Abstract
Objective
Nasal irrigation is a common treatment for sinonasal disorders; however, it is unknown if it can reduce SARS‐CoV‐2 nasopharyngeal viral load (NVL). This systematic review investigated the efficacy of nasal irrigation with saline, povidone iodine (PVP‐I), and intranasal corticosteroids (INCS) at reducing SARS‐CoV‐2 NVL and transmissibility.
Data Sources
Databases including Embase, MEDLINE, Web of Science, and ClinicalTrials.gov.
Review Methods
A systematic review was completed with pre‐defined search criteria using keywords related to nasal irrigation and COVID‐19 from 1946 through January 2024. This review followed PRISMA reporting guidelines and was registered on PROSPERO. Only in‐vivo studies testing nasal irrigation with either saline, PVP‐I, or INCS for reducing NVL were included.
Results
Nine out of ten studies on saline‐based solutions reported positive effects in reducing NVL, with benefits noted in earlier time to negative nasopharyngeal PCR and a greater decline in NVL during early study time points, compared with controls. Isotonic and hypertonic saline mediums were found to be effective with three studies demonstrating enhanced efficacy with additives. Four out of seven studies on PVP‐I showed a positive effect on reducing NVL, but results were heterogenous. Four studies demonstrated reduction of transmission with saline or PVP‐I. No studies were found on INCS.
Conclusion
Saline nasal irrigation showed the best efficacy in reducing SARS‐CoV‐2 NVL. Additives to saline may have a clinical benefit, but further studies are needed to elucidate their isolated impacts on NVL. Data on PVP‐I is inconclusive and further studies are warranted to determine the ideal concentration for irrigation. Laryngoscope, 135:517–528, 2025
Keywords: COVID‐19, viral load, nasal saline irrigation, PVP‐I, INCS
We conducted a systematic review to analyze the efficacy of three common nasal irrigation methods, saline, PVP‐I, and INCS at reducing SARS‐CoV‐2 nasopharyngeal viral load (NVL). The majority of saline nasal irrigation studies (9/10) showed that this could reduce NVL compared with control. The results for PVP‐I were mixed, with 4/7 studies showing improved SARS‐CoV‐2 NVL clearance compared with control, and unfortunately, no studies on INCS met inclusion criteria.
INTRODUCTION
Coronavirus Disease‐19 (COVID‐19) was declared a pandemic by the World Health Organization (WHO) on February 11, 2020, and has since led to the death of over 7 million individuals worldwide. 1 COVID‐19 is caused by the SARS‐CoV‐2 virus, which is a single‐stranded ribonucleic acid (RNA) virus transmitted via respiratory droplets and aerosols. 2 Host cell entry is facilitated through binding of the viral spike protein to angiotensin‐converting enzyme 2 (ACE2) receptors found in the epithelium of the upper respiratory tract. 2 The nasal cavity contains higher levels of ACE2 receptors compared with other areas of the respiratory tract and is considered the primary port of entry for SARS‐CoV‐2. 3 , 4 Viral replication in the nasopharynx produces infectious droplets that can be transmitted to other hosts and lead to the development of respiratory symptoms via seeding of the lower airway through micro‐aspiration. 5 Several studies have shown a correlation between SARS‐CoV‐2 nasopharyngeal viral load (NVL) and COVID‐19 transmission and symptom severity. 6 , 7 , 8 Thus, it is hypothesized that early NVL reduction could improve disease outcomes and reduce transmission.
Nasal irrigation (NI) is a common treatment for sinonasal disorders and post‐operative nasal care. 9 It consists of introducing an irrigation agent into one or both nostrils with a device, such as a squeeze bottle, syringe, or neti‐pot, to facilitate flushing of the nasal cavity. NI allows for mechanical clearance of mucus and pathogens, restores natural mucociliary clearance, and reduces concentration of pro‐inflammatory mediators. 9 It is considered to be a well‐tolerated, easy‐to‐use, and cost‐effective therapy. 10 Saline nasal irrigation (SNI) was shown in a previous 2019 randomized control trial (RCT) to be effective at reducing NVL of common causative viruses of URTIs, such as rhinovirus and adenovirus, and has been hypothesized to be able to elicit a similar effect on NVL of SARS‐CoV‐2. 11 , 12 In addition, two other irrigation agents, intranasal corticosteroids (INCS) and povidone iodine (PVP‐I), have demonstrated direct efficacy against COVID‐19. Specifically, INCS was shown to reduce COVID‐19 disease duration and has been shown in animal models to decrease respiratory SARS‐CoV‐2 viral load. 13 , 14 PVP‐I, a commonly used for surgical procedures, has been shown to inactivate SARS‐CoV‐2 in‐vitro. 15 , 16 Despite ongoing clinical trials, there is still no consensus for NI in COVID‐19 treatment.
