammation (as indicated byneutrophil eosinophil andmononuclear influx) into the sinuswith respect to the non-allergicones

Yes(Level V)

Shin et al2015 [45]

N = 36 CRSresponders vs 22CRS

non-responders 22healthy controls

(age lt 15 years)

Serumanalyses

Skin prick tests were performed alongwith serum total IgE TEC serumECP level and ImmunoCAPanalysis for common allergens

TEC ECP and total IgE levels weresignificantly higher in thenon-responder group than in theresponder and control groups

Yes(Level III)

Mikolajczyket al 2019[46bullbull]

N = 842 AR childrenand 96 controls

EOSnsMCT

All patients underwent saccharin andskin prick tests nasal smeareosinophilia total and specific IgEserum concentration and MCTmeasurement

Nasal MCT was significantly longerin AR patients than controlsEOSns were significantly higherin patients than controls A weakbut significant correlation wasobserved between EOSns andMCT

Yes(Level III)

Brożek-Mądryet al 2012[47]

N = 64 patients withchronicrhinosinusitiswithout polyps and30 controls (age5ndash18 years)

Epithelialcultures(middlemeatal cells)

Middle meatus culture and cytologicalexamination from the inferior nasalconcha and middle meatus

The most common strains of bacteriafound in patients with CRS wereassociated with a higher percentageof eosinophils in cytology and highprevalence in atopic patients

Yes(Level V)

AR allergic rhinitis CRS chronic rhinosinusitis MCT mucociliary transport time EOSns percentage of eosinophils in nasal smear TEC totaleosinophil count ECP serum eosinophil cationic protein

68 Page 8 of 13 Curr Allergy Asthma Rep (2020) 20 68

association between the number of aeroallergen sensitivitiesand the presence of atopic comorbidities with the subsequent

development of CRS suggesting that the severity of atopyalone may not be positively predictive of CRS development

Table 4 Clinical evidences linking allergy to chronic rhinosinusitis in children

Clinical evidences linking allergy to risk of CRS in children

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Sedaghatet al2014[55]

Retrospectiveanalysis

N = 4044 childrenwith CRS(89 years)

Retrospective review of childrendiagnosed as uncomplicated CRSby an otolaryngology or allergyoffice evaluation

Comorbidities observed in CRS childrenwere primary ciliary dyskinesia (02)cystic fibrosis (41) immunologicdisorder (123) and AR (269)

Inconclusive(Level IV)

Choi et al2012[32]

Prospectivestudy

N = 296(lt 13 years)with recurrentRS

To evaluate predisposing factors forchronic and recurrent RS

The prevalence of AR atopy and asthmawas significantly higher in patients withCRS and recurrent RS than those withacute and subacute RS

Yes(Level II)

Anamikaet al2019[56bull]

Cross-sectionalstudy

N = 110 childrenwith CRS(7-18 years)

To determine atopic profile ofchildren with CRS and impact ofatopic status on disease severity andquality of life

Positive skin prick test was present in 527of patients Atopic CRS had a significanthigher mean Lund-Mackay endoscopicscore and symptoms scores thannon-atopic ones

Yes(Level IV)

Huang2000[57]

Prospectiveobservationalstudy

N = 413 RAchildren

(3ndash15 years)

To evaluate mold allergy as risk factorfor sinusitis

The authors compared 215 PAR with198 SAR

The prevalence of sinusitis was significantlyhigher among patients with PAR thanamong those with SAR regardless of ageor season patients with mold allergy PARhad a higher risk than those with non-moldallergy

Yes(Level II)

Leo et al2007[58]

Cross-sectionalstudy

N = 351 childrenwith CRS(523 plusmn211 years)

CRS underwent allergen sensitizationwork-up by skin prick test withcommon inhalant allergens andtotal IgE measurement

Prevalence of sensitization to aeroallergens inchildren with CRS is comparable with thatof the general pediatric population

No(Level IV)

Nathanet al2004[62]

Prospectiveobservationalstudy

N = 114 RA andCRS (childrenand adult)

Patients were surveyed for globalsymptoms and specific symptomsrelated to the nose sinuses eyesand chest with the SOQ

Immunotherapy is an effective treatment forpatients with sinus disease and allergicrhinitis

Yes(Level II)

RamadanampHiner-man2006[61]

Prospectiveobservationalstudy

N = 141 patientswho underwentESS (7 years)

To evaluate outcome of ESS at 1 yearafter the operation

Children with AR who were on treatmentbefore surgery had an 84 success ratecompared with 62 for those childrenwith non-treated AR by immunotherapy

Yes(Level II)

Kim et al2005[63]

Retrospectiveobservationalstudy

N = 97 patients(age range

5ndash15 years)

Retrospective analysis of long-termsuccess rates of ESS with respect toseveral predisposing factors

Multivariate logistic regression analysisallergy was not correlated to pooroutcomes after pediatric ESS

No(Level IV)

ElSharka-wy2012[64]

Prospectiveobservationalstudy

N = 87 children(45 with nasalallergy)(age le 14)

To assess predictive factors ofoutcome after ESS

The success rate in CRS with nasal allergywas 875 and in CRS without nasalallergy was 857

No(Level II)

Lee et al2009[66]

Retrospectiveanalysis

N = 53 childrenwho underwentFESS(age lt 18 years)

To investigate factors leading toprotracted nasal discharge afterpediatric endoscopic sinus surgery

Blood eosinophil count did not differsignificantly between the ldquoprotractedrdquo andthe ldquoresolvedrdquo groups On the other handhistory of allergic rhinitis was morefrequently observed in the ldquoprotractedrdquogroup

Yes(Level IV)

Wu et al2019[67bull]

Retrospectiveanalysis

N = 188 childrenESS for CRS

To evaluate prognostic factors relatedto revision surgery after ESS

Patients with positive aeroallergen tests hadhigher rates of CRS recurrence after ESSand required revision surgery

Yes(Level IV)

CRS chronic rhinosinusitis RS rhinosinusitis AR allergic rhinitis PAR perennial allergic rhinitis SAR seasonal allergic rhinitis SOQ sinusitisoutcome questionnaire ESS endoscopic sinus surgery FESS functional endoscopic sinus surgery

Page 9 of 13 68Curr Allergy Asthma Rep (2020) 20 68

These articles were not included in the qualitative analysesdue to the type of article

Impact of Allergy on Outcome of Chronic RhinosinusitisTreatment

Ramadan and Hinerman [61] in a retrospective study notedthat children with AR underwent to endoscopic sinus surgery(ESS) do not have a poorer outcome respect non-allergic oneNevertheless children with AR who were on immunotherapybefore surgery had an 84 success rate compared with 62for those children with AR who were not treated (p = 0022)Accordingly Nathan et al [62] using the sinusitis outcomesquestionnaire (SOQ) demonstrated that immunotherapy wasan effective treatment for patients with sinus disease and ARin both children and adults

About surgery outcomes Kim et al [63] and El Sharkawyet al [64] observed that functional endoscopic sinus surgery inchildren with CRS and AR does not provide significantlydifferent results compared with children without AR whichis similar to what has been reported in adults [65] On thecontrary in a study by Lee et al [66] a significantly greaterchance of protracted mucopurulent discharge after FESS wasregistered in patients with AR The authors assumed that theinflammatory process of nasal allergy which led to the devel-opment of CRS probably impaired the postoperative woundhealing by mucosal congestion poor-functioning mucociliaryclearance and recurrent sneezing that placed pressure on the

denuded mucosa An analogous conclusion was made by Wuet al [67bull] who demonstrated that pediatric patients with pos-itive aeroallergen tests had higher rates of CRS recurrenceafter ESS and required revision surgery

Allergic Fungal Rhinosinusitis (AFRS) in Children

AFRS is also present in the pediatric age group and it shouldbe considered a differential in children presenting with nasalpolyposis along with the other causes like ciliary dysmotilitydisorders and cystic fibrosis [68] There is paucity of data inliterature regarding nature clinical course and its recurrencein children and it was not possible to perform a qualitativeanalysis Patro et al [69] in a single center prospective studycompared features of AFRS in children with adults The au-thors concluded that AFRS was more aggressive in childrenwith increased fungal load when compared with adults Theserum IgE levels were also found to be significantly higher inpediatric group suggesting a higher fungal load with in-creased sensitivity to fungal antigen in children TypicallyAFRS in children was less responsive to treatment with in-creased recurrence rates

Conclusions

AR is a common disease in childhood in industrialized coun-tries and it has a major impact on quality of life and healthcare

Fig 2 Practical algorithm based on different phenotypes of rhinosinusitisin children Abbreviations ARS acute rhinosinusitis CRS chronicrhinosinusitis URTI upper respiratory tract infections ABRS acute

bacterial rhinosinusitis RARS recurrent acute rhinosinusitis AFRSallergic fungal rhinosinusitis

68 Page 10 of 13 Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

1 Meltzer EO Hamilos DL Rhinosinusitis diagnosis and manage-ment for the clinician a synopsis of recent consensus guidelinesMayo Clin Proc 201186(5)427ndash43 httpsdoiorg104065mcp20100392

2 Wood RA Pediatric asthma JAMA 2002288(6)745ndash7 httpsdoiorg101001jama2886745

3 Bousquet J Van Cauwenberge P KhaltaevN et al Allergic rhinitisand its impact on asthma JAMA 2001108(5)S147ndash334 httpsdoiorg101034j1398-9995200223625

4 Borish L Allergic rhinitis systemic inflammation and implicationsfor management J Allergy Clin Immunol 2003112(6)1021ndash31httpsdoiorg101016jjaci200309015

5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

6 Tan YSL Hong CY Chong PN Tan ESL Lew YJ Lin RTPKnowledge that upper respiratory tract infection resolves on itsown is associated with more appropriate health-seeking behaviorand antibiotic cognition Singap Med J 200647(6)518ndash24

7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

9 Parker D Prince A Innate immunity in the respiratory epitheliumAm J Respir Cell Mol Biol 201145(2)189ndash201 httpsdoiorg101165rcmb2011-0011RT

Page 11 of 13 68Curr Allergy Asthma Rep (2020) 20 68

those with acute and subacute RS Veskitkul et al [33] eval-uated the clinical characteristics and predisposing factors ofRARS in children as well as the preventive therapy The au-thors detected allergy in 351 of cases and suggested thatchildren with RARS should be always evaluated for the pres-ence of underlying predisposing conditions including allergicdisease Nevertheless no comparison with a control group

was performed and for this reason data are not definitelysupporting a link between allergy and RARS

Allergy and Chronic Rhinosinusitis (CRS) in Children

Chronic rhinosinusitis (with or without nasal polyps) in chil-dren is defined as presence of two or more symptoms one of

