REVIEW

The role of nasal sprays or drops in nasal hygiene: a review of the evidence and clinical perspectives*

1 2 3 E. Santoro , P. Kalita , P. Novak Rhinology Online, Vol 4: 1 - 16, 2021 http://doi.org/10.4193/RHINOL/20.072 1 GSK Consumer Healthcare Company, Route de l’Etraz 2, 1260 Nyon, Switzerland 2 GSK Consumer Healthcare, 23 Rochester Park, 139234 Singapore *Received for publication: 3 GSK Consumer Healthcare, Hvězdova 1214/2a, 140 00 Praha 4, Czech Republic September 18, 2020 Accepted: December 26, 2020 Published: January 5, 2021

Abstract Background: This article provides, for the first time, a comprehensive view on everyday practice and evidence-based advice on the regular use of saline nasal sprays or drops to support nasal function and to help protect from airborne pollutants, pollens and viruses.

Method: An extensive literature search was conducted with PubMed, Google Scholar and national healthcare databases to iden- tify and summarise the evidence available to date on the role of saline nasal sprays or drops in nasal hygiene. Clinical perspectives from international respiratory specialists were included.

Results: Following the PubMed searches, twenty-three articles were assessed in adults and children using isotonic or hypertonic saline nasal sprays and drops, including five systematic reviews and 11 randomised controlled trials. Six national clinical guidance documents were included from the other database searches to give a total of 29 articles. The findings support that regular, daily use of saline nasal sprays or drops could provide relief from nasal symptoms in adults and children with upper respiratory tract infections or ; future studies are expected to demonstrate benefit following air pollutant exposure. No serious ad- verse events were reported. National guidance recommends daily nasal hygiene with saline sprays and drops, some from infancy.

Conclusion: Regular, daily use of saline or drops could reduce the effects of noxious stimuli in the nose, helping to support respiratory health.

Key words: Air pollution, nasal hygiene, pollen, saline nasal sprays or drops, respiratory viruses.

Introduction as congestion, rhinorrhoea and sneezing(3-5). Failure to clear Healthy humans are predominantly nose-breathing at rest(1). noxious stimuli from the upper respiratory system can lead to The nose and nasal mucosa play an essential role in maintaining an increased risk of infection or allergic response, and has been healthy airways by entrapping inhaled airborne aggressors such linked to long-term, chronic conditions of the lungs and other as pollutants, pollen and infectious viruses, as well as heating organs(3, 6). Thus, it is important to keep the nose functioning and humidifying inhaled air. This prevents irritation or damage effectively to control diseases of the lungs and support overall to delicate distal pulmonary tissues and allows the lungs to work health(2). efficiently(2). The rise in the levels of airborne pollutants, pollen and infectious Irritation of nasal mucosa by airborne aggressors can disrupt viruses around the world, as well as increasing numbers of pa- the functioning of the nose, and result in nasal symptoms such tients seeking advice on nasal symptoms and over-the-counter

1 Saline nasal sprays or drops and nasal hygiene

Figure 1. The flow chart of the literature review. The types of articles included systematic reviews, randomised controlled trials (RCTs), non-RCTs, observational studies, prospective and retrospective cohort studies, case control studies, cross-sectional studies and recommendations from respect- ed authorities. Studies involving patients with chronic respiratory infections or chronic diseases with respiratory features, such as cystic fibrosis, bron- chiolitis or those recovering from sinus surgery were excluded. Studies using larger volumes of saline nasal solutions (>5 mL) were excluded unless the comparator was a saline nasal spray or drops. In addition to PubMed, the following sources were searched for relevant references: World Health Organization reports, NICE Clinical Knowledge Summaries, the Cochrane Library, The Lancet Commissions, and guidelines for use of devices designed to reduce . Non-systematic searches of Google Scholar were conducted to retrieve grey literature and other sources of potential evi- dence. The full text of each potentially relevant study was evaluated to determine whether it met the inclusion and exclusion criteria for this review. Data from relevant studies were extracted and included year and country of study, sample size, study population, methodological quality, type of saline solution and device used as well as efficacy and safety outcomes.

treatments in community pharmacies, requires that healthcare Search strategy and selection criteria professionals possess the most recent and relevant knowledge A literature search was conducted to identify evidence on the to make appropriate recommendations. Here, saline nasal sprays role that saline nasal sprays and drops can play in nasal health and drops are evaluated as they offer convenience and ease of to inform expert advice for providers and patients. PubMed and use, which may increase patient acceptability and compliance Google Scholar were searched from 01 January 2000 to compared with high-volume nasal washes. 01 May 2020 using search terms relating to nasal saline sprays and drops, respiratory health and the airborne aggressors: air This review aims to: pollutants, pollen and viruses (Supplementary Table 1). These • Provide state-of-the-art information for healthcare profes- aggressors were evaluated knowing that: air pollutants are the sionals on the important, but often overlooked role that top environmental global threat to human health, pollen is the nose plays in protecting against the negative health im- the main aeroallergen causing respiratory and respira- pacts of exposure to airborne pollutants, pollen and viruses tory viral pathogens are the cause of most upper respiratory • Provide an evidence-based overview of the effective use of infections(7-9). Airborne bacteria were excluded as when infection saline nasal sprays and drops in adults and children is suspected it typically requires referral and follow-up, and • Share clinical perspectives and practical advice from treatment with prescription medicines may be indicated. The respiratory specialists on the use of saline nasal sprays and literature search was restricted to articles reporting findings in drops to support nasal health humans and written in the English language. The flow chart of • Identify remaining knowledge gaps and research directions the literature review is shown in Figure 1 and the search strategy for PubMed is shown in Supplementary Table 1. Additional articles are cited in this review to articulate the most recent

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Table 1. Critical functions of the nose.