As new COVID‐19 variants continue to emerge and strain health care resources, there is a need for interventions that limit the spread of infection. To bridge this gap, a systematic review was performed to assess the efficacy of three common nasal irrigation solutions, SNI, PVP‐I, and INCS, at reducing nasopharyngeal SARS‐CoV‐2 viral load in‐vivo. These interventions can be administered via a nasal irrigation or spray formulation, and patients can perform them at home with relative ease and minimal cost. Facilitating better insight into role of these interventions at reducing viral load may allow them to be repurposed for infection control strategies. In this review, “irrigation” was used to define interventions using high volumes of liquid while “spray” refers to low volume.
METHODS
The Preferred Reporting Systems for Systematic Reviews and Meta‐Analysis (PRISMA) guidelines were followed for this reporting this systematic review. 17 This study was registered on PROSPERO on January 23, 2024, registration number: CRD42024500158. The PICO framework for this review was as follows: population consisted of patients with COVID‐19 infection of all ages and genders; intervention was nasal irrigation with either saline, PVP‐I, and INCS; no defined comparator; primary outcomes were the effect of the irrigation on SARS‐CoV‐2 NVL and COVID‐19 transmission rates.
Search Strategy
A literature search was conducted using Embase, MEDLINE (PubMed), Web of Science, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL. ClinicalTrials.gov and the EU clinical trials register were also searched separately. The articles included were published from 1946 through January 2024. Keywords related to nasal irrigation and viral illnesses included virus‐related search terms: COVID‐19, virus, URTI, viral load and transmission, and nasal keywords; nasal and nasopharynx, as well as intervention‐related keywords; irrigation, rinse, saline, betadine, and corticosteroid.
Study Outcomes and Eligibility Criteria
The primary outcome was the impact of saline nasal irrigation, intranasal PVP‐I, and/or INCS on nasopharyngeal SARS‐CoV‐2 viral load. This review also included studies that assessed the impact of these interventions on COVID‐19 transmission, as this was a key clinical outcome related to the reduction of SARS‐CoV‐2 NVL.
Studies were included if they provided original in‐vivo data on these outcomes of interest and tested application of the three target interventions (saline, PVP‐I, or INCS) in the nasopharynx in either an irrigation or spray medium. Case reports, case series, cohort studies, and randomized controlled trials (RCTs) were all included. Studies were excluded if they did not report human in‐vivo data (such as animal studies, computer models, or in‐vitro studies, etc.), reported viral load data from outside the nasopharynx or from viruses other than SARS‐CoV‐2, used non‐nasal interventions, did not contain original data (i.e., literature review, letter to the editor, etc.), or if data from clinical trials were unavailable. There was no age restriction on study populations. Meta‐analysis was not possible in this review due to heterogeneous data and various methods for measuring viral load or transmission across included studies. Instead, qualitative comparison of studies was performed to summarize the available evidence.
Review Process and Risk of Bias Assessment
Articles underwent an initial abstract screening followed by a full‐text review to identify if they met criteria for data extraction. At both stages, articles were excluded if they did not meet inclusion criteria as defined above. In the case of clinical trials where data were unavailable, authors from these trials were contacted via email to obtain the data. In cases where pre‐print or preliminary articles were available for the same publication, the most recent publication was included for full‐text review. Demographic, intervention, and clinical outcome data were extracted using a standardized spreadsheet. Randomized studies underwent a risk of bias assessment, which was conducted using the Cochrane risk of bias (ROB) tool for randomized control trials version 2. 18 Two independent reviewers (KG & FP) conducted the literature search, abstract screening, full‐text review, data extraction, and ROB assessment. Conflicts at each stage were addressed through discussion and consensus.