Table 2 Articles investigating clinical association between allergy and upper respiratory infections

Clinical evidence linking allergy to risk of upper respiratory tract infections

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Karevoldet al2006[19]

Cross-sectionalsurvey

N = 5125(10 years)

Assess co-morbidity and risk factors forrecurrent upper and lower respiratoryinfections

Atopic disease was a constitutional riskfactor for upper and lower airwayinfections

Yes(Level IV)

Ciprandiet al2009[20]

Prospective study N = 117(402 plusmn10 years) 46allergic

Evaluate the number and duration of RIin allergic and non-allergic children

Allergic children showed a significantlyhigher number (mean 126 plusmn 073)and longer duration of RI (892 days)in comparison with non-allergicgroup (094 plusmn 137 and 485 days)

Yes(Level II)

Kvaeligrneret al1996[21]

Retrospectiveanalysis

N = 7992 (meanage not known)

Estimate comorbidity between earinfections tonsillitis sinusitis andrelated childhood diseases

The correlation between the infectiousand atopic diseases was weak

Inconclusive(Level IV)

Suumltccediluumlet al2016[22]

Retrospectiveanalysis

N = 507 children(46 range4ndash190 months)

Evaluate children presenting with thecomplaint of recurrent infections andto determine the possible predictivefactors

Atopic children had longer episodes ofrecurrent URTI compared to controlshowever the number of episodes peryear was not significantly different

No(Level IV)

Role of anti-allergy treatment in preventing upper respiratory infections

Ciprandi1999[20]

Double-blind andplacebo--controlled study

N = 20 childrenwith allergy

10 terfenadinegroup(85 plusmn 3 years)10 placebo

(79 plusmn 27 years)

Continuous terfenadine (1 mgkg perbody weight per day) vs placebo for1 year Outcome Symptomsinflammatory cells and ICAM-1measured by nasal scraping

Terfenadine treatment reduces ICAM-1expression on nasal epithelial cellschildren treated with terfenadine hadsignificantly fewer extra visits andschool absences than the placebogroup

Yes(Level I)

Fasce1996[14]

Double-blindplacebocontrolledrandomizedstudy

N = 20 children(5ndash14 yearsold) with miteallergy

Cetirizine vs placebo for 15 days Nasalscrapings were performed to evaluateinflammatory cell infiltration andICAM-I expression on epithelial cells

Cetirizine-treated children showed asignificant reduction (or even totalabsence) of ICAM-I expression onepithelial cells (p = 0002) and areduction trend in inflammatory cellcounts compared with placebo

Yes(Level I)

Barebri2015[25]

Prospective casecontrolobservationalstudy notrandomized

N = 40 HDMallergic children(93 years)

Patients were subdivided in 2 groups 20treated by symptomatic drugs and 20by high-dose HDM-SLIT

SLIT-treated children had significantly(p = 001) less RI episodes (35) thancontrol group (545)

Yes(Level II)

Barberi2018[24]

Retrospectiveanalysis

N = 33 HDMallergic children(93 years)

Investigate whether 3 year high-doseHDM-SLIT affects respiratoryinfections in children with allergicrhinitis

SLIT-treated children had significantlyfewer RI episodes thansymptomatically treated children Inaddition they had less fever and tookfewer medications such as antibioticsand antipyretics

Yes(Level IV)

HDM house dust mites SLIT sub-lingual immunotherapy URTI upper respiratory tract infections RI respiratory infections ICAM intercellularadhesion molecule

68 Page 6 of 13 Curr Allergy Asthma Rep (2020) 20 68

which should be either nasal blockageobstructioncongestionor nasal discharge (anteriorposterior nasal drip) with or with-out facial painpressure andor cough for ge 12 weeks associat-ed with pathognomonic endoscopic signs or CT changes [5]The prevalence of CRS in children is lower than in adults (2ndash4) nevertheless the negative impact on quality of life seemsto be similar to that observed in adults Studies on CRS inchildren are less common and it is more difficult to investi-gate the relationship with allergy [5] Several factors contrib-ute to complicate the analyses including incomplete evalua-tion (nasal endoscopy andor imaging are rarely performed inmany children) and the difficulty to differentiate CRS fromadenoid hypertrophy adenoiditis and (allergic) rhinitis Infact nasal blockage may occur in AR children due to edem-atous mucosa neurogenic and vascular responses over-production of secretions and impaired mucociliary clearanceleading to congestion of the ostia and symptoms simulatingrhinosinusitis On the other hand the blockage leads to stag-nant debris and acidotic environment that might stimulatebacteria overgrowth [34 35]

Histopathological analysis [36 37] demonstrated that pe-diatric CRS is quite different from the adult form showinggreater inflammatory cellularity higher density of submucosallymphocytes less eosinophilic inflammation basement mem-brane thickening and mucous gland hyperplasia suggesting adifferent pathway compared with the adult CRS patternwhich is predominantly characterized by a Th2-oriented re-sponse with polypoid changes The presence of nasal polypsin a pediatric patient should suggest the hypothesis of cysticfibrosis that has not been included in this paper More specif-ically some evidence supports the hypothesis that CRS inchildren over the age of 13 seems to be based more on eosin-ophilic inflammation while under this age CRS seems to bebased more on neutrophilic inflammation thus justifying thelower prevalence of nasal polyps in children than in adult [3637]

Several manuscripts support the hypothesis that AR andCRS could be different faces of the same disease AR in factis typically characterized by a Th2 immune response involv-ing IL-4 IL-5 and IL-13 which drives IgE production andrecruitment of eosinophil granulocytes It has been suggested[38ndash42] that eosinophils by generating potent toxic agents(cationic proteins oxygen-free radicals and proinflammatorycytokines) may play a major role in initiating and perpetuat-ing inflammation of sinonasal mucosa in patients with AR

Evidence from the Lab and Biomarkers Linking AllergicInflammation to Increased Risk of Chronic Rhinosinusitisin Children

All studies included in a qualitative analysis support a specificlink between CRS and AR in children (Table 3) Chawes [43]studied nasal eosinophilia and nasal airway patency (assessed

by acoustic rhinometry) in children with AR non-allergic rhi-nitis and healthy controls Nasal eosinophilia and irreversiblenasal airway obstruction were significantly associated withAR while there was no such association with non-allergicrhinitis The authors suggested that chronic inflammationand structural remodeling of the sinonasal mucosa may occurin allergic children even at 6 years of age

Some authors suggested that allergic sinonasal inflamma-tion may support bacterial infection Blair et al [44] in ananimal model showed that allergic inflammatory reactionmay obstruct sinus drainage encouraging bacterial infectioninto the maxillary sinus Shin et al [45] demonstrated thattotal IgE total eosinophil count and serum eosinophil cationicprotein levels were significantly higher in CRS childrenwhose symptoms and radiologic abnormalities did not resolveafter 12 weeks despite appropriate antibiotic therapy (non-responder) compared with responders and healthy controlsMoreover AR in children may affect the efficiency ofmucociliary clearance which is one of the most importantprotective functions of the respiratory epitheliumDeterioration of mucociliary system appears to be related tomore severe rhinitis with a higher intensity of local nasal in-flammation reflected in nasal smear eosinophilia [46bullbull]

Brożek-Mądry and co-workers [47] evaluated the relationbetween bacterial strains and cytological examination of nasalmucosa in children with CRS they found that the most com-mon strains of bacteria observed in CRS (Hemophilusinfluenzae Moraxella catarrhalis and Staphylococcusaureus) were associated with a higher prevalence of atopyand percentage of eosinophils in cytology It must be notedthat S aureus enterotoxins are able to induce increased sever-ity of the disease amplifying eosinophilic inflammation inatopic patients [48]

Clinical Evidences Linking Allergic Inflammation to IncreasedRisk of Chronic Rhinosinusitis

The association between allergy and CRS in adults has beendiscussed for years and a strong association has been observedwith particular subtypes of CRS with nasal polyps(CRSwNP) such as central compartment atopic disease andallergic fungal rhinosinusitis (AFRS) [49 50] Manuscripts onpediatric CRS are less common predominantly because ofethical issues regarding administration of X-rays in the pedi-atric population The publications included in the qualitativeanalyses are summarized in Table 4 Conclusions of the stud-ies included in the qualitative analyses were not unanimouslylinking allergy to chronic rhinosinusitis

Several manuscripts seem to support a positive clinical as-sociation between AR and CRS describing a prevalence vary-ing between 27 and 59 of patients [51ndash53] Brietzke et al[54] in an expert panel consensus suggested that there is aclinically relevant association between AR and pediatric

Page 7 of 13 68Curr Allergy Asthma Rep (2020) 20 68

CRS particularly in older children Sedaghat et al[55] analyzing a large series of 4044 pediatric cases observedAR in 269 children with CRS but their results were incon-clusive because no comparison with control group wasprovided Choi et al [32] showed that age atopy AR andasthma may be predisposing factors for pediatric CRS andrecurrent RS The authors proposed that specific evaluationfor allergic diseases should be considered when managingchronic or recurrent RS More recently Anamika et al [56bull]demonstrated a positive skin prick test in 53 of the cases in acohort of 110 children with CRS moreover those with atopyhad higher mean Lund-Mackay endoscopic score and sinusand nasal quality of life survey score than non-atopic patients

Huang et al [57] attempted discrimination among differentallergies and reported that mold allergy represents a significant

risk factor for development of sinusitis compared with non-mold allergy in a case series of 413 children followed for5 years These data suggest that perennial allergy may be astronger risk factor for CRS compared with seasonal allergy

On the other hand some studies suggested a lack of corre-lation between allergic disease and pediatric CRS Leo et al[58] in a report on 351 children affected by CRS demonstrat-ed that the prevalence of sensitization to aeroallergens wascomparable with that of the general pediatric population Noclinical evidence could account for a higher rate of nasal con-gestion nor a harsher clinical course in allergic children [59]Sedaghat et al [51 60] observed that pediatric patients withAR and CRS seem to have the same aeroallergen sensitivityprofile compared with the general pediatric population withAR Furthermore the authors did not find a positive

Table 3 Evidence of inflammatory cells and mediators linking allergy to chronic rhinosinusitis in children

Biomarkers linking allergy to risk of CRS

AuthorYear() ref

No of cases Experimentalmodels

Methods Relevant results Association(Level ofevidence)

Chawes 2011[43]

N = 411 children withAR non-AR andhealthy controls(6 years)

Nasal airwaypatency wasassessed byacousticrhinometry

Acoustic rhinometry was performedtwice in the childrsquos 6th year of lifewith or without allergy Nasaleosinophilia was assessed by nasalscraping

Nasal eosinophilia correlated withirreversible nasal airwayobstruction in allergic childrenalready at age 6 years No changein nasal airway patency wereobserved in non-allergic rhinitis