Physiology and physical attributes of the nose and its function

Warming, humidifying and cleansing/filtering the air to prepare it for delivery to the lungs

Trapping large particles with the nose hairs and small particles via mucous membranes

Regulating the direction and velocity of the air stream via shelf-like bony structures in the nose (the turbinates) – this maximises exposure of inhaled air to the vasculature and nerves, as well as the mucous blanket to facilitate clearance of noxious stimuli

Slowing the air stream also allows mixing of the air with NO produced in the nasal sinuses; NO is a vasodilator and bronchodilator that increases oxygen transport throughout the body

Increasing oxygen uptake; nose breathing imposes ~50% more resistance to the air stream than mouth breathing, resulting in 10–20% more oxygen uptake and maintaining the elasticity of the lungs

Retaining some moisture from exhaled air, preventing nasal dryness Figure 2. The nasal mucosa and mucociliary clearance. Specialised cells lining the are covered by up to 200 hair-like microprojec- NO, nitric oxide. tions, termed cilia. Motile microtubules in cilia enable them to move rhythmically in one direction within the that bathes the inside of This protective role can be compromised by exposure to airbor- the nose(12, 13). The synchronised movement of cilia propels mucus, along ne aggressors, leading to inflammation of the nasal membrane with captured particles such as air pollutants and pollen, to the back and nasal congestion that can impair mucociliary function(13, 18, of the nasopharynx, where they can be swallowed or coughed up(12, 13). 19). Trapped particles, pollens and pathogens spend longer in the Mucociliary clearance of insoluble particles concludes after nose, which further increases the risk of inflammation, damage 24 hours of deposition in the healthy nose(15). Mucociliary transport time and symptoms of nasal congestion, rhinorrhoea and sneezing(2, ranges from 1–10 mm per hour in different regions of the nose, and is 19). These symptoms can negatively impact quality of life (QoL), dependent on the number of ciliated cells, length of cilia, ciliary beat fre- causing reduced productivity, sleep deprivation, low mood, ir- quency and mucus viscosity(11, 12). Mucociliary clearance is a vital process. ritability and fatigue(20-24). Nasal airway inflammation can activate Airborne aggressors may impair cilia activity and can lead to symptoms the systemic immune response making the lower airway more such as a congested or runny nose and potentially wider effects on the prone to severe inflammation(2). Other systemic health effects airways or distal organs(3, 8, 13, 16, 17). have been linked to exposure to airborne aggressors and are illustrated in Figure 3. understanding around the physiology and function of the nose, Certain populations, including young children, people with the impact of airborne aggressors and to provide an overview of existing conditions such as asthma, COPD or heart disease, older nasal saline irrigation solutions and delivery devices. people and pregnant women, are more at risk than others from the effects of airborne aggressors(4, 30-32). Results and discussion Anatomy, function and protective role of the nose Maintenance of nasal health The respiratory tract is exposed daily to various airborne ag- Individuals should be advised to minimise their exposure to gressors with the constant threat of airway inflammation and airborne aggressors, where possible. Clear guidance is available infection(10). The respiratory system uses several defence me- on personal strategies that can help providers, patients and the chanisms against inhaled pathogens and particulates, including public minimise daily exposure to air pollution to benefit respi- cough clearance, anatomical barriers, aerodynamic changes and ratory health(33). Guidance exists to help minimise exposure to immune mechanisms(2, 3). Critically, the first line of defence is the allergens such as pollen(34, 35) and the WHO has further updated nose. By cleaning the air we breathe, the nose provides a natural its advice on minimising exposure to respiratory viruses in the barrier to prevent potentially harmful airborne aggressors from context of the COVID-19 pandemic(36). entering the body and causing harm(2). Mechanical separation of the largest airborne particles (>3 µm) occurs in the vestibule It may not always be feasible to avoid exposure to airborne and nasal valve area. Smaller particles (0.5–3 µm) are deposited aggressors(37, 38). Providing information on the role of the nose in on the nasal mucosa and filtered by mucociliary transport(11-13), protecting health, and education on how to care for the nose, described in Figure 2. Highly water-soluble components are may reduce the negative effects of airborne aggressors. Saline ‘scrubbed’ from inhaled air by the nasal mucous layer(3, 11, 14). nasal solutions are available over the counter and can be used alone or as an adjunct to other therapies such as intranasal Keeping the nose clear, clean and moisturised is vital for it to steroids and oral antihistamines to reduce the effect of airborne carry out its functions to protect health, as shown in Table 1(2). aggressors in the nose and to improve nasal health(39, 40).

3 Saline nasal sprays or drops and nasal hygiene

Figure 3. The nose plays a critical role in our body’s response to airborne aggressors. Nasal airway inflammation can reduce mucociliary clearance(3, 8, 13, 17) and activate the systemic immune response making the lower airway more prone to severe inflammation(2). Pollens are some of the most com- mon precipitants of an allergic response mounted by the nasal epithelium(25, 26). Air pollutants can also induce inflammation in the nasal epithelium, activate various immunocompetent cells, and may aggravate pollen- or viral-induced damage of the nasal epithelium(27, 28). When they bypass the nose and reach the lower airways of sensitised people, they can induce allergic asthma, which can be life-threatening(4). Systemic health effects may include cardiovascular disease, stroke and gastrointestinal inflammatory diseases(6, 29). Viral pathogens reaching the lungs can cause secondary infec- tions such as pneumonia, bronchitis and bronchiolitis; these conditions can be severe or fatal(8).

The exact mechanism of action of saline nasal irrigation is un- There is some evidence in adults and children that tonicity of known; the general consensus is that benefits are primarily due the saline solution alters its efficacy, with hypertonic saline (HS) to mechanical intervention(41-46): solutions (>0.9% NaCl) associated with greater symptom impro- • Flushing out thick mucus, crusts, debris and airborne ag- vement and MCC than isotonic saline (IS) solutions (0.9% NaCl) gressors (38, 51, 52). In addition to a mechanical action in the nose, hypertoni- • Washing away inflammatory mediators, thus favouring city may reduce mucosal oedema due to osmotic pressure-indu- resolution of nasal symptoms ced water transport through the mucosal epithelial membrane, • Improving mucociliary clearance (MCC). thereby reducing nasal congestion and improving MCC(52).