RESULTS
The initial search yielded 2049 non‐duplicate results, which underwent title and abstract screening by the reviewers. Of these, 113 articles met inclusion criteria for full‐text review. During the full‐text review, 93 of these studies were excluded with the most common reasons being that the studies reported on the wrong study outcomes, did not contain original data (such as a review, letter to the editor, etc.), or full text/results were not available. Ultimately, 20 studies qualified for full‐text review. The PRISMA diagram summarizing the systematic review process is displayed in Figure 1.
FIGURE 1.
PRISMA diagram for systematic review. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
The basic characteristics of the 20 studies included in the full‐text review are included in Table I. All studies included in this review were published between 2021 and 2023. A total of 13 studies assessed SNI as their primary intervention, of which 10 reported data pertaining to viral load while three separately reported data pertaining only to transmission rates. Of these 12 studies, seven were RCTs while the other six consisted of pilot studies (N = 2), non‐randomized control trials (N = 2), or non‐randomized quasi‐experimental studies (N = 2). Across these studies, 1551 participants were included, 780 male and 702 female (gender breakdown not reported for Baxter et al. 2022). All studies consisted of adult participants (greater than age 18) except for one pediatric study (Liu et al. 2023). Seven studies assessed PVP‐I as their primary intervention and all seven reported data pertaining to viral load. One study, Elsersy et al. (2022), also reported results pertaining to COVID‐19 transmission rates which were analyzed separately. Of these seven studies, six were RCTs while two were pilot studies. Across these studies, 612 participants were included, 351 male and 261 female. All PVP‐I studies were conducted in adult populations. Our review did not yield any studies on INCS that met inclusion criteria.
TABLE I.
Characteristics of the Studies That Underwent Full‐Text Review.
Primary Author (Year Published) | Study Type | Country | Study Population (Adult/Pediatric) and Sample Size (M/F) | Primary Intervention | Reference Number |
---|---|---|---|---|---|
Ioannis Pantazopoulos (2022) | RCT | Greece | Adult (N = 50; 28/22) | SNI | 19 |
Giacomo Spinato (2021) | Non‐randomized control trial | Italy | Adult (N = 140; 64/76) | SNI | 20 |
Li Liu (2023) | Non‐randomized quasi‐experimental study | China | Pediatric (N = 60; 30/30) | SNI | 21 |
Li Liu (2022) | Non‐randomized quasi‐experimental study | China | Adult (N = 80; 44/36) | SNI | 22 |
Tairong Wang (2023) | Pilot study | China | Adult (N = 55; 26/29) | SNI | 23 |
Yetkin Zeki Yilmaz (2021) | RCT | Turkey | Adult (N = 60; 36/24) | SNI | 24 |
Ioannis Pantazopoulos (2023) | RCT | Greece | Adult (N = 52; 33/19) | SNI | 25 |
At Varricchio (2021) | Non‐randomized pilot study | Italy | Adult (N = 76; 40/36) | SNI | 26 |
Luca Cegolon (2022) | Non‐randomized control trial | Italy | Adult (N = 108; 43/65) | SNI | 27 |
Charles Esther (2022) | RCT | USA | Adult (N = 72; 35/37) | SNI | 28 |
Pranav Sharma (2022) | RCT | India | Adult (N = 32; 15/17) | PVP‐I | 29 |
Mostafa Komal Arefin (2022) | RCT | Bangladesh | Adult (N = 189; 153/36) | PVP‐I | 30 |
Hazem Elsersy (2022) | RCT | Egypt | Adult (N = 200; 100/100) | PVP‐I | 31 |
Aysegul Batioglu‐Karaaltin (2023) | RCT | Turkey | Adult (N = 120; 48/72) | PVP‐I | 32 |
Jeremy Guenezan (2021) | RCT | France | Adult (N = 24; 12/12) | PVP‐I | 33 |
Rujipas Sirijatuphat (2022) | Non‐randomized pilot study | Thailand | Adult (N = 12; 6/6) | PVP‐I | 34 |
David Zarabanda (2022) | RCT | USA | Adult (N = 35; 17/18) | PVP‐I | 35 |
Rafael Guiterrez‐Garcia (2022) | RCT | Mexico | Adult (N = 163; 43/120) | SNI | 36 |
Amy Baxter (2022) | RCT | USA | Adult (N = 79; NR) | SNI | 37 |
Damian Balmforth (2022) | RCT | India | Adult (N = 556; 348/208) | SNI | 39 |
Abbreviations: NR = not reported; PVP‐I = povidone iodine; RCT = randomized controlled trial; SNI = saline nasal irrigation.