Yes(Level III)

Blair et al2001 [44]

NA Mousesensitized toovalbuminbyintraperito-nealinjection

Sinuses of the mouse were infected byS pneumoniae with or withoutconcomitant administration ofovalbumin to induce or not allergicinflammation

Mice with allergic sinonasalinflammation had significantlymore bacteria and significantlymore inflammation (as indicated byneutrophil eosinophil andmononuclear influx) into the sinuswith respect to the non-allergicones

Yes(Level V)

Shin et al2015 [45]

N = 36 CRSresponders vs 22CRS

non-responders 22healthy controls

(age lt 15 years)

Serumanalyses

Skin prick tests were performed alongwith serum total IgE TEC serumECP level and ImmunoCAPanalysis for common allergens

TEC ECP and total IgE levels weresignificantly higher in thenon-responder group than in theresponder and control groups

Yes(Level III)

Mikolajczyket al 2019[46bullbull]

N = 842 AR childrenand 96 controls

EOSnsMCT

All patients underwent saccharin andskin prick tests nasal smeareosinophilia total and specific IgEserum concentration and MCTmeasurement

Nasal MCT was significantly longerin AR patients than controlsEOSns were significantly higherin patients than controls A weakbut significant correlation wasobserved between EOSns andMCT

Yes(Level III)

Brożek-Mądryet al 2012[47]

N = 64 patients withchronicrhinosinusitiswithout polyps and30 controls (age5ndash18 years)

Epithelialcultures(middlemeatal cells)

Middle meatus culture and cytologicalexamination from the inferior nasalconcha and middle meatus

The most common strains of bacteriafound in patients with CRS wereassociated with a higher percentageof eosinophils in cytology and highprevalence in atopic patients

Yes(Level V)

AR allergic rhinitis CRS chronic rhinosinusitis MCT mucociliary transport time EOSns percentage of eosinophils in nasal smear TEC totaleosinophil count ECP serum eosinophil cationic protein

68 Page 8 of 13 Curr Allergy Asthma Rep (2020) 20 68

association between the number of aeroallergen sensitivitiesand the presence of atopic comorbidities with the subsequent

development of CRS suggesting that the severity of atopyalone may not be positively predictive of CRS development

Table 4 Clinical evidences linking allergy to chronic rhinosinusitis in children

Clinical evidences linking allergy to risk of CRS in children

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Sedaghatet al2014[55]

Retrospectiveanalysis

N = 4044 childrenwith CRS(89 years)

Retrospective review of childrendiagnosed as uncomplicated CRSby an otolaryngology or allergyoffice evaluation

Comorbidities observed in CRS childrenwere primary ciliary dyskinesia (02)cystic fibrosis (41) immunologicdisorder (123) and AR (269)

Inconclusive(Level IV)

Choi et al2012[32]

Prospectivestudy

N = 296(lt 13 years)with recurrentRS

To evaluate predisposing factors forchronic and recurrent RS

The prevalence of AR atopy and asthmawas significantly higher in patients withCRS and recurrent RS than those withacute and subacute RS

Yes(Level II)

Anamikaet al2019[56bull]

Cross-sectionalstudy

N = 110 childrenwith CRS(7-18 years)

To determine atopic profile ofchildren with CRS and impact ofatopic status on disease severity andquality of life

Positive skin prick test was present in 527of patients Atopic CRS had a significanthigher mean Lund-Mackay endoscopicscore and symptoms scores thannon-atopic ones

Yes(Level IV)

Huang2000[57]

Prospectiveobservationalstudy

N = 413 RAchildren

(3ndash15 years)

To evaluate mold allergy as risk factorfor sinusitis

The authors compared 215 PAR with198 SAR

The prevalence of sinusitis was significantlyhigher among patients with PAR thanamong those with SAR regardless of ageor season patients with mold allergy PARhad a higher risk than those with non-moldallergy

Yes(Level II)

Leo et al2007[58]

Cross-sectionalstudy

N = 351 childrenwith CRS(523 plusmn211 years)

CRS underwent allergen sensitizationwork-up by skin prick test withcommon inhalant allergens andtotal IgE measurement

Prevalence of sensitization to aeroallergens inchildren with CRS is comparable with thatof the general pediatric population

No(Level IV)

Nathanet al2004[62]

Prospectiveobservationalstudy

N = 114 RA andCRS (childrenand adult)

Patients were surveyed for globalsymptoms and specific symptomsrelated to the nose sinuses eyesand chest with the SOQ

Immunotherapy is an effective treatment forpatients with sinus disease and allergicrhinitis

Yes(Level II)

RamadanampHiner-man2006[61]

Prospectiveobservationalstudy

N = 141 patientswho underwentESS (7 years)

To evaluate outcome of ESS at 1 yearafter the operation

Children with AR who were on treatmentbefore surgery had an 84 success ratecompared with 62 for those childrenwith non-treated AR by immunotherapy

Yes(Level II)

Kim et al2005[63]

Retrospectiveobservationalstudy

N = 97 patients(age range

5ndash15 years)

Retrospective analysis of long-termsuccess rates of ESS with respect toseveral predisposing factors

Multivariate logistic regression analysisallergy was not correlated to pooroutcomes after pediatric ESS

No(Level IV)

ElSharka-wy2012[64]

Prospectiveobservationalstudy

N = 87 children(45 with nasalallergy)(age le 14)

To assess predictive factors ofoutcome after ESS

The success rate in CRS with nasal allergywas 875 and in CRS without nasalallergy was 857

No(Level II)

Lee et al2009[66]

Retrospectiveanalysis

N = 53 childrenwho underwentFESS(age lt 18 years)

To investigate factors leading toprotracted nasal discharge afterpediatric endoscopic sinus surgery

Blood eosinophil count did not differsignificantly between the ldquoprotractedrdquo andthe ldquoresolvedrdquo groups On the other handhistory of allergic rhinitis was morefrequently observed in the ldquoprotractedrdquogroup

Yes(Level IV)

Wu et al2019[67bull]

Retrospectiveanalysis

N = 188 childrenESS for CRS

To evaluate prognostic factors relatedto revision surgery after ESS

Patients with positive aeroallergen tests hadhigher rates of CRS recurrence after ESSand required revision surgery

Yes(Level IV)

CRS chronic rhinosinusitis RS rhinosinusitis AR allergic rhinitis PAR perennial allergic rhinitis SAR seasonal allergic rhinitis SOQ sinusitisoutcome questionnaire ESS endoscopic sinus surgery FESS functional endoscopic sinus surgery

Page 9 of 13 68Curr Allergy Asthma Rep (2020) 20 68

These articles were not included in the qualitative analysesdue to the type of article

Impact of Allergy on Outcome of Chronic RhinosinusitisTreatment

Ramadan and Hinerman [61] in a retrospective study notedthat children with AR underwent to endoscopic sinus surgery(ESS) do not have a poorer outcome respect non-allergic oneNevertheless children with AR who were on immunotherapybefore surgery had an 84 success rate compared with 62for those children with AR who were not treated (p = 0022)Accordingly Nathan et al [62] using the sinusitis outcomesquestionnaire (SOQ) demonstrated that immunotherapy wasan effective treatment for patients with sinus disease and ARin both children and adults

About surgery outcomes Kim et al [63] and El Sharkawyet al [64] observed that functional endoscopic sinus surgery inchildren with CRS and AR does not provide significantlydifferent results compared with children without AR whichis similar to what has been reported in adults [65] On thecontrary in a study by Lee et al [66] a significantly greaterchance of protracted mucopurulent discharge after FESS wasregistered in patients with AR The authors assumed that theinflammatory process of nasal allergy which led to the devel-opment of CRS probably impaired the postoperative woundhealing by mucosal congestion poor-functioning mucociliaryclearance and recurrent sneezing that placed pressure on the

denuded mucosa An analogous conclusion was made by Wuet al [67bull] who demonstrated that pediatric patients with pos-itive aeroallergen tests had higher rates of CRS recurrenceafter ESS and required revision surgery

Allergic Fungal Rhinosinusitis (AFRS) in Children

AFRS is also present in the pediatric age group and it shouldbe considered a differential in children presenting with nasalpolyposis along with the other causes like ciliary dysmotilitydisorders and cystic fibrosis [68] There is paucity of data inliterature regarding nature clinical course and its recurrencein children and it was not possible to perform a qualitativeanalysis Patro et al [69] in a single center prospective studycompared features of AFRS in children with adults The au-thors concluded that AFRS was more aggressive in childrenwith increased fungal load when compared with adults Theserum IgE levels were also found to be significantly higher inpediatric group suggesting a higher fungal load with in-creased sensitivity to fungal antigen in children TypicallyAFRS in children was less responsive to treatment with in-creased recurrence rates

Conclusions

AR is a common disease in childhood in industrialized coun-tries and it has a major impact on quality of life and healthcare

Fig 2 Practical algorithm based on different phenotypes of rhinosinusitisin children Abbreviations ARS acute rhinosinusitis CRS chronicrhinosinusitis URTI upper respiratory tract infections ABRS acute

bacterial rhinosinusitis RARS recurrent acute rhinosinusitis AFRSallergic fungal rhinosinusitis

68 Page 10 of 13 Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

1 Meltzer EO Hamilos DL Rhinosinusitis diagnosis and manage-ment for the clinician a synopsis of recent consensus guidelinesMayo Clin Proc 201186(5)427ndash43 httpsdoiorg104065mcp20100392

2 Wood RA Pediatric asthma JAMA 2002288(6)745ndash7 httpsdoiorg101001jama2886745

3 Bousquet J Van Cauwenberge P KhaltaevN et al Allergic rhinitisand its impact on asthma JAMA 2001108(5)S147ndash334 httpsdoiorg101034j1398-9995200223625

4 Borish L Allergic rhinitis systemic inflammation and implicationsfor management J Allergy Clin Immunol 2003112(6)1021ndash31httpsdoiorg101016jjaci200309015

5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

6 Tan YSL Hong CY Chong PN Tan ESL Lew YJ Lin RTPKnowledge that upper respiratory tract infection resolves on itsown is associated with more appropriate health-seeking behaviorand antibiotic cognition Singap Med J 200647(6)518ndash24

7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

9 Parker D Prince A Innate immunity in the respiratory epitheliumAm J Respir Cell Mol Biol 201145(2)189ndash201 httpsdoiorg101165rcmb2011-0011RT