Saline nasal sprays and drops Clinical effectiveness of saline nasal sprays and drops Saline can be administered to the nose in a small volume (less Based on the literature search findings, 29 articles were analysed than 5 mL per nostril) via spray devices that deliver a fine mist or to determine the clinical effectiveness of saline nasal sprays and jet of saline into the nose(40), low volume nebulisers (micronised drops. These articles comprised: 19 articles identified from the nasal douches) or via nasal drops that are often preferred for use PubMed searches, four articles identified from the Cochrane sys- with young children. Evidence suggests that nasal sprays effec- tematic reviews (three of which were published prior to the year tively reach the nasal cavity(47); this is important when targeting 2000) and six guidance documents identified from the other the nasal mucosa, whereas high-pressure and high-volume searches (Figure 1). The publications varied considerably with saline can penetrate sinus cavities(47). High-volume devices have regard to study design, number of subjects, study duration and been associated with a greater incidence of discomfort, burning, the parameters assessed. Despite the heterogeneity, a congru- and eustachian tube dysfunction as compared with low-volume ent trend in the findings could be established. devices(48). Nasal saline sprays offer convenience, acceptability and ease of use, all of which are likely to increase compliance(48, National guidelines and clinical summaries recommend the use 49). Among practising family physicians in the US who actively re- of saline nasal sprays or drops for nasal conditions as well as for commended saline nasal irrigation to their patients, nasal spray daily nasal hygiene, (some advise starting from birth), to support was the method of choice (recommended by 78%)(50). optimal nasal function. These are summarised in Table 2.

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Table 2. Guidelines and healthcare organisations that recommend use of saline nasal irrigation.

Reference Guideline Population Treatment Recommendations CHU Sainte-Justine. Healthcare guidance in From birth onwards IS (syringe, <2 years old) Daily nasal cleaning with saline Nasal hygiene, 2018(53) Canada Up to 10 mL* solutions is recommended from Minimum frequency: birth to eliminate secretions and Summer: Once daily small particles, thus reducing Winter: 2–3 times per day congestion. Cold/congestion: 3–6 times per A nasal spray can help acceptabi- day lity in older children. IS (spray, >2 years old) 5 sprays per nostril Minimum frequency: Summer: Once daily Winter: 2 times per day Cold/congestion: 3–4 times per day France Health Insu- Healthcare guidance in From birth onwards IS (vials, <6 months old) Daily nasal cleaning with saline rance. Nose wash in France IS (spray, >6 months old) solutions is recommended from children, 2019(54) birth to reduce congestion. National Institute National Institute for Children with rhinitis IS (sprays and drops) Use of nasal saline drops or spray for Health and Care Health and Care Excel- is recommended to help liquefy Excellence. Treatment lence mucous secretions in children summary: Rhinitis, with rhinitis, especially in infants 2019(55) before feeding. Scadding et al., 2017(56) British Society for Children with AR IS (sprays and wash) IS nasal irrigation in children with Allergy & Clinical Im- AR is well tolerated, inexpensive, munology easy to use with no evidence of adverse effect to health with regular use. Green et al., 2012(57) Allergic rhinitis in Children with AR Not stated Use of saline nasal preparations is South Africa strongly recommended in infants. National Institute National Institute for Adults and children IS (sprays and drops) Nasal saline drops may help for Health and Care Health and Care Excel- with relieve nasal congestion in some Excellence. Clinical lence people. Sterile sodium chloride Knowledge Summary: 0.9% nasal drops are available on Common Cold, 2016(58) prescription or over the counter. One or two drops applied to the nostrils of infants can help feeding.

*Premature: 1–3 mL per nostril, <6 months: 3–5 mL per nostril, >6 months: 5–10 mL per nostril. AR, allergic rhinitis; IS, isotonic saline.

Allergic rhinitis (AR) use, HS spray used 4 times per day significantly improved QoL Several small randomised controlled trials (RCTs) in adults and and symptom scores in adults with AR vs histamine alone(61). children with AR or rhinoconjunctivitis have demonstrated Addition of twice-daily HS nasal spray to intranasal corticoste- that use of HS nasal sprays 2–4 times per day improved nasal roid (INS) therapy provided a significant improvement in nasal symptoms and QoL vs no treatment or baseline(51, 59, 60), reduced symptoms in children compared with INS or saline alone(62).The antihistamine use(59, 60) and improved the efficacy of other topical key studies are summarised in Table 3. therapies(61, 62). According to the meta-analysis by Hermelingmei- er et al., the application of nasal saline via a small-volume spray Other benefits of nasal saline include its potential to reduce the was found to yield more distinct improvements in symptoms of use of nasal decongestants, which is important since they are AR than the use of nasal irrigation with larger volumes appropriate for use on a short-term basis only. In a cross-secti- (200–400 mL)(46). onal study of 895 adults self-medicating persistent rhinitis (AR or rhinosinusitis), the risk of intranasal decongestant overuse In adults and children with AR, clearing excessive nasal secre- was reduced with use of saline nasal solution (odds ratio: 0.61; tions and decreasing pre-existing oedema may improve the p<0.01), although the method of saline nasal delivery was not efficacy of topical therapies. When combined with antihistamine specified(65).