IMPACT OF SALINE NASAL IRRIGATION ON SARS‐CoV‐2 NASOPHARYNGEAL VIRAL LOAD
Ten studies assessed the impact of SNI on the impact of SARS‐CoV‐2 NVL. Among these, nine studies demonstrated that SNI was superior to control at reducing NVL, 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 while one did not. 28 A summary of all these studies is presented in Table II.
TABLE II.
Data Extraction Table for Studies That Assessed the Impact of Saline Nasal Irrigation on SARS‐CoV‐2 Nasopharyngeal Viral Load.
Study | Intervention Group | Control Group | Irrigation Regimen | Measurement of NVL | Key Results for NVL |
---|---|---|---|---|---|
Yilmaz et al. (2021) |
HANI and HCQ (400 mg/day) N = 30 |
HCQ (400 mg/day) alone N = 30 |
4x/day for 7 days | RT‐PCR on days 0, 3, 7 | ΔViral Load from day 0 to 3 greater in intervention versus control group (p = 0.019). However, there was no difference in the change in viral load from day 0 to 7. No difference in absolute value of viral densities on day 0, 3, and 7. |
Spinato et al. (2021) |
Isotonic saline (NaCl 0.9%) irrigation N = 68 |
Historical data set of COVID‐19‐positive patients N = 72 |
1x/day with 250 mL for 12 days | PCR test on day 10 | 91.1% (62/68) participants in intervention group had a negative PCR test on day 10 versus 2.8% (2/72) in the control group (p < 0.00001). |
Wang et al. (2023) |
5% sodium bicarbonate irrigation plus oral rinse with same solution N = 23 |
Standard COVID‐19 care N = 32 |
Two nasal irrigations in 30‐40 mL of solution, one on day 1 and 2 | Time in days to viral clearance defined as two consecutive negative RT‐PCR tests | Mean viral clearance time = 1.63 ± 1.25 days in intervention group. Mean viral clearance time not specified in control group but was reported as being greater than control. |
Varricchio et al. (2021) |
Nebulized hypertonic (NaCl 3%) saline with tobramycin 0.45%, lincomycin 0.75%, sodium hyaluronate 0.2%, and xylitol 5%. Volume 5 mL. N = 76 |
COVID‐19‐positive household contacts of participants in intervention group who performed no interventions N = unknown |
2x/day for 7 days | PCR test on day 10 for intervention group and PCR test on day 14 for control group | All participants in intervention group had a negative PCR test on day 10 while all those in the control had a positive PCR test on day 14. |
Pantazopoulos et al. (2022) |
Isotonic (NaCl 0.9%) saline irrigation N = 24 |
No intervention N = 26 |
Every 4 h with 10 mL of saline for a 16 h period | Absolute value of viral load measured in Ct of RT‐PCR at baseline and 24 h. Participants also had a COVID‐19 PCR test 2 weeks after discharge. |
Intervention group had an 8.9% decrease in viral load between baseline and 24 h (ΔCtday2−day1 = 1.87 ± 3.11 cycles, p = 0.007, 95% CI: 0.55 to 3.18) versus a 9.7% increase in the control group (ΔCtday2−day1 = −2.12 ± 2.66, p < 0.001 95% CI: −3.20 to −1.05). Mean group difference at 24 h was 3.09 cycles (p = 0.005, 95% CI: 0.97 to 5.20). At 2 weeks post‐discharge, the intervention group has 15 patients with a negative COVID‐19 PCR versus 2 in the control group (p = 0.02). |
Pantazopoulos et al. (2023) |
Hypertonic saline irrigation (NaCl 2.3%) + blue and brown algae and essential oils (eucalyptus globulus and Mentha spicata, and Thymus vulgaris extract) N = 28 |
No intervention N = 28 |