Page 11 of 13 68Curr Allergy Asthma Rep (2020) 20 68

which should be either nasal blockageobstructioncongestionor nasal discharge (anteriorposterior nasal drip) with or with-out facial painpressure andor cough for ge 12 weeks associat-ed with pathognomonic endoscopic signs or CT changes [5]The prevalence of CRS in children is lower than in adults (2ndash4) nevertheless the negative impact on quality of life seemsto be similar to that observed in adults Studies on CRS inchildren are less common and it is more difficult to investi-gate the relationship with allergy [5] Several factors contrib-ute to complicate the analyses including incomplete evalua-tion (nasal endoscopy andor imaging are rarely performed inmany children) and the difficulty to differentiate CRS fromadenoid hypertrophy adenoiditis and (allergic) rhinitis Infact nasal blockage may occur in AR children due to edem-atous mucosa neurogenic and vascular responses over-production of secretions and impaired mucociliary clearanceleading to congestion of the ostia and symptoms simulatingrhinosinusitis On the other hand the blockage leads to stag-nant debris and acidotic environment that might stimulatebacteria overgrowth [34 35]

Histopathological analysis [36 37] demonstrated that pe-diatric CRS is quite different from the adult form showinggreater inflammatory cellularity higher density of submucosallymphocytes less eosinophilic inflammation basement mem-brane thickening and mucous gland hyperplasia suggesting adifferent pathway compared with the adult CRS patternwhich is predominantly characterized by a Th2-oriented re-sponse with polypoid changes The presence of nasal polypsin a pediatric patient should suggest the hypothesis of cysticfibrosis that has not been included in this paper More specif-ically some evidence supports the hypothesis that CRS inchildren over the age of 13 seems to be based more on eosin-ophilic inflammation while under this age CRS seems to bebased more on neutrophilic inflammation thus justifying thelower prevalence of nasal polyps in children than in adult [3637]

Several manuscripts support the hypothesis that AR andCRS could be different faces of the same disease AR in factis typically characterized by a Th2 immune response involv-ing IL-4 IL-5 and IL-13 which drives IgE production andrecruitment of eosinophil granulocytes It has been suggested[38ndash42] that eosinophils by generating potent toxic agents(cationic proteins oxygen-free radicals and proinflammatorycytokines) may play a major role in initiating and perpetuat-ing inflammation of sinonasal mucosa in patients with AR

Evidence from the Lab and Biomarkers Linking AllergicInflammation to Increased Risk of Chronic Rhinosinusitisin Children

All studies included in a qualitative analysis support a specificlink between CRS and AR in children (Table 3) Chawes [43]studied nasal eosinophilia and nasal airway patency (assessed

by acoustic rhinometry) in children with AR non-allergic rhi-nitis and healthy controls Nasal eosinophilia and irreversiblenasal airway obstruction were significantly associated withAR while there was no such association with non-allergicrhinitis The authors suggested that chronic inflammationand structural remodeling of the sinonasal mucosa may occurin allergic children even at 6 years of age

Some authors suggested that allergic sinonasal inflamma-tion may support bacterial infection Blair et al [44] in ananimal model showed that allergic inflammatory reactionmay obstruct sinus drainage encouraging bacterial infectioninto the maxillary sinus Shin et al [45] demonstrated thattotal IgE total eosinophil count and serum eosinophil cationicprotein levels were significantly higher in CRS childrenwhose symptoms and radiologic abnormalities did not resolveafter 12 weeks despite appropriate antibiotic therapy (non-responder) compared with responders and healthy controlsMoreover AR in children may affect the efficiency ofmucociliary clearance which is one of the most importantprotective functions of the respiratory epitheliumDeterioration of mucociliary system appears to be related tomore severe rhinitis with a higher intensity of local nasal in-flammation reflected in nasal smear eosinophilia [46bullbull]

Brożek-Mądry and co-workers [47] evaluated the relationbetween bacterial strains and cytological examination of nasalmucosa in children with CRS they found that the most com-mon strains of bacteria observed in CRS (Hemophilusinfluenzae Moraxella catarrhalis and Staphylococcusaureus) were associated with a higher prevalence of atopyand percentage of eosinophils in cytology It must be notedthat S aureus enterotoxins are able to induce increased sever-ity of the disease amplifying eosinophilic inflammation inatopic patients [48]

Clinical Evidences Linking Allergic Inflammation to IncreasedRisk of Chronic Rhinosinusitis

The association between allergy and CRS in adults has beendiscussed for years and a strong association has been observedwith particular subtypes of CRS with nasal polyps(CRSwNP) such as central compartment atopic disease andallergic fungal rhinosinusitis (AFRS) [49 50] Manuscripts onpediatric CRS are less common predominantly because ofethical issues regarding administration of X-rays in the pedi-atric population The publications included in the qualitativeanalyses are summarized in Table 4 Conclusions of the stud-ies included in the qualitative analyses were not unanimouslylinking allergy to chronic rhinosinusitis

Several manuscripts seem to support a positive clinical as-sociation between AR and CRS describing a prevalence vary-ing between 27 and 59 of patients [51ndash53] Brietzke et al[54] in an expert panel consensus suggested that there is aclinically relevant association between AR and pediatric

Page 7 of 13 68Curr Allergy Asthma Rep (2020) 20 68

CRS particularly in older children Sedaghat et al[55] analyzing a large series of 4044 pediatric cases observedAR in 269 children with CRS but their results were incon-clusive because no comparison with control group wasprovided Choi et al [32] showed that age atopy AR andasthma may be predisposing factors for pediatric CRS andrecurrent RS The authors proposed that specific evaluationfor allergic diseases should be considered when managingchronic or recurrent RS More recently Anamika et al [56bull]demonstrated a positive skin prick test in 53 of the cases in acohort of 110 children with CRS moreover those with atopyhad higher mean Lund-Mackay endoscopic score and sinusand nasal quality of life survey score than non-atopic patients

Huang et al [57] attempted discrimination among differentallergies and reported that mold allergy represents a significant

risk factor for development of sinusitis compared with non-mold allergy in a case series of 413 children followed for5 years These data suggest that perennial allergy may be astronger risk factor for CRS compared with seasonal allergy

On the other hand some studies suggested a lack of corre-lation between allergic disease and pediatric CRS Leo et al[58] in a report on 351 children affected by CRS demonstrat-ed that the prevalence of sensitization to aeroallergens wascomparable with that of the general pediatric population Noclinical evidence could account for a higher rate of nasal con-gestion nor a harsher clinical course in allergic children [59]Sedaghat et al [51 60] observed that pediatric patients withAR and CRS seem to have the same aeroallergen sensitivityprofile compared with the general pediatric population withAR Furthermore the authors did not find a positive

Table 3 Evidence of inflammatory cells and mediators linking allergy to chronic rhinosinusitis in children

Biomarkers linking allergy to risk of CRS

AuthorYear() ref

No of cases Experimentalmodels

Methods Relevant results Association(Level ofevidence)

Chawes 2011[43]

N = 411 children withAR non-AR andhealthy controls(6 years)

Nasal airwaypatency wasassessed byacousticrhinometry

Acoustic rhinometry was performedtwice in the childrsquos 6th year of lifewith or without allergy Nasaleosinophilia was assessed by nasalscraping

Nasal eosinophilia correlated withirreversible nasal airwayobstruction in allergic childrenalready at age 6 years No changein nasal airway patency wereobserved in non-allergic rhinitis

Yes(Level III)

Blair et al2001 [44]

NA Mousesensitized toovalbuminbyintraperito-nealinjection

Sinuses of the mouse were infected byS pneumoniae with or withoutconcomitant administration ofovalbumin to induce or not allergicinflammation

Mice with allergic sinonasalinflammation had significantlymore bacteria and significantlymore inflammation (as indicated byneutrophil eosinophil andmononuclear influx) into the sinuswith respect to the non-allergicones

Yes(Level V)

Shin et al2015 [45]

N = 36 CRSresponders vs 22CRS

non-responders 22healthy controls

(age lt 15 years)

Serumanalyses

Skin prick tests were performed alongwith serum total IgE TEC serumECP level and ImmunoCAPanalysis for common allergens

TEC ECP and total IgE levels weresignificantly higher in thenon-responder group than in theresponder and control groups

Yes(Level III)

Mikolajczyket al 2019[46bullbull]

N = 842 AR childrenand 96 controls

EOSnsMCT

All patients underwent saccharin andskin prick tests nasal smeareosinophilia total and specific IgEserum concentration and MCTmeasurement

Nasal MCT was significantly longerin AR patients than controlsEOSns were significantly higherin patients than controls A weakbut significant correlation wasobserved between EOSns andMCT

Yes(Level III)

Brożek-Mądryet al 2012[47]

N = 64 patients withchronicrhinosinusitiswithout polyps and30 controls (age5ndash18 years)

Epithelialcultures(middlemeatal cells)

Middle meatus culture and cytologicalexamination from the inferior nasalconcha and middle meatus

The most common strains of bacteriafound in patients with CRS wereassociated with a higher percentageof eosinophils in cytology and highprevalence in atopic patients

Yes(Level V)

AR allergic rhinitis CRS chronic rhinosinusitis MCT mucociliary transport time EOSns percentage of eosinophils in nasal smear TEC totaleosinophil count ECP serum eosinophil cationic protein

68 Page 8 of 13 Curr Allergy Asthma Rep (2020) 20 68

association between the number of aeroallergen sensitivitiesand the presence of atopic comorbidities with the subsequent

development of CRS suggesting that the severity of atopyalone may not be positively predictive of CRS development

Table 4 Clinical evidences linking allergy to chronic rhinosinusitis in children

Clinical evidences linking allergy to risk of CRS in children

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Sedaghatet al2014[55]

Retrospectiveanalysis

N = 4044 childrenwith CRS(89 years)

Retrospective review of childrendiagnosed as uncomplicated CRSby an otolaryngology or allergyoffice evaluation

Comorbidities observed in CRS childrenwere primary ciliary dyskinesia (02)cystic fibrosis (41) immunologicdisorder (123) and AR (269)

Inconclusive(Level IV)

Choi et al2012[32]

Prospectivestudy

N = 296(lt 13 years)with recurrentRS

To evaluate predisposing factors forchronic and recurrent RS

The prevalence of AR atopy and asthmawas significantly higher in patients withCRS and recurrent RS than those withacute and subacute RS

Yes(Level II)

Anamikaet al2019[56bull]

Cross-sectionalstudy

N = 110 childrenwith CRS(7-18 years)

To determine atopic profile ofchildren with CRS and impact ofatopic status on disease severity andquality of life

Positive skin prick test was present in 527of patients Atopic CRS had a significanthigher mean Lund-Mackay endoscopicscore and symptoms scores thannon-atopic ones

Yes(Level IV)

Huang2000[57]

Prospectiveobservationalstudy

N = 413 RAchildren

(3ndash15 years)