5 Saline nasal sprays or drops and nasal hygiene - - - No reported AEs in the saline groups No reported AEs in adults or children using nasal sprays well IS and HS were Saline nasal tolerated. reported be to sprays than accepted better other NSIs that No evidence daily SNI ad regular, the pa affects versely health or causes tient’s unexpected AEs AEs not reported wit patients Two AEs due to hdrew not group (treatment stated) Adverse effects Adverse ------from base from and and antihista . (p=0.01) in both adults and , being accepted and , being accepted appeared to have a positive a positive have to appeared (p=0.035) vs no treatment. (p=0.035) vs vs no SNI (p<0.1). vs SNI, including with sprays, may reduce reduce may SNI, including with sprays, disease severity with no SNI. with AR compared children improved SNI, including with sprays, and of AR in children local symptoms adults relie than IS in effective be more HS may in children. ving local symptoms SNI Overall, impact on QoL in the majority of children tolerated (78–100%). the most accepted was nasal spray Fine method of delivery symptoms Regular use of HS improved of AR in adults and children vs use in children antihistamine reduced with antihis combined When baseline. QoL and improved HS spray tamine use, in subjectssymptoms with AR. yielded nasal saline sprays Small-volume in symptoms distinctmore improvements (200–400 mL). volumes of AR than larger decreased significantly HS nasal spray nasal symptoms mine use worse in the no tre significantly was MCC baseline (p=0.011) but vs group atment suggesting group, not in the treatment elution of the allergen. HS SNI favoured clinically and signifi HS nasal spray symptoms improved cantly 23%. by line (p<0.0001); QoL improved with IS. improvement No significant Key findings Key - 1. Patient-reported 1. Patient-reported disease severity scores 1. Symptom and 1. Acceptability of SNI tolerance control 2. Symptom 3. QoL scores in 1. Improvement (sneezing, symptoms obstruction, itching, and secretion) 2. QoL 3. MCT 1. Nasal symptoms (rhinorrhoea, nasal blockage, nasal it ching and sneezing) use 2. Antihistamine 3. MCC 1. Rhinoconjunctivitis QoL score Primary clinical endpoint(s) SNI delivered by any any by SNI delivered means (including nasal and with any sprays) tonicity and volume, alkalinity delivery Various methods (including with any nasal sprays), frequency and duration delivery Various methods (including with any nasal sprays), frequency and duration delivery Various methods (including with any nasal sprays), frequency and duration spray, HS nasal aerosol one puff (0.13 mL) in both nostrils 3 times in 6 days for per day, season and 6 low-pollen in peak season days per sprays two HS spray, 3 times per day;nostril, aqueous triamcinolone each nostril 110 µg into daily;once IS spray, 3 per nostril, sprays two times per day Treatment protocol Treatment Five studies used nasal Five vs: sprays 1. No SNI 2. Other pharmacological treatments no SNI 1. SNI vs INS spray 2. SNI vs or oral 3. SNI + INS spray AH or oral INS spray AH vs HS 4. IS vs Various 1. HS or IS SNI 2. No treatment 3. Other treatment 1. HS SNI 2. No treatment as Rescue antihistamines, needed Nasal spray 1. HS (Dead Sea) triamcinolone 2. Aqueous 3. IS as a control Study groups Study Adults and Adults (aged children 2–15 years), (747 14 RCTs participants) up November to 2017 with RCTs adults and (aged children 12 3–16 years); articles (819 patients) 40 studies with (aged children (819 4–12 years) patients) (n>400) 10 RCTs in adults and (aged children 5–15 years) 40 adults with seasonal AR (pollen) 15 adults with seasonal AR (pollen) Population, Population, sample size* - - Cochrane syste Cochrane review matic Systematic and review meta-analysis December up to 2018 Systematic from review January 1946 to June 2015 Systematic and review meta-analysis 1994 to from 2010 RCT (two-arm, non-blinded, single-centre, parallel-group) periwith two ods of 6 days each RCT (three-arm, single-blinded, parallel-group, with 7-day of duration and treatment follow-up) Study design Study - (59) (40) (63) (49) (46) (51) Head et al., Head et al., 2018 et al., Wang 2020 Gutierrez- et al., Cardona 2017 Hermeling meier et al., 2012 et Di Berardino 2017 al., et al., Cordray 2005 Reference Reference Table 3. Saline nasal irrigation and allergic rhinitis in children and adults. rhinitis in children 3. Saline nasal irrigation and allergic Table

6 Santoro et al. - - No AEs reported No AEs reported in the group treatment No AEs reported AEs not reported of INS with nasal Use well was saline spray in a paedia tolerated tric population Adverse effects Adverse - - for daytime and daytime for in combination with a in combination (p<0.05). at Weeks 4, 8, and 12 compared 4, 8, and 12 compared Weeks at after the 7th week in comparison in comparison after the 7th week Addition of HS nasal spray to antihis to of HS nasal spray Addition a significant provided tamine therapy additional benefit 4 (p≤0.05) Week at symptoms night-time (p≤0.02). and QoL of the patients significant Clinically and statistically reduction with HS nasal in symptoms spray with study start. was 5% less antihistamine On average nasal used during the period of regular irrigation. total in improvements Significant FP given in patients scores symptom + saline FP or saline (p<0.05). given with patients sleep questionnaire Mean paediatric before post-SNI vs decreased score treatment with rhinitis improved SNI in children of rhinitis, and signs nasal symptoms and their and quality of sleep children caregivers. with a saline Daily nasal irrigation tre adjuvant an effective was spray AR for atment dose of INS. reduced Key findings Key - - 1. Daytime and night- 1. Daytime score time symptom 2. QoL index rhinoma 3. Acoustic nometry 1. Nasal and ocular score symptom as 1. Disease severity, patient- by measured reported nasal symp assessed on score tom scale (nasal a 4-point rhinorrhoea, itching, nasal obstruction and sneezing) 1. Mean paediatric sleep questionnaire score Clinical symptoms score Primary clinical endpoint(s) 10 mg of cetirizine 10 mg of cetirizine daily with and without 4 times HS nasal spray per day per sprays 3% HS, three nostril (50 μL per spray) 3 times per day 4 200 μg FP daily for then 100 μg weeks, then 4 weeks daily for 4 weeks; 50 μg daily for of HS, twice 4–6 sprays FP + 12 weeks; for a day both as above HS spray, 12 weeks for per sprays 0.9% IS, two for twice a day nostril, by followed 20 days for 1% HS, twice a day was Treatment 10 days a period of for repeated 6 months Saline nasal spray Treatment protocol Treatment -

(62) 1. 10 mg cetirizine with HS 1. 10 mg cetirizine nasal spray 2. 10 mg cetirizine 1. 3% HS 2. No treatment 1. FP nasal spray nasal spray 2. HS (seawater) + HS 3. FP nasal spray nasal spray (seawater) 1% HS by 0.9% IS followed post-treatment Pre- vs Chen Only the study by na included HS (seawater) in the treatment sal spray arm Study groups Study - - 14 adults with AR (pollen) 40 children (aged 9.1 ± with 2.5 years) seasonal rhino conjunctivitis (pollen) with 61 children AR (mode severe); to rate mean age 6 (range years 2–15 years) 49 children (aged 3–6 with years) rhinitis studies in Two with children AR (aged 2–15 (101 years) subjects) Population, Population, sample size* - RCT (two-arm, non-blinded, parallel-group, with 4-week of duration and treatment follow-up) RCT (two-arm, non-blinded, parallel-group, with 7-week of duration and treatment follow-up) RCT (three-arm, non-blinded, parallel-group, with 12-week of duration and treatment follow-up) Observational, retrospective study re Literature 2008 view from Octoberto 2015 Study design Study (61) (60) (62) (64) (37) Rogkakou et al., 2005 et al., Garavello 2005 Chen et al., 2014 et al., Marcuccio 2019 Madison et al., 2016 Reference Reference *Number of subjects included in analysis, where known. where *Number of subjects included in analysis, mucociliary clear mucociliary MCT, clearance; saline; MCC, IS, isotonic corticosteroid; HS, hypertonic saline; INS, intranasal fluticasone propionate; rhinitis; FP, AR, allergic AH, antihistamine; effect; adverse AE, SNI, saline nasal irrigation. trial; RR, risk ratio; controlled randomised RCT, time; QoL, qualityance of life;