Every 4 h with 100 mL of saline for a 16 h period after baseline | Absolute value of viral load measured in Ct of RT‐PCR at baseline and 48 h. Participants also had a COVID‐19 PCR test 2 weeks after discharge. |
Intervention group had a 18.2% decline in viral load between baseline and 48 h (mean ΔCt 48–0 h = 3.86 ± 3.03 cycles, p < 0.001, 95% CI: 2.69–5.04) versus no change in the control group (mean ΔCt 48–0 h = −0.14 ± 4.29, p = 0.866, 95% CI: −1.80 to −1.52). Between‐group difference at 48 h was 4 cycles (p < 0.001, 95% CI: −6.82 to −1.10). At 2 weeks post‐discharge, the intervention group has 17 patients with a negative COVID‐19 PCR versus 9 in the control group (p = 0.03). |
Liu et al. (2022) |
Hypertonic saline (NaCl 3%) N = 40 |
LhQw granules and other unspecifies traditional Chinese medicine formulations N = 40 |
2x/day with 10 mL of saline until participant achieved viral clearance. | Time in days to viral clearance, defined as two consecutive days with a negative COVID PCR test measurements began on day 7. | Mean viral clearance in intervention group was 17.58 days ±7.31 versus control group 29.10 days ±3.70 (p < 0.001). |
Liu et al. (2023) |
Arm 1: Isotonic saline (0.9% NaCl) irrigation + LhQw granules N = 20 Arm 2: Hypertonic Saline Irrigation (3% NaCl) + LhQw granules N = 20 |
LhQw granules and other unspecifies Traditional Chinese Medicine formulation but no nasal interventions N = 20 |
2x/day with 10 mL of saline until participant achieved viral clearance. | Time in days to viral clearance, defined as two consecutive days with a negative COVID PCR test (tested daily). Measurements began on day 7 post‐infection | Mean viral clearance in isotonic saline group was 17.25 ± 4.16 and 16.98 ± 2.80 days in hypertonic saline group. There was no significant difference between the two intervention groups (p = 0.30). Both intervention groups had significantly lower mean viral clearance times compared with control, 22.46 ± 7.10 days (p < 0.001). |
Cegolon et al. (2023) |
Hypertonic spray containing seawater, xylitol, panthenol, lactic acid N = 50 |
Standard COVID‐19 care N = 58 |
3x/day until viral clearance, for up to 15 days. | Time in days to viral clearance, defined as the first day with a negative antigenic swab | Participants in the intervention group more likely to have a negative antigenic swab 2 days before control group during the first 5 days of infection [Pooled ARI 0.23 (95% CI 0.1–0.36), OR 7.39 (95% CI 1.83–29.8), HR 6.12 (95% CI 1.76–21.32)]. Participants in control group more likely after day 7 [Pooled ARI −0.24 (95% CI −0.09 to −0.38), OR 0.22 (95% CI 0.08–0.65), HR NA]. |
Esther et al. (2022) |
Arm 1: Hypertonic (3% NaCl) saline irrigation N = 24 Arm 2: Hypertonic saline +1% Surfactant (2.5 mL of J&J baby shampoo) Irrigation N = 24 |
No intervention N = 24 |
2x/day with 240 mL of saline for 21 days. | Viral load quantified on days 1, 3, 5, 7, 10, 14, 21 with qRT‐PCR, measured by Ct. | No statistical difference in Ct values between either intervention arm versus control or with each other at any time point. |
Abbreviations: ARI = absolute risk increase; CI = confidence interval; Ct = cycles threshold; HANI = Hypertonic alkaline nasal irrigation; HCQ = hydroxychloroquine; HR = hazard ratio; J&J = Johnson and Johnson; LhQw = Lianhua Qingwen granules; N = Number of participants in study arm; OR = odds ratio; qRT‐PCR = quantitative real time polymerase chain reaction; RT‐PCR = real time polymerase chain reaction; Δ = delta/change in.