To evaluate mold allergy as risk factorfor sinusitis

The authors compared 215 PAR with198 SAR

The prevalence of sinusitis was significantlyhigher among patients with PAR thanamong those with SAR regardless of ageor season patients with mold allergy PARhad a higher risk than those with non-moldallergy

Yes(Level II)

Leo et al2007[58]

Cross-sectionalstudy

N = 351 childrenwith CRS(523 plusmn211 years)

CRS underwent allergen sensitizationwork-up by skin prick test withcommon inhalant allergens andtotal IgE measurement

Prevalence of sensitization to aeroallergens inchildren with CRS is comparable with thatof the general pediatric population

No(Level IV)

Nathanet al2004[62]

Prospectiveobservationalstudy

N = 114 RA andCRS (childrenand adult)

Patients were surveyed for globalsymptoms and specific symptomsrelated to the nose sinuses eyesand chest with the SOQ

Immunotherapy is an effective treatment forpatients with sinus disease and allergicrhinitis

Yes(Level II)

RamadanampHiner-man2006[61]

Prospectiveobservationalstudy

N = 141 patientswho underwentESS (7 years)

To evaluate outcome of ESS at 1 yearafter the operation

Children with AR who were on treatmentbefore surgery had an 84 success ratecompared with 62 for those childrenwith non-treated AR by immunotherapy

Yes(Level II)

Kim et al2005[63]

Retrospectiveobservationalstudy

N = 97 patients(age range

5ndash15 years)

Retrospective analysis of long-termsuccess rates of ESS with respect toseveral predisposing factors

Multivariate logistic regression analysisallergy was not correlated to pooroutcomes after pediatric ESS

No(Level IV)

ElSharka-wy2012[64]

Prospectiveobservationalstudy

N = 87 children(45 with nasalallergy)(age le 14)

To assess predictive factors ofoutcome after ESS

The success rate in CRS with nasal allergywas 875 and in CRS without nasalallergy was 857

No(Level II)

Lee et al2009[66]

Retrospectiveanalysis

N = 53 childrenwho underwentFESS(age lt 18 years)

To investigate factors leading toprotracted nasal discharge afterpediatric endoscopic sinus surgery

Blood eosinophil count did not differsignificantly between the ldquoprotractedrdquo andthe ldquoresolvedrdquo groups On the other handhistory of allergic rhinitis was morefrequently observed in the ldquoprotractedrdquogroup

Yes(Level IV)

Wu et al2019[67bull]

Retrospectiveanalysis

N = 188 childrenESS for CRS

To evaluate prognostic factors relatedto revision surgery after ESS

Patients with positive aeroallergen tests hadhigher rates of CRS recurrence after ESSand required revision surgery

Yes(Level IV)

CRS chronic rhinosinusitis RS rhinosinusitis AR allergic rhinitis PAR perennial allergic rhinitis SAR seasonal allergic rhinitis SOQ sinusitisoutcome questionnaire ESS endoscopic sinus surgery FESS functional endoscopic sinus surgery

Page 9 of 13 68Curr Allergy Asthma Rep (2020) 20 68

These articles were not included in the qualitative analysesdue to the type of article

Impact of Allergy on Outcome of Chronic RhinosinusitisTreatment

Ramadan and Hinerman [61] in a retrospective study notedthat children with AR underwent to endoscopic sinus surgery(ESS) do not have a poorer outcome respect non-allergic oneNevertheless children with AR who were on immunotherapybefore surgery had an 84 success rate compared with 62for those children with AR who were not treated (p = 0022)Accordingly Nathan et al [62] using the sinusitis outcomesquestionnaire (SOQ) demonstrated that immunotherapy wasan effective treatment for patients with sinus disease and ARin both children and adults

About surgery outcomes Kim et al [63] and El Sharkawyet al [64] observed that functional endoscopic sinus surgery inchildren with CRS and AR does not provide significantlydifferent results compared with children without AR whichis similar to what has been reported in adults [65] On thecontrary in a study by Lee et al [66] a significantly greaterchance of protracted mucopurulent discharge after FESS wasregistered in patients with AR The authors assumed that theinflammatory process of nasal allergy which led to the devel-opment of CRS probably impaired the postoperative woundhealing by mucosal congestion poor-functioning mucociliaryclearance and recurrent sneezing that placed pressure on the

denuded mucosa An analogous conclusion was made by Wuet al [67bull] who demonstrated that pediatric patients with pos-itive aeroallergen tests had higher rates of CRS recurrenceafter ESS and required revision surgery

Allergic Fungal Rhinosinusitis (AFRS) in Children

AFRS is also present in the pediatric age group and it shouldbe considered a differential in children presenting with nasalpolyposis along with the other causes like ciliary dysmotilitydisorders and cystic fibrosis [68] There is paucity of data inliterature regarding nature clinical course and its recurrencein children and it was not possible to perform a qualitativeanalysis Patro et al [69] in a single center prospective studycompared features of AFRS in children with adults The au-thors concluded that AFRS was more aggressive in childrenwith increased fungal load when compared with adults Theserum IgE levels were also found to be significantly higher inpediatric group suggesting a higher fungal load with in-creased sensitivity to fungal antigen in children TypicallyAFRS in children was less responsive to treatment with in-creased recurrence rates

Conclusions

AR is a common disease in childhood in industrialized coun-tries and it has a major impact on quality of life and healthcare

Fig 2 Practical algorithm based on different phenotypes of rhinosinusitisin children Abbreviations ARS acute rhinosinusitis CRS chronicrhinosinusitis URTI upper respiratory tract infections ABRS acute

bacterial rhinosinusitis RARS recurrent acute rhinosinusitis AFRSallergic fungal rhinosinusitis

68 Page 10 of 13 Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

1 Meltzer EO Hamilos DL Rhinosinusitis diagnosis and manage-ment for the clinician a synopsis of recent consensus guidelinesMayo Clin Proc 201186(5)427ndash43 httpsdoiorg104065mcp20100392

2 Wood RA Pediatric asthma JAMA 2002288(6)745ndash7 httpsdoiorg101001jama2886745

3 Bousquet J Van Cauwenberge P KhaltaevN et al Allergic rhinitisand its impact on asthma JAMA 2001108(5)S147ndash334 httpsdoiorg101034j1398-9995200223625

4 Borish L Allergic rhinitis systemic inflammation and implicationsfor management J Allergy Clin Immunol 2003112(6)1021ndash31httpsdoiorg101016jjaci200309015

5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

6 Tan YSL Hong CY Chong PN Tan ESL Lew YJ Lin RTPKnowledge that upper respiratory tract infection resolves on itsown is associated with more appropriate health-seeking behaviorand antibiotic cognition Singap Med J 200647(6)518ndash24

7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

9 Parker D Prince A Innate immunity in the respiratory epitheliumAm J Respir Cell Mol Biol 201145(2)189ndash201 httpsdoiorg101165rcmb2011-0011RT

Page 11 of 13 68Curr Allergy Asthma Rep (2020) 20 68

CRS particularly in older children Sedaghat et al[55] analyzing a large series of 4044 pediatric cases observedAR in 269 children with CRS but their results were incon-clusive because no comparison with control group wasprovided Choi et al [32] showed that age atopy AR andasthma may be predisposing factors for pediatric CRS andrecurrent RS The authors proposed that specific evaluationfor allergic diseases should be considered when managingchronic or recurrent RS More recently Anamika et al [56bull]demonstrated a positive skin prick test in 53 of the cases in acohort of 110 children with CRS moreover those with atopyhad higher mean Lund-Mackay endoscopic score and sinusand nasal quality of life survey score than non-atopic patients

Huang et al [57] attempted discrimination among differentallergies and reported that mold allergy represents a significant

risk factor for development of sinusitis compared with non-mold allergy in a case series of 413 children followed for5 years These data suggest that perennial allergy may be astronger risk factor for CRS compared with seasonal allergy

On the other hand some studies suggested a lack of corre-lation between allergic disease and pediatric CRS Leo et al[58] in a report on 351 children affected by CRS demonstrat-ed that the prevalence of sensitization to aeroallergens wascomparable with that of the general pediatric population Noclinical evidence could account for a higher rate of nasal con-gestion nor a harsher clinical course in allergic children [59]Sedaghat et al [51 60] observed that pediatric patients withAR and CRS seem to have the same aeroallergen sensitivityprofile compared with the general pediatric population withAR Furthermore the authors did not find a positive

Table 3 Evidence of inflammatory cells and mediators linking allergy to chronic rhinosinusitis in children

Biomarkers linking allergy to risk of CRS

AuthorYear() ref

No of cases Experimentalmodels

Methods Relevant results Association(Level ofevidence)

Chawes 2011[43]

N = 411 children withAR non-AR andhealthy controls(6 years)

Nasal airwaypatency wasassessed byacousticrhinometry

Acoustic rhinometry was performedtwice in the childrsquos 6th year of lifewith or without allergy Nasaleosinophilia was assessed by nasalscraping

Nasal eosinophilia correlated withirreversible nasal airwayobstruction in allergic childrenalready at age 6 years No changein nasal airway patency wereobserved in non-allergic rhinitis

Yes(Level III)

Blair et al2001 [44]

NA Mousesensitized toovalbuminbyintraperito-nealinjection

Sinuses of the mouse were infected byS pneumoniae with or withoutconcomitant administration ofovalbumin to induce or not allergicinflammation

Mice with allergic sinonasalinflammation had significantlymore bacteria and significantlymore inflammation (as indicated byneutrophil eosinophil andmononuclear influx) into the sinuswith respect to the non-allergicones

Yes(Level V)

Shin et al2015 [45]

N = 36 CRSresponders vs 22CRS

non-responders 22healthy controls

(age lt 15 years)

Serumanalyses

Skin prick tests were performed alongwith serum total IgE TEC serumECP level and ImmunoCAPanalysis for common allergens

TEC ECP and total IgE levels weresignificantly higher in thenon-responder group than in theresponder and control groups

Yes(Level III)

Mikolajczyket al 2019[46bullbull]

N = 842 AR childrenand 96 controls

EOSnsMCT

All patients underwent saccharin andskin prick tests nasal smeareosinophilia total and specific IgEserum concentration and MCTmeasurement

Nasal MCT was significantly longerin AR patients than controlsEOSns were significantly higherin patients than controls A weakbut significant correlation wasobserved between EOSns andMCT

Yes(Level III)

Brożek-Mądryet al 2012[47]

N = 64 patients withchronicrhinosinusitiswithout polyps and30 controls (age5ndash18 years)

Epithelialcultures(middlemeatal cells)

Middle meatus culture and cytologicalexamination from the inferior nasalconcha and middle meatus

The most common strains of bacteriafound in patients with CRS wereassociated with a higher percentageof eosinophils in cytology and highprevalence in atopic patients