7 Saline nasal sprays or drops and nasal hygiene - No serious AEs; minor nasal discomfort reported was by a minority of subjects subjects due withdrew Two nasal drynessto during No period. the nasal spray serious AEs reported group, In the HS nasal spray 32% of subjects bur noted 13% in the IS group ning vs (p=0.05) AEs not reported No serious AEs reported; discomfort associated was rate with the higher flow than the of the jet rather saline solution or spray Adverse effects Adverse . ------

IS nasal spray norma IS nasal spray (mean 6.4 days) vs the observation vs (mean 6.4 days) S micronised nasal spray, but not nasal nasal spray, S micronised NSI (liquid, drops or spray) may improve improve may or spray) drops NSI (liquid, URTIs. of acute symptoms the number reduced Daily use of IS spray and/or bloc with nasal secretion of days nose ked p=0.027); 40% symp period (mean 11 days; Subjects use. had reduction with spray tom a mean of 0.7 episodes URTI during the 1.0 episode during period observa vs spray tion only (p=0.05). had an effect Neither saline preparation of nasal symptoms or severity on duration control. with no treatment compared duration the length of treatment However, not recorded. was I and expira inspiratory improved lavage, (p<0.01) tory rhinomanometric resistance rhinometry) (acoustic and nasal volumes baseline. (p<0.001) vs (p<0.001) level lised MCT a physiological to (p<0.001) vs scores symptom and reduced baseline. using IS children illness, During acute of resolution faster and jet) showed (spray and obstruction,nasal secretion improve common for score in health status ment and reduction in nasal decongestant cold, use (all p<0.05) medication and mucolytic was control and jet) vs 8, IS (spray Week By and nasal secretions with reduced associated nasal obstruction (p<0.05); less use of other (31% illness days (p<0.05); fewer medications 35%), and (15% vs 75%), school absences vs 32%) (all p<0.05). (8% vs complications Key findings Key - - - - 1. Symptom relief relief 1. Symptom resolu to Time 2. tion of symptomatic illness via 1. Symptoms diarypatient 1. Nasal symptom (nasal con score gestion, rhinorrhoea and headache) 1. Inspiratory and expiratory rhinoma nometric resistance rhino 2. Acoustic metry 3. MCT 4. Nasal symptoms score 1. Nasal symptom score 2. Nasal breathing score score 3. Health status assessed) (physician 4. Other medication use Primary clinical endpoint(s) - SNI delivered by by SNI delivered means and with any tonicity volume, any and alkalinity IS saline spray three (twice daily, per nostril) puffs HS or IS nasal spray two 3 times per day, squirts per nostril symptom until resolution spray, IS micronised for 4 times per day IS lavage 15 days; (via a 20 mL syringe) IS via a fine spray or medium jet, 6 times per day illness during acute phase and 3 times during the per day phase; preventative larger were volumes than typical aeroso lised sprays Treatment protocol Treatment - - Topical nasal sa Topical (liquid, line treatment vs: or spray) drops 1. Routine care 2. Other nose sprays 1. IS nasal spray 2. No treatment (pick 1. HS nasal spray ling salt and baking soda) 2. IS nasal spray 3. No treatment spray 1. IS micronised 2. IS lavage + treatment Standard delivery IS via different methods: 1. Medium jet flow spray 2. Fine and nose wash 3. Eye with a fine spray treatment 4. Standard only (control) Study groups Study - Adults and Adults (3 children 12 to weeks RCTs five years), (749 partici up to pants) 2014 August 60 adult males with URTI symptoms 119 adults with URTI 200 adults viral with acute rhinosinusitis cold) (common 390 children (aged 6–10 with URTI years) cold (common or flu) Population, Population, sample size* - - - - Cochrane syste Cochrane review matic RCT (crossover 10 weeks study, of treatment, of 2 weeks and washout of 10 weeks observation) RCT (three-arm, 1 year) over RCT (two-arm non-blinded, parallel-group, with 15-day of duration treatment) RCT (multicen open-label, tre, treat 3-week phase ment by followed preven 9-week tion phase) Study design Study (39) (72) (70) (71) (66) King et al., King et al., 2015 & Tano, Tano 2004 et al., Adam 1998 et al., Passali 2005 Šlapak et al., 2008 Reference Reference Table 4. Saline nasal irrigation tract and upper respiratory infection. Table

8 Santoro et al. - No difference in nasal blee No difference no treatment ding between groups and treatment (p>0.05) 6/15 subjects did not with treatment tolerate 7/16 did saline nasal drops; with treatment not tolerate drops phenylephrine Crying and nasal bleeding reported in both were resolved mild, were groups, not and considered rapidly Two treatment. to related reported serious AEs were not related and considered treatment to AEs not reported Adverse effects Adverse - - to their pa to (p>0.05); no after 10 days of after 10 days Both HS and IS nasal drops improved nasal improved Both HS and IS nasal drops and rhinorrhoea congestion HS and IS between difference significant groups. improved were Sleep quality and feeding groups no treatment vs in both treatment (p<0.001). with improved Subjects groups in all three and the IS group between no difference endpoint. any for group the no treatment reporting only mean incomplete, were Data baseline and follow- at each group for scores varying with baseline scores later, up 2 days considerably. improved significantly Both treatments and other up breathing, rhinorrhoea, oral symptoms per respiratory not reported). baseline (p value vs treatment decreased and IS drops of nasal aspirator Use IS drops the number of EOM episodes vs alone (p<0.05). in the 90% of practising family physicians SNI USA actively recommended nasal conditions; upper respiratory for tients recommended the most frequently was spray method (78%). Key findings Key - 1. Nasal symptom 1. Nasal symptom scores 1. Nasal symptom score 2. Respiratory symp severity tom 3. Activity signs 1. Clinical assessment NA Primary clinical endpoint(s) - - - Daily instillation of Daily instillation use HS or IS drops; or of nasal aspirator al nasal pumps was in all groups lowed drops four IS drops, per nostril every 2 hours as needed; phenylephrine 4 drops four drops, ≤ 3 days times a day then IS Aspirator then a sub drops, aspiration, sequent ≥3 times per day feeding; and before ≥3 times IS drops, and before per day feeding Electronic question naire Treatment protocol Treatment 1. HS (2.3%) nasal drops 2. IS (0.9%) nasal drops 3. No intervention (0.9%) 1. IS drops 2. Phenylephrine (0.25%) drops 3. No treatment and 1. Nasal aspirator IS drops 2. IS drops NA Study groups Study - Children with Children URTI (aged <2 years) 46 children (aged 3 weeks with 2 years) to URTIacute 435 children (aged 2 months with 2 years) to of symptoms cold common 330 practising family physici ans in the USA Population, Population, sample size* - RCT (double- blind study) RCT (2-day duration) Observati non- onal, interventional, prospective, comparative, cohort study for over 5 months the common season cold Survey Study design Study (68) (69) (67) (50) Koksal et al., Koksal et al., 2016 Bollag et al., 1984 Montanari et al., 2010 Rabago et al., 2009 Reference Reference *Number of subjects included in analysis, where known. where *Number of subjects included in analysis, trial; SNI, saline nasal irrigation; URTI, controlled randomised mucociliary time; NA, not applicable; RCT, clearance EOM, external effects; saline; MCT, adverse otitis media; HS, hypertonic saline; IS, isotonic AEs, tractupper respiratory infection.