Isotonic SNI was found to be effective in three studies. Pantazopoulos et al. (2022) reported that isotonic SNI performed four times in a 16‐h period led to a statistically greater proportional decline in NVL after 24 h, compared with control. 19 Spinato et al. (2021) found that most participants who performed daily high‐volume lavage had a negative molecular test after 10 days compared with a historical control in which most were still positive at this time point. 20 Liu et al. (2023) found that twice daily isotonic SNI resulted in a negative polymerase chain reaction (PCR) test approximately 5 days before the control group (p < 0.005). 21 None of these studies used additives to the solution.
Seven studies found hypertonic saline to be effective, but the formulations in which it was used varied greatly across studies. Liu et al. (2022) found that twice daily hypertonic SNI led to a faster time to average negative PCR test approximately 11 days before the control group in adults (p < 0.005). 22 Liu et al. (2023) found that the same regimen achieved a faster average negative PCR time approximately 5 days before the control group (p < 0.005) in pediatric patients. 21 Liu et al. (2023) found no difference in viral clearance time between the isotonic and hypertonic study arms (p = 0.30). 21 Two studies reported successful usage of hypertonic alkaline saline. Wang et al. (2023) reported that two isolated nasal irrigations with 5% sodium bicarbonate solution led to an average negative PCR time of just under 2 days, but the conversion time for the control group was never officially reported. 23 Yilmaz et al. (2021) found that four times daily hypertonic alkaline saline nasal spray combined with oral hydroxychloroquine led to a greater average proportional decline in NVL from day 0 to 3 compared with HCQ alone. 24
Finally, three studies utilized hypertonic saline with additives to the solution. Pantazopoulos et al. (2023) showed that frequent use of hypertonic SNI with algae and essential oils in a 16 h period led to a greater average proportional decline in NVL after 48 h, compared with control (p < 0.001). 25 Varricchio et al. (2021) found that all participants treated with twice daily nebulized hypertonic saline with antibiotics, sodium hyaluronate, and xylitol had a negative molecular test on day 10, while all their household contacts, who served as the control group, were all still positive on day 14. 26 Lastly, Cegolon et al. (2023) found that three times daily use of a hypertonic seawater nasal spray with xylitol and other agents increased the likelihood of having a negative COVID‐19 antigen test 2 days earlier than control during the first 5 days of infection. 27
In general, the positive saline studies showed that frequent, prolonged daily use of SNI led to faster NVL clearance compared with respective study controls. Specifically, six studies showed that their SNI arm achieved either a faster average time to negative PCR or a greater proportion of PCR‐negative patients at fixed time points. 20 , 21 , 22 , 23 , 26 , 27 Reported “earlier time to negative PCR” in these studies ranged from 2 to 11 days. Three studies also showed a greater proportional decline in viral load during early study time points (day 1–3), which suggests SNI may have an immediate benefit for NVL clearance. 19 , 24 , 25 The only study that did not show a positive impact of SNI on SARS‐CoV‐2 NVL was Esther et al. (2022), which found no statistical difference in viral load at any point during the study (day 1–21) between participants who performed twice daily lavage with hypertonic saline, hypertonic saline with 1% surfactant, and no intervention. 28
IMPACT OF PVP‐I NASAL IRRIGATION ON SARS‐CoV‐2 NASOPHARYNGEAL VIRAL LOAD
Seven studies tested the effects of PVP‐I, as the primary intervention, on the impact of SARS‐CoV‐2 NVL. Among these, four studies demonstrated a positive impact on NVL while three did not. 29 , 30 , 31 , 32 , 33 , 34 , 35 Table III displays a summary of all PVP‐I studies.
TABLE III.
Data Extraction Table for Studies That Assessed the Impact of Povidone Iodine Irrigation on SARS‐CoV‐2 Nasopharyngeal Viral Load.