Yes(Level V)

AR allergic rhinitis CRS chronic rhinosinusitis MCT mucociliary transport time EOSns percentage of eosinophils in nasal smear TEC totaleosinophil count ECP serum eosinophil cationic protein

68 Page 8 of 13 Curr Allergy Asthma Rep (2020) 20 68

association between the number of aeroallergen sensitivitiesand the presence of atopic comorbidities with the subsequent

development of CRS suggesting that the severity of atopyalone may not be positively predictive of CRS development

Table 4 Clinical evidences linking allergy to chronic rhinosinusitis in children

Clinical evidences linking allergy to risk of CRS in children

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Sedaghatet al2014[55]

Retrospectiveanalysis

N = 4044 childrenwith CRS(89 years)

Retrospective review of childrendiagnosed as uncomplicated CRSby an otolaryngology or allergyoffice evaluation

Comorbidities observed in CRS childrenwere primary ciliary dyskinesia (02)cystic fibrosis (41) immunologicdisorder (123) and AR (269)

Inconclusive(Level IV)

Choi et al2012[32]

Prospectivestudy

N = 296(lt 13 years)with recurrentRS

To evaluate predisposing factors forchronic and recurrent RS

The prevalence of AR atopy and asthmawas significantly higher in patients withCRS and recurrent RS than those withacute and subacute RS

Yes(Level II)

Anamikaet al2019[56bull]

Cross-sectionalstudy

N = 110 childrenwith CRS(7-18 years)

To determine atopic profile ofchildren with CRS and impact ofatopic status on disease severity andquality of life

Positive skin prick test was present in 527of patients Atopic CRS had a significanthigher mean Lund-Mackay endoscopicscore and symptoms scores thannon-atopic ones

Yes(Level IV)

Huang2000[57]

Prospectiveobservationalstudy

N = 413 RAchildren

(3ndash15 years)

To evaluate mold allergy as risk factorfor sinusitis

The authors compared 215 PAR with198 SAR

The prevalence of sinusitis was significantlyhigher among patients with PAR thanamong those with SAR regardless of ageor season patients with mold allergy PARhad a higher risk than those with non-moldallergy

Yes(Level II)

Leo et al2007[58]

Cross-sectionalstudy

N = 351 childrenwith CRS(523 plusmn211 years)

CRS underwent allergen sensitizationwork-up by skin prick test withcommon inhalant allergens andtotal IgE measurement

Prevalence of sensitization to aeroallergens inchildren with CRS is comparable with thatof the general pediatric population

No(Level IV)

Nathanet al2004[62]

Prospectiveobservationalstudy

N = 114 RA andCRS (childrenand adult)

Patients were surveyed for globalsymptoms and specific symptomsrelated to the nose sinuses eyesand chest with the SOQ

Immunotherapy is an effective treatment forpatients with sinus disease and allergicrhinitis

Yes(Level II)

RamadanampHiner-man2006[61]

Prospectiveobservationalstudy

N = 141 patientswho underwentESS (7 years)

To evaluate outcome of ESS at 1 yearafter the operation

Children with AR who were on treatmentbefore surgery had an 84 success ratecompared with 62 for those childrenwith non-treated AR by immunotherapy

Yes(Level II)

Kim et al2005[63]

Retrospectiveobservationalstudy

N = 97 patients(age range

5ndash15 years)

Retrospective analysis of long-termsuccess rates of ESS with respect toseveral predisposing factors

Multivariate logistic regression analysisallergy was not correlated to pooroutcomes after pediatric ESS

No(Level IV)

ElSharka-wy2012[64]

Prospectiveobservationalstudy

N = 87 children(45 with nasalallergy)(age le 14)

To assess predictive factors ofoutcome after ESS

The success rate in CRS with nasal allergywas 875 and in CRS without nasalallergy was 857

No(Level II)

Lee et al2009[66]

Retrospectiveanalysis

N = 53 childrenwho underwentFESS(age lt 18 years)

To investigate factors leading toprotracted nasal discharge afterpediatric endoscopic sinus surgery

Blood eosinophil count did not differsignificantly between the ldquoprotractedrdquo andthe ldquoresolvedrdquo groups On the other handhistory of allergic rhinitis was morefrequently observed in the ldquoprotractedrdquogroup

Yes(Level IV)

Wu et al2019[67bull]

Retrospectiveanalysis

N = 188 childrenESS for CRS

To evaluate prognostic factors relatedto revision surgery after ESS

Patients with positive aeroallergen tests hadhigher rates of CRS recurrence after ESSand required revision surgery

Yes(Level IV)

CRS chronic rhinosinusitis RS rhinosinusitis AR allergic rhinitis PAR perennial allergic rhinitis SAR seasonal allergic rhinitis SOQ sinusitisoutcome questionnaire ESS endoscopic sinus surgery FESS functional endoscopic sinus surgery

Page 9 of 13 68Curr Allergy Asthma Rep (2020) 20 68

These articles were not included in the qualitative analysesdue to the type of article

Impact of Allergy on Outcome of Chronic RhinosinusitisTreatment

Ramadan and Hinerman [61] in a retrospective study notedthat children with AR underwent to endoscopic sinus surgery(ESS) do not have a poorer outcome respect non-allergic oneNevertheless children with AR who were on immunotherapybefore surgery had an 84 success rate compared with 62for those children with AR who were not treated (p = 0022)Accordingly Nathan et al [62] using the sinusitis outcomesquestionnaire (SOQ) demonstrated that immunotherapy wasan effective treatment for patients with sinus disease and ARin both children and adults

About surgery outcomes Kim et al [63] and El Sharkawyet al [64] observed that functional endoscopic sinus surgery inchildren with CRS and AR does not provide significantlydifferent results compared with children without AR whichis similar to what has been reported in adults [65] On thecontrary in a study by Lee et al [66] a significantly greaterchance of protracted mucopurulent discharge after FESS wasregistered in patients with AR The authors assumed that theinflammatory process of nasal allergy which led to the devel-opment of CRS probably impaired the postoperative woundhealing by mucosal congestion poor-functioning mucociliaryclearance and recurrent sneezing that placed pressure on the

denuded mucosa An analogous conclusion was made by Wuet al [67bull] who demonstrated that pediatric patients with pos-itive aeroallergen tests had higher rates of CRS recurrenceafter ESS and required revision surgery

Allergic Fungal Rhinosinusitis (AFRS) in Children

AFRS is also present in the pediatric age group and it shouldbe considered a differential in children presenting with nasalpolyposis along with the other causes like ciliary dysmotilitydisorders and cystic fibrosis [68] There is paucity of data inliterature regarding nature clinical course and its recurrencein children and it was not possible to perform a qualitativeanalysis Patro et al [69] in a single center prospective studycompared features of AFRS in children with adults The au-thors concluded that AFRS was more aggressive in childrenwith increased fungal load when compared with adults Theserum IgE levels were also found to be significantly higher inpediatric group suggesting a higher fungal load with in-creased sensitivity to fungal antigen in children TypicallyAFRS in children was less responsive to treatment with in-creased recurrence rates

Conclusions

AR is a common disease in childhood in industrialized coun-tries and it has a major impact on quality of life and healthcare

Fig 2 Practical algorithm based on different phenotypes of rhinosinusitisin children Abbreviations ARS acute rhinosinusitis CRS chronicrhinosinusitis URTI upper respiratory tract infections ABRS acute

bacterial rhinosinusitis RARS recurrent acute rhinosinusitis AFRSallergic fungal rhinosinusitis

68 Page 10 of 13 Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

1 Meltzer EO Hamilos DL Rhinosinusitis diagnosis and manage-ment for the clinician a synopsis of recent consensus guidelinesMayo Clin Proc 201186(5)427ndash43 httpsdoiorg104065mcp20100392

2 Wood RA Pediatric asthma JAMA 2002288(6)745ndash7 httpsdoiorg101001jama2886745

3 Bousquet J Van Cauwenberge P KhaltaevN et al Allergic rhinitisand its impact on asthma JAMA 2001108(5)S147ndash334 httpsdoiorg101034j1398-9995200223625

4 Borish L Allergic rhinitis systemic inflammation and implicationsfor management J Allergy Clin Immunol 2003112(6)1021ndash31httpsdoiorg101016jjaci200309015

5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

6 Tan YSL Hong CY Chong PN Tan ESL Lew YJ Lin RTPKnowledge that upper respiratory tract infection resolves on itsown is associated with more appropriate health-seeking behaviorand antibiotic cognition Singap Med J 200647(6)518ndash24

7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

9 Parker D Prince A Innate immunity in the respiratory epitheliumAm J Respir Cell Mol Biol 201145(2)189ndash201 httpsdoiorg101165rcmb2011-0011RT

Page 11 of 13 68Curr Allergy Asthma Rep (2020) 20 68

association between the number of aeroallergen sensitivitiesand the presence of atopic comorbidities with the subsequent

development of CRS suggesting that the severity of atopyalone may not be positively predictive of CRS development

Table 4 Clinical evidences linking allergy to chronic rhinosinusitis in children

Clinical evidences linking allergy to risk of CRS in children

AuthorYear(ref)

Type of article No of cases (meanage)

Methods Relevant results Association( L e v e l o fevidence)

Sedaghatet al2014[55]

Retrospectiveanalysis

N = 4044 childrenwith CRS(89 years)

Retrospective review of childrendiagnosed as uncomplicated CRSby an otolaryngology or allergyoffice evaluation

Comorbidities observed in CRS childrenwere primary ciliary dyskinesia (02)cystic fibrosis (41) immunologicdisorder (123) and AR (269)

Inconclusive(Level IV)

Choi et al2012[32]

Prospectivestudy

N = 296(lt 13 years)with recurrentRS

To evaluate predisposing factors forchronic and recurrent RS

The prevalence of AR atopy and asthmawas significantly higher in patients withCRS and recurrent RS than those withacute and subacute RS

Yes(Level II)

Anamikaet al2019[56bull]

Cross-sectionalstudy

N = 110 childrenwith CRS(7-18 years)

To determine atopic profile ofchildren with CRS and impact ofatopic status on disease severity andquality of life

Positive skin prick test was present in 527of patients Atopic CRS had a significanthigher mean Lund-Mackay endoscopicscore and symptoms scores thannon-atopic ones

Yes(Level IV)

Huang2000[57]

Prospectiveobservationalstudy

N = 413 RAchildren

(3ndash15 years)

To evaluate mold allergy as risk factorfor sinusitis

The authors compared 215 PAR with198 SAR

The prevalence of sinusitis was significantlyhigher among patients with PAR thanamong those with SAR regardless of ageor season patients with mold allergy PARhad a higher risk than those with non-moldallergy

Yes(Level II)