9 Saline nasal sprays or drops and nasal hygiene

Acute upper respiratory tract infections Clinical perspective 1. Dr Glenis Scadding, MD Honorary Consultant Physician in Allergy and Rhinology at the Saline nasal sprays and drops probably improve symptoms of Royal National Throat, Nose and Ear Hospital, and Honorary Sen- acute upper respiratory tract infections (URTIs) such as the com- ior Lecturer at University College London, UK. (39) mon cold and rhinosinusitis . In a study of 390 children aged Washing the nose gently with saline helps to remove unwanted 6–10 years with URTI, use of IS delivered 6 times per day for substances, preventing allergic reactions and improving mucocili- ary function. The simplest way to do this is by using a sterile saline 3 weeks via fine spray or medium-strength jet resulted in signi- nasal spray: One or two puffs in each nostril, aimed at the inside of ficantly faster resolution of nasal secretion and obstruction, as the lateral nasal wall. Such treatment is suitable for all ages, even for well as reduced nasal decongestant and mucolytic medication pregnant women. A solution that is slightly hypertonic, or sterilised sea water, can give the best results in some people. The only people use. No serious adverse effects were reported; discomfort was for whom I do not suggest this are those with hypertension as they associated with the higher flow rate of the jet rather than the should not be taking in extra sodium. However, if necessary, they (66) could use the spray and then spit it out when it reaches the back of nasal saline solution or spray . the throat, rather than swallowing it. For a child over 4 years of age, being taught how to administer the spray and then being allowed to Nasal drops may be easier to administer for infants than nasal do it themselves is more likely to result in acceptance. sprays. Studies in children under 2 years old with symptoms My practice is to advise patients with seasonal allergic rhinitis to use of URTI have shown that daily use of HS or IS nasal drops, with saline sprays regularly – on waking, after exposure to allergens and pollutants, and on retiring. Coupled with avoidance of known al- and without nasal aspirator use, can significantly improve nasal lergens, this may be sufficient to give good symptom control. If this is symptoms vs baseline or no treatment(67, 68) leading to impro- not achieved, then pharmacotherapy such as an intranasal corticoste- vements in feeding and sleeping(68). Combined use of IS nasal roid can be added, at least 10 minutes after the saline. When rhinitis is perennial, a once- or twice-daily application can be employed to drops with aspiration of mucus may help avoid further compli- reduce symptoms and to clean the nose prior to intranasal cortico- cations such as ear infections(67), which are common in young steroid use. There is also evidence that daily nasal saline use reduces the likelihood of symptomatic colds. Therefore, for patients who suffer (58) children, occurring after approximately 20% of common colds . with frequent or debilitating colds, I suggest use of nasal saline after One small RCT in infants with URTI aged 3 weeks to 2 years using public transport or being in contact with several other people. found no difference in respiratory symptoms following 2 days of treatment with normal saline drops, phenylephrine drops or no treatment; a similar number of infants did not tolerate saline or Clinical perspective 2 Dr Gary Wong, MD (69) Professor, Department of Pediatrics and School of Public Health, phenylephrine drops . Chinese University of Hong Kong, Hong Kong. One should minimise exposure to various noxious stimuli, and this There are very few studies with well-defined inclusion criteria is particularly important for people with underlying nasal . that have examined saline nasal sprays and symptom relief for Nasal airway inflammation can also activate the systemic immune res- (70, 71) ponse making the lower airway more prone to severe inflammation adults with URTIs; those published report conflicting results . (one airway response). However, prophylactic use of IS saline nasal sprays for URTIs may be beneficial. A well-designed study of 60 adult males with URTI If we can wash the irritants away regularly with saline nasal spray, this will reduce the chance of the cells from the immune system reacting symptoms found that twice-daily use of an IS nasal spray for to these irritants and, thus, reduce nasal inflammation. Saline nose 10 weeks resulted in significantly fewer episodes of URTIs and drops/sprays are widely used in children of all age groups, from infants to adolescents, during episodes of URTI, exacerbations of al- fewer days with nasal symptoms compared with an observation lergic rhinitis, or irritation from exposure to air pollutants. (no intervention) phase(72). In a study of children with URTI, use of IS during a preventative phase (after 8 weeks of daily use of Saline nose drops/sprays may be of particular benefit for infants and young children who have smaller, less developed nasal passages than IS spray or jet) supported prophylactic use with significantly adults, meaning nasal congestion is very common. Infants are obliga- fewer illness days (31% vs 75%), school absences (15% vs 35%), tory nose-breathers and so blockage of nasal passages is of impor- tance, because it tends to impair their feeding and sleep. Nasal saline and complications (8% vs 32%) (p<0.05 for all) than the control sprays and drops can facilitate relief of the blockage prior to feeding group. There was higher parent satisfaction with IS use vs or sleeping, especially during episodes of URTI, and frequency of use is best matched to their feeding and sleeping schedule (i.e. around standard care(66). The studies are summarised in Table 4. 4–6 times per day). Note that URTIs in newborns are very uncommon and allergic rhinitis does not manifest so early in life. Therefore, a Further well-designed, sufficiently powered RCTs are warranted newborn (first 4–6 weeks of age) with symptoms suggestive of nasal blockage must be referred to a physician to rule out the possibility of in both adults and children to establish the place of saline nasal other congenital problems causing such symptoms. sprays as a standard intervention in acute URTI treatment and In general, nasal spray is simple to use and does not pose major dif- prevention. ficulties for most parents and caregivers. Side effects with saline nose drops/sprays are minimal to none. Isotonic solutions may be less irrita- Daily nasal hygiene in healthy individuals ting than hypertonic solutions in children and are often used to help clear thick secretions, washing away potential allergens and irritants The health benefits of daily nasal hygiene are well recognised (e.g. air pollutants). in infants and children(73-76) and regular, daily use of nasal saline