Study | Intervention Group | Control Group | Irrigation Regimen | Measurement of NVL | Key Results for NVL |
---|---|---|---|---|---|
Guenezan et al. (2021) |
1% PVP‐I nasal spray with 10% PVP‐I ointment applied in nasal cavity plus 1% PVP‐I oral gargle N = 12 |
No intervention N = 12 |
4x/day for 5 days | Viral copies measured via RT‐PCR on days 0, 1, 3, 5, 7. Viral titers (TCID50/mL) obtained on baseline and day 1. | No significant difference between intervention and control group in viral copy. Mean relative difference between baseline and day 1 in intervention group was 75% (95% CI, 43%–95%) and in control group was 32% (95% CI, 10%–65%), but no statistical comparison was made between the two groups. |
Sirijatuphat et al. (2022) |
0.4% PVP‐I nasal spray N = 12 |
Participants served as their own controls N = 12 |
One time application | Viral load quantified at baseline, 3 min, and 4 h using three different methods: Ct of N gene from RT‐PCR, Ct of ORF1ab gene from RT‐PCR, and viral titer (TCID50/mL). | No significant difference between intervention and control group in median viral load in the study population using any of the three methods in the following time intervals: baseline vs 3 min (left nostril), 3 min left vs right nostril, 3 min vs 4 h (right nostril). |
Sharma et al. (2022) |
0.5% PVP‐I nasal spray and 0.5% PVP‐I oral gargle N = 16 |
Distilled water as a nasal spray and gargle N = 16 |
One time application | Viral load quantified at baseline, 5 min, and 3 h via Ct from RT‐PCR and viral titer (TCID50/mL). |
ΔMean Ct values of control group vs. intervention group at baseline‐5 min and baseline‐3 h was statistically significant; ANOVA (F (2,60) = 3.332, p = 0.042). ΔMean viral titer at the same time points between intervention and control groups was not statistically significant; ANOVA (F (2,60) = 2.305, p = 0.109). |
Elsersy et al. (2022) |
Nasal spray containing 0.5% PVP‐I and 2.5 mg/mL ammonium glycyrrhizate and oral spray containing same ingredients as nasal spray N = 100 |
Placebo nasal and oral sprays N = 100 |
6x/day for 10 days | Number of COVID‐19 PCR‐positive patients measured on day 4, 7, and 10. |
Day 4 (Positive/Negative): 70/30 (30%) intervention group vs. 99/1 (1%) control group, p < 0.0001 Day 7 (Positive/Negative): 21/79 (79%) intervention group vs. 65/35 (35%) control group, p = 0.001 Day 10 (Positive/Negative): 1/99 (99%) intervention group vs. 10/90 (90%) control group, p = 0.005 |
Zarabanda et al. (2021) |
Arm 1: 0.5% PVP‐I nasal N = 11 Arm 2: 2.0% nasal spray N = 13 |
Isotonic saline (0.9% NaCl) nasal spray N = 11 |
One time administration (2 sprays each nostril) before initial 1 h measurement and then 4x/day for the next 48 h (day 3). Each pump delivered 0.1 mL of spray. | Viral load quantified using Ct values from qPCR at baseline, 1 h, and day 3 |
There was an increase in Ct values in the overall cohort, meaning there was a decline in NVL in all three groups (mean difference = 0.055 cycles/hour; 95% CI 0.037 to 0.074). There was no difference in decline across the study time frame in NVL between the two PVP‐I sprays and the control group. Saline: reference; 0.5% PVP‐I: mean difference = −0.349 cycles/hour; (95% CI −1.584 to 0.886); 2.0% PVP‐I: mean difference −1.059 cycles/hour; (95% CI −2.318 to 0.201). No difference in NVL from 0 to 1 h in participants who used PVP‐I versus saline sprays (saline mean change in Ct: 0.31, PVP‐I combined group mean change in Ct: 0.29, p = 0.89). |
Arefin et al. (2022) |
Arm 1: 0.4% PVP‐I nasal irrigation N = 27 Arm 2: 0.5% PVP‐I nasal irrigation N = 27 Arm 3: 0.6% PVP‐I nasal irrigation N = 27 Arm 4: 0.5% PVP‐I nasal spray N = 27 Arm 5: 0.6% PVP‐I nasal spray N = 27 |
Nasal irrigation (N = 27) or nasal spray (N = 27) with distilled water. Irrigation groups compared with irrigation control and vice versa. | One time administration | Proportion of COVID‐19 negative PCR patients after intervention (swab taken anywhere from 1 to 15 min post‐intervention. |