Leo et al2007[58]

Cross-sectionalstudy

N = 351 childrenwith CRS(523 plusmn211 years)

CRS underwent allergen sensitizationwork-up by skin prick test withcommon inhalant allergens andtotal IgE measurement

Prevalence of sensitization to aeroallergens inchildren with CRS is comparable with thatof the general pediatric population

No(Level IV)

Nathanet al2004[62]

Prospectiveobservationalstudy

N = 114 RA andCRS (childrenand adult)

Patients were surveyed for globalsymptoms and specific symptomsrelated to the nose sinuses eyesand chest with the SOQ

Immunotherapy is an effective treatment forpatients with sinus disease and allergicrhinitis

Yes(Level II)

RamadanampHiner-man2006[61]

Prospectiveobservationalstudy

N = 141 patientswho underwentESS (7 years)

To evaluate outcome of ESS at 1 yearafter the operation

Children with AR who were on treatmentbefore surgery had an 84 success ratecompared with 62 for those childrenwith non-treated AR by immunotherapy

Yes(Level II)

Kim et al2005[63]

Retrospectiveobservationalstudy

N = 97 patients(age range

5ndash15 years)

Retrospective analysis of long-termsuccess rates of ESS with respect toseveral predisposing factors

Multivariate logistic regression analysisallergy was not correlated to pooroutcomes after pediatric ESS

No(Level IV)

ElSharka-wy2012[64]

Prospectiveobservationalstudy

N = 87 children(45 with nasalallergy)(age le 14)

To assess predictive factors ofoutcome after ESS

The success rate in CRS with nasal allergywas 875 and in CRS without nasalallergy was 857

No(Level II)

Lee et al2009[66]

Retrospectiveanalysis

N = 53 childrenwho underwentFESS(age lt 18 years)

To investigate factors leading toprotracted nasal discharge afterpediatric endoscopic sinus surgery

Blood eosinophil count did not differsignificantly between the ldquoprotractedrdquo andthe ldquoresolvedrdquo groups On the other handhistory of allergic rhinitis was morefrequently observed in the ldquoprotractedrdquogroup

Yes(Level IV)

Wu et al2019[67bull]

Retrospectiveanalysis

N = 188 childrenESS for CRS

To evaluate prognostic factors relatedto revision surgery after ESS

Patients with positive aeroallergen tests hadhigher rates of CRS recurrence after ESSand required revision surgery

Yes(Level IV)

CRS chronic rhinosinusitis RS rhinosinusitis AR allergic rhinitis PAR perennial allergic rhinitis SAR seasonal allergic rhinitis SOQ sinusitisoutcome questionnaire ESS endoscopic sinus surgery FESS functional endoscopic sinus surgery

Page 9 of 13 68Curr Allergy Asthma Rep (2020) 20 68

These articles were not included in the qualitative analysesdue to the type of article

Impact of Allergy on Outcome of Chronic RhinosinusitisTreatment

Ramadan and Hinerman [61] in a retrospective study notedthat children with AR underwent to endoscopic sinus surgery(ESS) do not have a poorer outcome respect non-allergic oneNevertheless children with AR who were on immunotherapybefore surgery had an 84 success rate compared with 62for those children with AR who were not treated (p = 0022)Accordingly Nathan et al [62] using the sinusitis outcomesquestionnaire (SOQ) demonstrated that immunotherapy wasan effective treatment for patients with sinus disease and ARin both children and adults

About surgery outcomes Kim et al [63] and El Sharkawyet al [64] observed that functional endoscopic sinus surgery inchildren with CRS and AR does not provide significantlydifferent results compared with children without AR whichis similar to what has been reported in adults [65] On thecontrary in a study by Lee et al [66] a significantly greaterchance of protracted mucopurulent discharge after FESS wasregistered in patients with AR The authors assumed that theinflammatory process of nasal allergy which led to the devel-opment of CRS probably impaired the postoperative woundhealing by mucosal congestion poor-functioning mucociliaryclearance and recurrent sneezing that placed pressure on the

denuded mucosa An analogous conclusion was made by Wuet al [67bull] who demonstrated that pediatric patients with pos-itive aeroallergen tests had higher rates of CRS recurrenceafter ESS and required revision surgery

Allergic Fungal Rhinosinusitis (AFRS) in Children

AFRS is also present in the pediatric age group and it shouldbe considered a differential in children presenting with nasalpolyposis along with the other causes like ciliary dysmotilitydisorders and cystic fibrosis [68] There is paucity of data inliterature regarding nature clinical course and its recurrencein children and it was not possible to perform a qualitativeanalysis Patro et al [69] in a single center prospective studycompared features of AFRS in children with adults The au-thors concluded that AFRS was more aggressive in childrenwith increased fungal load when compared with adults Theserum IgE levels were also found to be significantly higher inpediatric group suggesting a higher fungal load with in-creased sensitivity to fungal antigen in children TypicallyAFRS in children was less responsive to treatment with in-creased recurrence rates

Conclusions

AR is a common disease in childhood in industrialized coun-tries and it has a major impact on quality of life and healthcare

Fig 2 Practical algorithm based on different phenotypes of rhinosinusitisin children Abbreviations ARS acute rhinosinusitis CRS chronicrhinosinusitis URTI upper respiratory tract infections ABRS acute

bacterial rhinosinusitis RARS recurrent acute rhinosinusitis AFRSallergic fungal rhinosinusitis

68 Page 10 of 13 Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

1 Meltzer EO Hamilos DL Rhinosinusitis diagnosis and manage-ment for the clinician a synopsis of recent consensus guidelinesMayo Clin Proc 201186(5)427ndash43 httpsdoiorg104065mcp20100392

2 Wood RA Pediatric asthma JAMA 2002288(6)745ndash7 httpsdoiorg101001jama2886745

3 Bousquet J Van Cauwenberge P KhaltaevN et al Allergic rhinitisand its impact on asthma JAMA 2001108(5)S147ndash334 httpsdoiorg101034j1398-9995200223625

4 Borish L Allergic rhinitis systemic inflammation and implicationsfor management J Allergy Clin Immunol 2003112(6)1021ndash31httpsdoiorg101016jjaci200309015

5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

6 Tan YSL Hong CY Chong PN Tan ESL Lew YJ Lin RTPKnowledge that upper respiratory tract infection resolves on itsown is associated with more appropriate health-seeking behaviorand antibiotic cognition Singap Med J 200647(6)518ndash24

7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

9 Parker D Prince A Innate immunity in the respiratory epitheliumAm J Respir Cell Mol Biol 201145(2)189ndash201 httpsdoiorg101165rcmb2011-0011RT

Page 11 of 13 68Curr Allergy Asthma Rep (2020) 20 68

These articles were not included in the qualitative analysesdue to the type of article

Impact of Allergy on Outcome of Chronic RhinosinusitisTreatment

Ramadan and Hinerman [61] in a retrospective study notedthat children with AR underwent to endoscopic sinus surgery(ESS) do not have a poorer outcome respect non-allergic oneNevertheless children with AR who were on immunotherapybefore surgery had an 84 success rate compared with 62for those children with AR who were not treated (p = 0022)Accordingly Nathan et al [62] using the sinusitis outcomesquestionnaire (SOQ) demonstrated that immunotherapy wasan effective treatment for patients with sinus disease and ARin both children and adults

About surgery outcomes Kim et al [63] and El Sharkawyet al [64] observed that functional endoscopic sinus surgery inchildren with CRS and AR does not provide significantlydifferent results compared with children without AR whichis similar to what has been reported in adults [65] On thecontrary in a study by Lee et al [66] a significantly greaterchance of protracted mucopurulent discharge after FESS wasregistered in patients with AR The authors assumed that theinflammatory process of nasal allergy which led to the devel-opment of CRS probably impaired the postoperative woundhealing by mucosal congestion poor-functioning mucociliaryclearance and recurrent sneezing that placed pressure on the

denuded mucosa An analogous conclusion was made by Wuet al [67bull] who demonstrated that pediatric patients with pos-itive aeroallergen tests had higher rates of CRS recurrenceafter ESS and required revision surgery

Allergic Fungal Rhinosinusitis (AFRS) in Children

AFRS is also present in the pediatric age group and it shouldbe considered a differential in children presenting with nasalpolyposis along with the other causes like ciliary dysmotilitydisorders and cystic fibrosis [68] There is paucity of data inliterature regarding nature clinical course and its recurrencein children and it was not possible to perform a qualitativeanalysis Patro et al [69] in a single center prospective studycompared features of AFRS in children with adults The au-thors concluded that AFRS was more aggressive in childrenwith increased fungal load when compared with adults Theserum IgE levels were also found to be significantly higher inpediatric group suggesting a higher fungal load with in-creased sensitivity to fungal antigen in children TypicallyAFRS in children was less responsive to treatment with in-creased recurrence rates

Conclusions

AR is a common disease in childhood in industrialized coun-tries and it has a major impact on quality of life and healthcare

Fig 2 Practical algorithm based on different phenotypes of rhinosinusitisin children Abbreviations ARS acute rhinosinusitis CRS chronicrhinosinusitis URTI upper respiratory tract infections ABRS acute

bacterial rhinosinusitis RARS recurrent acute rhinosinusitis AFRSallergic fungal rhinosinusitis

68 Page 10 of 13 Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

1 Meltzer EO Hamilos DL Rhinosinusitis diagnosis and manage-ment for the clinician a synopsis of recent consensus guidelinesMayo Clin Proc 201186(5)427ndash43 httpsdoiorg104065mcp20100392

2 Wood RA Pediatric asthma JAMA 2002288(6)745ndash7 httpsdoiorg101001jama2886745

3 Bousquet J Van Cauwenberge P KhaltaevN et al Allergic rhinitisand its impact on asthma JAMA 2001108(5)S147ndash334 httpsdoiorg101034j1398-9995200223625

4 Borish L Allergic rhinitis systemic inflammation and implicationsfor management J Allergy Clin Immunol 2003112(6)1021ndash31httpsdoiorg101016jjaci200309015

5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

6 Tan YSL Hong CY Chong PN Tan ESL Lew YJ Lin RTPKnowledge that upper respiratory tract infection resolves on itsown is associated with more appropriate health-seeking behaviorand antibiotic cognition Singap Med J 200647(6)518ndash24

7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

9 Parker D Prince A Innate immunity in the respiratory epitheliumAm J Respir Cell Mol Biol 201145(2)189ndash201 httpsdoiorg101165rcmb2011-0011RT