10 Santoro et al.

sprays or drops is recommended in several guidelines (Table 2). Clinical perspective 3. Dr Sundeep Salvi, MD, PhD in the health effects of air pollution. Pulmonologist, Pulmocare Research and Education (PURE) Foun- A large survey of primary care paediatricians in Italy revealed dation, India. that almost all of the respondents (99.3%) recommended use of In the same way that people brush their teeth every day to maintain saline nasal irrigation. It was considered both a prophylactic and their oral hygiene, encouraging regular, daily use of a saline nasal spray seems a logical step to support optimal nasal function. This a therapeutic measure by most respondents who prescribed it may be especially important for patients who present with nasal every day for healthy children and more frequently when they symptoms when air pollution or pollen levels are elevated, or during were ill. Most of the primary care paediatricians (87%) indicated the winter months. an isotonic solution as the preferred solution, and the most fre- Regular use of nasal saline is unlikely to be associated with adverse quently recommended administration device was a nasal spray. effects, meaning the potential for benefit far outweighs any risk. Thus, it appears to be an effective, inexpensive and well-tolerated treatment (75) IS was preferred for prophylaxis and HS for therapy . for different nasal ailments, and may help to prevent problems in healthy individuals exposed to everyday airborne aggressors. Further Studies in healthy adults have also shown significantly improved studies will help define the optimal volume, frequency and tonicity of the solutions used, which could then be tailored to the individual nasal function following the use of IS and HS nasal sprays(52, 77), patient’s needs. summarised in Table 5. With global levels of air pollution rising, increasing pollen counts and the omnipresent threat of a major respiratory viral outbreak, now Other benefits of daily nasal hygiene may include the following: more than ever, patients are seeking advice on everyday practical solutions to protect their health. In our recent review article, we • Helps clear inhaled airborne aggressors that can cause detail recommendations to assist healthcare providers when advising nasal congestion, allergies and sinus problems patients and the public regarding personal-level strategies to mitigate (33) • Improves MCC the risk imposed by air pollution to benefit respiratory health . Other strategies to consider include regular, daily nasal hygiene. • Thins excess mucus in the nose, which can help relieve nasal congestion and discomfort • Helps cleanse and hydrate nasal tissues, to prevent nasal dryness symptoms and QoL, as well as reduced antihistamine use, could • Improves the effectiveness of medicated nasal sprays, when be obtained using IS rather than HS nasal sprays. nasal saline is used first A pilot study in adults with acute URTI found that use of an Tolerability of saline nasal sprays and drops HS nasal wash and oral gargle significantly reduced duration Adults and children (aged 2–15 years) generally have minimal of illness, use of symptomatic medication, transmission to side effects from use of saline nasal sprays(40), with no evidence household contacts and viral shedding vs no intervention(81). In of adverse effect to health with regular use. No serious adverse a subgroup of patients with coronavirus infection, the interven- effects occurred in children aged 3 weeks to 2 years treated tion appeared likely to be effective in reducing symptoms and with IS nasal drops, although parents noted some babies had duration of the illness(82), suggesting nasal washes could play a difficulty with the drops(39). Intranasal saline is considered to be role in preventing and controlling the transmission of respira- a low-risk, and often effective, intervention during pregnancy(78). tory infectious pathogens, including severe acute respiratory Most people, including children, find saline nasal sprays useful syndrome coronavirus 2 (SARS-CoV-2). A larger study, powered and easy to use(49, 79). for clinical and virological endpoints to confirm these findings(81, 83), could be extended to include the use of HS nasal sprays to Transient adverse reactions, such as nasal irritation and nasal increase treatment acceptability and compliance. discomfort have been described(39). A systematic review and meta-analysis of HS use in children with AR found there was a hi- A limitation of this review is the small number of RCTs availa- gher rate of adverse effects in those using HS (4.5%) than those ble for evaluation as well as the heterogeneity of the available using IS (2.3%); this was not statistically significant (p=0.36)(38). studies regarding the amount, frequency and duration of nasal Side effects were more common (10–20% of the cases) when irrigation, the type of saline solution used and the range of very-high-volume devices were used(44). Patients should be outcome measures reported. The evidence suggests that saline advised to keep saline nasal spray and drop devices clean and to nasal sprays and drops improve nasal function and are easy to not share them with others to avoid potential contamination(80). use, with no evidence of adverse effect to health with regular use. High-quality, adequately powered research into their use Areas for further research for daily hygiene in both adults and children is warranted, par- Few RCTs have evaluated the use of IS nasal spray in adults and ticularly in the context of rising air pollution and pollen levels, children with AR; it is not known if similar improvements in and the heightened threat of respiratory viral outbreaks.

