Table 1.

Studies of clinical use of topic HA in upper respiratory tract including respiratory infections, rhinosinusitis, and nasal polyposis.

First Author (Year)	Study Design	N; Male (%); Mean Age	Inclusion and Exclusion Criteria	Intervention	Results	Adverse Events
Macchi (2013)	Prospective, randomised, double-blind, parallel-group, placebo-controlled	75; 40 (53.3%); 13	Inclusion: recurrent upper-respiratory tract infections. Exclusion: history of immunological or autoimmune diseases, genetic syndromes, malformations or presenting with any indication for surgery.	Intranasal 9 mg of HA in 3 mL of IS or 6 mL of IS alone twice-daily for 15 consecutive days per month for 3 consecutive months.	HA nasal washes + IS was superior to IS alone in adenoid hypertrophy, presence of bacteria, neutrophils, rhinitis, nasal dyspnoea and biofilm. The number of days of absence from school was significantly lower in the HA group compared to controls.	Not reported.
Macchi (2013)	Prospective, randomised, double-blind, parallel-group, placebo-controlled	46; 23 (50%); 38.5	Inclusion: patients > 4 years who underwent FESS for rhino-sinusal tract infections. Exclusion: no exclusion criteria.	Intranasal 9 mg of HA in 3 mL of IS or 6 mL of IS alone twice-daily for 15 consecutive days per month for 3 consecutive months.	HA + IS following FESS was associated with significant improvements in nasal dyspnoea, appearance of nasal mucosa at endoscopy and ciliary motility vs. IS alone, while improving the presence of post-surgery biofilms.	HA was well-tolerated.
Gelardi (2013)	Prospective, randomised, simple-blind, controlled	36; 16 (44.4%); 47	Inclusion: patients undergoing FESS to treat grade II nasal polyposis. Exclusion: patients affected by grade I nasal polyposis, CF, primitive ciliary dyskinesia and choanal atresia.	Intranasal 9 mg of HA plus 3 mL or 5 mL of IS alone twice-daily for 30 days on the second day after surgery.	At 1 month, patients receiving HA had a significantly faster mucociliary clearance time, experienced a lower incidence of rhinorrhoea, less nasal obstruction and a lower incidence of exudate on endoscopy than control subjects.	HA was well-tolerated in patients following FESS.
Casale (2013)	Prospective, randomised, controlled	57; (50 completed the study); 25 (43.9%); 45.6	Inclusion: patients with nasal obstruction resulting from inferior turbinate hypertrophy refractory to medical therapy who underwent radiofrequency volumetric tissue reduction. Exclusion: patients with previous turbinate surgery, significant septal deformity, septal perforation, ala collapse, nasal polyposis, benign or malignant tumours of the nasal cavity, nasal radiotherapy and other comorbidities.	Intranasal 3 mL of HA dissolved in 2 mL of IS or IS alone twice-daily for 15 days from the 1st postoperative day.	The mean VAS of the HA group at the 1st week was lower than the IS group and remained significantly lower in the HA group also at the 2nd week. The HA group showed lower endoscopic nasal scores than the IS group, especially for crusts. Compliance in the HA group was lower than in the IS group (76% vs. 98%).	No adverse outcomes related to HA were recorded.
Cantone (2014)	Prospective, randomised, double-blind, controlled	124; (122 completed the study); 70 (56.4%); 41.2	Inclusion: patients undergoing FESS for medically resistant chronic rhinosinusitis and nasal polyposis. Exclusion: patients suffering from systemic diseases, acetylsalicylic acid sensitivity, CF, primitive ciliary dyskinesia, grade I nasal polyposis, choanal atresia and with a history of previous interventions.	Intranasal 9 mg of HA (3 mL) plus 2 mL of IS or 5 mL of IS alone twice-daily for 30 days from the 1st postoperative day.	After postoperative treatment, the endoscopic score, the total VAS score, the mean SNOT-22 and SF-36 results were better in the HS group than in the IS group.	HA was significantly better-tolerated than IS in patients undergoing FESS.
Monzani (2020)	Prospective, single arm, not controlled	87; (86 completed the study); 41 (47.1%); 56	Inclusion: history of previously diagnosed or recurrent chronic rhinosinusitis or a clinical diagnosis of chronic rhinosinusitis. Exclusion: patients who underwent previous sinus-nasal surgery in the last 12 m before study inclusion, with a history or presence of benign and malignant tumours of the nasal cavity, history of recurrent epistaxis, coagulation disorders, evidence or history of chronic bacterial rhinosinusitis and other comorbidities.	Patients were instructed to use HA solution twice-daily for 20 days.	HA was significantly effective in the relief of symptoms of recurrent chronic rhinosinusitis. Nasal blockage, nasal congestion, nasal drainage and rhinorrhoea improved. Middle turbinate oedema and nasal secretion at nasal endoscopic evaluation significantly improved.	No secondary effects related with HA were reported.

HS, hypertonic saline, IS, isotonic saline, HA, hyaluronic acid, CF, cystic fibrosis, FESS, functional endoscopic sinus surgery, VAS, visual analogue scale, SNOT-22, Sino-nasal outcome test-22 and SF-36, short form-36.