Page 11 of 13 68Curr Allergy Asthma Rep (2020) 20 68

resources Improving the understanding of the pathophysiol-ogy of allergy and relationship with its comorbidities is im-portant to correctly develop timed preventive measures as wellas perform adequate monitoring and treatment of childrenwith rhinitis The correct management of allergic diseasescan in fact decrease the inflammatory response and mostlikely lead to better control of comorbidities We summarizedin a practical algorithm our conclusions per phenotype ofrhinosinusitis in order to elucidate when prompt accurate di-agnosis and treatment of allergy is recommended (Fig 2)

Our qualitative analyses demonstrated that there isclear evidence from the lab of a link between allergyand an overall impairment of mechanical and immunolog-ical defense function of nasal mucosa against virusesClinical studies support the hypothesis of a positive asso-ciation between allergy and viral ARSURTI and onlylow-quality retrospective studies reached conflicting re-sults Proof of this is the existence of high-quality inves-tigations showing that anti-allergy treatments may signif-icantly decrease the number and severity of URTI includ-ing common colds We did not find any articles investi-gating specifically the link between allergy and upper air-way involvement by the new coronavirus in children

Current experimental and clinical experience does not sup-port an etiological link between allergy and post-viralrhinosinusitis ABRS and RARS At the moment anti-allergy treatments are not advised in these phenotypes eventhough well design high-quality studies are required to im-prove our knowledge in this field reaching firm conclusions

Despite the growing knowledge related to allergy and CRSin children it is not yet clear whether AR may promote CRSor if they only share a common pathway of pathogenesisEven if AR has been positively associated with CRS in severalexperimental and clinical studies in children conflicting re-sults have also been reported probably because of discrepan-cies in definitions of the disease processes for both CRS andAR and allergy testing methodologies Researchers have useda variety of techniques to document the presence of sinusitissuch as patient surveys radiography CT scan rhinoscopyand routine physical examination and therefore the resultsmay not reflect homogeneous populations In addition exper-imental studies and radiological assessment are oftenprevented by local ethical committees in the pediatric popula-tion for comprehensible reasons Furthermore the evidencesupports the hypothesis that CRS in children over the age of13 seems to be more frequently associated with eosinophilicinflammation whereas in younger patients with CRS neutro-philic inflammation is often observed [8 9] We did not findinvestigations analyzing the impact of allergy on CRS basedon age and we believe that more data from large epidemio-logical studies using explicit criteria is needed

Although there is no proof of causation several studiessuggested that evaluation of underlying allergies in CRS

children is equally recommended at least to exclude allergyas a concomitant disease and to improve control of symptomsavoiding exposure to known allergens and promoting allergytherapies Future studies are needed to confirm that anti-allergy treatment may improve outcomes of endoscopic sinussurgery for CRS in children

We finally believe that authors that will face with this topicin the near future should prefer prospective studies includingmultiple evaluations and paying particular attention to the dif-ferent phenotypes of rhinosinusitis in children

Compliance with Ethical Standards

Conflict of Interest This research did not receive any specific grant fromfunding agencies in the public commercial or not-for-profit sectors Theauthors do not have any conflicts of interests to declare

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors

References

Papers of particular interest published recently have beenhighlighted asbull Of importancebullbull Of major importance

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5 Fokkens WJ Lund VJ Hopkins C Hellings PW Kern R ReitsmaS et al European position paper on rhinosinusitis and nasal polyps2020 Rhinology 202058(Supplement 29)1ndash464 httpsdoiorg104193Rhin20600

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7 Garcia ML Rey CC Del Rosal Rabes T Pediatric asthma and viralinfection Arch Bronconeumol 201652(5)269ndash73 httpsdoiorg101016jarbr201603010

8 Larsen JM Brix S Thysen AH Birch S Rasmussen MA BisgaardH Children with asthma by school age display aberrant immuneresponses to pathogenic airway bacteria as infants J Allergy ClinImmunol 2014133(4)1008ndash13 httpsdoiorg101016jjaci201401010

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21 Kvaeligrner KJ Tambs K Harris JR Mair IW Magnus P Otitis me-dia relationship to tonsillitis sinusitis and atopic diseases Int JPediatr Otorhinolaryngol 199635(2)127ndash41 httpsdoiorg1010160165-5876(95)01299-0

22 Suumltccediluuml M Acar M Aktuumlrk H Hanccedilerli-Toumlruumln S Salman N SomerA Recognizing immunodeficiency in children with recurrent infec-tions What are the predictive factors The Turk J Pediatr201658(6)609ndash15 httpsdoiorg1024953turkjped201606006

23 Ciprandi G Tosca M Passalacqua G Canonica GW Ricca VLandi M Continuous antihistamine treatment controls allergic in-flammation and reduces respiratory morbidity in children with miteallergy Allergy 199954(4)358ndash65 httpsdoiorg101034j1398-9995199900920x

24bullbull Barberi S Bernardo L DAuria E Ferrara F Tosi S Incorvaia Cet al Allergen immunotherapy and respiratory infections in chil-dren an encouraging experience Minerva Pediatr 201870(1)1ndash4httpsdoiorg1023736s0026-49461604394-2 The authorsdemonstrated that 3 year high-dose HDM-SLIT significantlyreduced respiratory infections in children with allergic rhinitis

25 Barberi S Ciprandi G Verduci E Effect of high-dose sublingualimmunotherapy on respiratory infections in children allergic tohouse dust mite Asia Pac Allergy 20155(3)163ndash9 httpsdoiorg105415apallergy201553163

26 Chow AW Benninger MS Brook I Brozek JL Goldstein EJHicks LA et al Infectious Diseases Society of America IDSAclinical practice guideline for acute bacterial rhinosinusitis in chil-dren and adults Clin Infect Dis 201254(8)72ndash112 httpsdoiorg101093cidcis370

27 Lin SW Wang YH Lee MY Ku MS Sun HL Lu KH et alClinical spectrum of acute rhinosinusitis among atopic andnonatopic children in Taiwan Int J Pediatr Otorhinolaryngol201276(1)70ndash5 httpsdoiorg101016jijporl201110002

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29 Alho OP Karttunen TJ Karttunen R Tuokko H Koskela MSuramo I et al Subjects with allergic rhinitis show signs of moreseverely impaired paranasal sinus functioning during viral coldsthan nonallergic subjects Allergy 200358(8)767ndash71 httpsdoiorg101034j1398-9995200300252

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trafficking and symptoms in chronic sino-nasal eosinophilic inflam-mation Rhinology 201149(2)174ndash9 httpsdoiorg104193rhino10133

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51 Sedaghat AR Phipatanakul W Cunningham MJ Atopy and thedevelopment of chronic rhinosinusitis in children with allergic rhi-nitis J Allergy Clin Immunol Pract 20136(1)689ndash691e2

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53 Chandy Z Ference E Lee JT Clinical Guidelines on ChronicRhinosinusitis in Children Curr Allergy Asthma Rep201919(2)14 httpsdoiorg101007s11882-019-0845-7

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55 Sedaghat AR PhipatanakulW CunninghamMJ Prevalence of andassociations with allergic rhinitis in children with chronicrhinosinusitis Int J Pediatr Otorhinolaryngol 201478(2)343ndash7httpsdoiorg101016jijporl201312006

56bull Anamika A Chakravarti A Kumar R Atopy and quality of life inpediatric chronic rhinosinusitis Am J Rhinol Allergy 201933(5)586ndash90 httpsdoiorg1011771945892419854266 The authorsdemonstrated that atopic children with chronic rhinosinusitishad a significant higher mean Lund-Mackay endoscopic scoreand symptoms scores than non-atopic ones

57 Huang SW The risk of sinusitis in children with allergic rhinitisAllergy Asthma Proc 20002185ndash8 httpsdoiorg102500108854100778250905

58 Leo G Piacentini E Incorvaia C Consonni D Frati F Chronicrhinosinusitis and allergy Pediatr Allergy Immunol 20071819ndash21 httpsdoiorg101111j1399-3038200700626x|

59 Gelardi M Marchisio P Caimmi D Incorvaia C Albertario GBianchini S et al Pathophysiology favoring factors and associat-ed disorders in otorhinosinusology Pediatr Allergy Immunol2012235ndash16 httpsdoiorg101111j1399-3038201201323

60 Sedaghat AR Phipatanakul W Cunningham MJ Characterizationof aeroallergen sensitivities in children with allergic rhinitis andchronic rhinosinusitis Allergy Rhinol (Providence) 20145(3) ar-2014 httpsdoiorg102500ar201450102

61 Ramadan HH Hinerman RA Outcome of endoscopic sinus sur-gery in children with allergic rhinitis Am J Rhinol 200620(4)438ndash40 httpsdoiorg102500ajr2006202879

62 Nathan RA Santilli J Rockwell W Glassheim J Effectiveness ofimmunotherapy for recurring sinusitis associated with allergic rhi-nitis as assessed by the Sinusitis Outcomes Questionnaire AnnAllergy Asthma Immunol 200492(6)668ndash72 httpsdoiorg101016S1081-1206(10)61435-4

63 Kim HY Dhong HJ Chung SK Chung YJ Min JY Prognosticfactors of pediatric endoscopic sinus surgery Int J PediatrOtorhinolaryngol 200569(11)1535ndash9 httpsdoiorg101016jijporl200504010

64 El Sharkawy AA Elmorsy SM Eladl HM Functional endoscopicsinus surgery in children predictive factors of outcome Eur ArchOtorhinolaryngol 2012269(1)107ndash11 httpsdoiorg101007s00405-011-1680-1

65 Robinson S Douglas R Wormald PJ The relationship betweenatopy and chronic rhinosinusitis Am J Rhinol 200620(6)625ndash8httpsdoiorg102500ajr2006202907

66 Lee TJ Liang CW Chang PH Huang CC Risk factors forprotracted sinusitis in pediatrics after endoscopic sinus surgeryAuris Nasus Larynx 200936(6)655ndash60 httpsdoiorg101016janl200902008

67bull Wu PW Huang CC Yang SW Huang Y Huang CC Chang PHet al Endoscopic sinus surgery for pediatric patients prognosticfactors related to revision surgery Laryngoscope 2020130(4)1051ndash5 httpsdoiorg101002lary28106 The authorsdemonstrated that pediatric patients with positiveaeroallergen tests had higher rates of CRS recurrence afterESS and required revision surgery

68 Thorp BD McKinney KA Rose AS Ebert CS Allergic fungalsinusitis in children Otolaryngol Clin N Am 201245(3)631ndash42httpsdoiorg101016jotc201203003

69 Patro SK Verma RK Panda NK Chakrabarti A Understandingpaediatric allergic fungal sinusitis is it more aggressive Int JPediatr Otorhinolaryngol 201579(11)1876ndash80 httpsdoiorg101016jijporl201508032

Publisherrsquos Note Springer Nature remains neutral with regard to jurisdic-tional claims in published maps and institutional affiliations

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