11 Saline nasal sprays or drops and nasal hygiene AEs not reported AEs not reported Over 98% of respondents use of nasal considered saline irrigation in pre- and as safe school children effective Adverse effects Adverse - (p=0.007);

No change in nasal patency (healthy No change in nasal patency (healthy MCC times decreased by 17% in normal by times decreased MCC subjects after of 3% healthy instillation vs baseline HS solution buffered vs baseline (2% for IS difference no significant p=0.71). decrease; in transit a mean improvement HS produced (p=0.002) and baseline of 3.1 minutes time vs (p=0.69). in the IS group 0.14 minutes nasal Both saline solutions improved with faster was but clearance clearance; 3% HS. adults without nasal oedema). times MCC improved HS and IS spray HS (p<0.0001 and p=0.002, respectively); MCT 24.1%; than IS (39.6% vs improved more p=0.007). 99.3% of respondents, used by NSI was Most frequency. although with differing IS solution and the most (87%) preferred a method was recommended frequently (67.7%). nasal spray and both a prophylactic It considered was 60.3% of respon by measure a therapeutic healthy it every who prescribed for day dents, when they frequently and more children ill. were Key findings Key 1. MCC pre- and 1. MCC post- 10–20 minutes treatment pre- and 1. MCC post- 10–20 minutes treatment 2. Nasal patency rhinometry(acoustic post- 10 minutes treatment) NA Primary clinical endpoint(s) - Ten sprays with an sprays Ten of HS or IS atomiser to (both buffered one side pH 7.6) to of the nose; after 1 another ten minute, given sprays per nost sprays Ten only once ril, NA Treatment protocol Treatment 1. HS (3%) nasal spray 2. IS (0.9%) nasal spray 1. HS (3%) nasal spray 2. IS (0.9%) nasal spray Included IS nasal spray Study groups Study - 21 healthy 21 healthy adults 22 healthy adults Survey of 860 se randomly lected National Health Service primary care paediatricians Population, Population, sample size* Crossover study Crossover with subjects acting as their control own Double-blind trial with subjects acting as their own control Cross-sectional survey Study design Study (52) (77) (75) Talbot et al., et al., Talbot 1997 Keojampa et al., 2004 et al., Marchisio 2014 Reference Reference Table 5. Saline nasal irrigation in healthy subjects. 5. Saline nasal irrigation in healthy Table known. where *Number of subjects included in analysis, mucociliary time; NA, not applicable. clearance mucociliary MCT, clearance; saline; MCC, HS, hypertonic saline; IS, isotonic event; adverse AE,

12 Santoro et al.

Conclusions Acknowledgments Minimising exposure to airborne aggressors such as air pollu- Editorial writing assistance, supported financially by GSK, was tants, pollen and respiratory viruses is important for everyone provided by Gill McFeat of Ogilvy Health. to reduce associated ill-health effects. Daily nasal hygiene may reduce the effects of noxious stimuli in the nose, helping to sup- Authorship contribution port respiratory health. Several small RCTs have demonstrated ES, PK, PN: Conceptualisation, Methodology, Writing - original that the daily use of saline nasal sprays (IS or HS) significantly draft, Writing - Review & Editing. All authors approved the final reduced nasal symptoms vs no treatment in adults and children manuscript for submission. with AR. There are few studies with well-defined inclusion crite- ria in the area of symptom relief for URTIs; however, prophylactic Contributors use of IS nasal sprays may be beneficial. SS, GS and GW contributed their clinical perspectives to the manuscript. The content within the ‘clinical perspectives’ sec- Thus, saline nasal sprays are effective in cleansing the nose, and tions represents the independent perspective and opinion of offer convenience and ease of use, which may increase patient each specialist; GSK Consumer Healthcare does not promote or acceptability and compliance compared with high-volume nasal recommend any off-label usage of any mentioned products. washes. The consensus in the literature is that use of HS and IS nasal sprays is well tolerated, easy to use, with no evidence that Conflict of interest regular, daily use adversely affects the patient’s health or causes ES, PK and PN are employees of GSK Consumer Health Care. unexpected side effects(46). Funding Saline nasal irrigation techniques are easily taught in primary Not applicable. care settings, including the pharmacy. Patients report effective education as key to successful initiation and maintenance of na- Consent for publication sal cleansing(49, 50). Healthcare providers, including the commu- Not applicable. nity pharmacist, can play a vital role in the successful initiation and maintenance of saline nasal spray use, helping patients to Availability of data and materials breathe well and stay healthy. Not applicable.

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15 Saline nasal sprays or drops and nasal hygiene

Supplementary Material

Supplementary Table 1. PubMed search strategy details.

Search terms [Title/abstract] Results (n) Potentially Relevant articles relevant articles (n) (n) Saline nasal irrigation and respiratory health #1 (spray OR drop OR solution OR atomi* OR nebuli* OR irrigat* OR hygien*) AND (nose 313 60 19 OR nasal OR intranasal) AND (saline OR sea OR salt OR sodium chloride OR hypertonic OR hypotonic OR isotonic) NOT (cystic fibrosis OR surgery) NOT (chronic[Title]) AND #2 (respiratory OR health OR airway OR lung OR rhinit* OR rhinorrhoea OR obstruction OR congest* OR discharg* OR blocked OR stuffy OR runny OR sneezing) Saline nasal irrigation and allergic rhinitis #1 (spray OR drop OR solution OR atomi* OR nebuli* OR irrigat* OR hygien*) AND (nose 123 23 10† OR nasal OR intranasal) AND (saline OR sea OR salt OR sodium chloride OR hypertonic OR hypotonic OR isotonic) NOT (cystic fibrosis OR surgery) NOT (chronic[Title]) AND #3 (allergic rhinitis OR allerg* OR hayfever OR hay fever OR pollen OR aeroallergen OR hypersensitivit* Saline nasal irrigation and upper respiratory tract infections #1 (spray OR drop OR solution OR atomi* OR nebuli* OR irrigat* OR hygien*) AND (nose 238 28 7† OR nasal OR intranasal) AND (saline OR sea OR salt OR sodium chloride OR hypertonic OR hypotonic OR isotonic) NOT (cystic fibrosis OR surgery) NOT (chronic[Title]) AND #4 (respiratory tract infection OR respiratory infection OR viral infection OR virus OR rhinit* OR rhinosinusitis OR common cold OR rhinovirus OR influenza OR flu OR corona- virus OR COVID-19 OR SARS-COV Saline nasal irrigation and air pollutants #1 (spray OR drop OR solution OR atomi* OR nebuli* OR irrigat* OR hygien*) AND (nose 3 0 0 OR nasal OR intranasal) AND (saline OR sea OR salt OR sodium chloride OR hypertonic OR hypotonic OR isotonic) NOT (cystic fibrosis OR surgery) NOT (chronic[Title]) AND #5 (air pollut* OR particulate matter OR particle pollut* OR air contamina*)

*The asterisk at the end of a truncated word was used to search for all terms that began with the word root. PubMed searches include US and UK spelling variants of search terms. †These articles were included in the results for saline nasal irrigation and respiratory health.

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