Patients with negative PCR after intervention: 0.4% Irrigation vs. CNI: 18 vs. 8 (p = 0.006) 0.5% Irrigation vs. CNI: 25 vs. 8 (p < 0.001) 0.6% Irrigation vs. CNI: 23 vs. 8 (p = 0.018) 0.5% Spray vs. CNS: 18 vs. 2 (p < 0.001) 0.6% Spray vs. CNS: 22 vs. 2 (p < 0.001) ORs for interventions in multivariable regression analysis of factors affecting outcome: 0.4% NI 21.03 (3.63–121. 96) 0.5% NI 141.883 (15.92–1264.59) 0.6% NI 81.20 (11.53–572.13) 0.5% NS 19.71 (3.15–123.25) 0.6% NS 50.93 (7.16–362.10) |
Batioglu‐Karaaltin et al. (2023) |
Arm 1: Nasal irrigation with isotonic (0.9% NaCl) saline N = 30 Arm 2: Nasal irrigation with 1% PVP‐I N = 30 Arm 3: Nasal irrigation with 1% PVP‐I + HANI N = 30 |
Standard COVID‐19 treatment N = 30 |
4x/day at 6 h intervals for 5 days | Viral load quantified using Ct values from qPCR at baseline, day 3, and day 5. |
Median NVL decreased from baseline to 3 and baseline to day 5 statistically within all groups (p = 0.0000001). Between‐group comparisons of ΔViral Load from study time points:
|
Abbreviations: CNI = control nasal irrigation; CNS = control nasal spray; Ct = cycles threshold; N = Number of participants in study arm; NVL = nasopharyngeal viral load; ORs = odds ratios; PVP‐I = povidone iodine; RT‐PCR = real time polymerase chain reaction; TCID50/mL = Tissue Culture Infectious Dose 50% per milliliter; Δ = delta/change in.
Two studies demonstrated an immediate effect from a one time application of PVP‐I. Sharma et al. (2022) showed a significant reduction in NVL at 5 min and 3 h in the intervention group (0.5% PVP‐I spray) compared with the control group (distilled water). 29 Arefin et al. (2022) found that 0.4%–0.6% PVP‐I nasal irrigation and 0.5% and 0.6% PVP‐I nasal spray led to a statistically greater number of negative COVID‐19 swabs 1–15 min post‐intervention compared with either irrigation or spray with distilled water. 30 Furthermore, two studies showed a positive effect of multi‐day application of PVP‐I. Elsersy et al. (2022) showed that six times daily use of a 0.5% PVP‐I nasal spray with 2.5 mg/mL ammonium gliclazide lead to a significantly greater number of negative covid swabs in the intervention compared with the placebo control, at days 4, 7, and 10. 31 Batioglu‐Karaaltin et al. (2023) tested 4 times daily irrigation with normal saline, 1% PVP‐I, and 1%‐PVP‐I plus hypertonic alkaline solution against no intervention at day 0, 3, and 5. 32 Between day 0 and 3, the change in NVL in the 1%‐PVP‐I plus hypertonic alkaline solution group was statistically higher than all groups (p < 0.05), but there was no difference between the no intervention, saline, or 1.0% PVP‐I groups. 32 From day 0 to 5, the 1.0% PVP‐I group and the 1%‐PVP‐I plus hypertonic alkaline solution group showed a greater decline in NVL compared with no intervention, but there was no difference between these two groups or with the saline group. 32
The study by Arefin et al. (2021) allowed for an interesting comparison between the efficacy of nasal irrigation versus spray. 30 When examining the 0.5% and 0.6% concentrations, the nasal irrigation groups demonstrated superior outcomes compared with their spray counterparts. 30 The odds ratios (OR) were significantly higher for the irrigation groups, with the 0.5% NI group yielding an OR of 141.883 (95% CI, 15.92–1264.59) and the 0.6% NI group achieving an OR of 81.20 (95% CI, 11.53–572.13). 30 By contrast, the nasal spray groups at equivalent concentrations manifested lower efficacy, with the 0.5% NS and 0.6% NS groups presenting ORs of 19.71 (95% CI, 3.15–123.25) and 50.93 (95% CI, 7.16–362.10), respectively. 30 Furthermore, although there was a numerical difference in the odds ratio for the saline irrigation group compared with the saline spray group at 4.05 (95% CI, 0.69–23.66), this did not translate into statistical significance, as the confidence interval crossed the null value of 1. 30 This finding suggests that nasal irrigation in this study was more effective than sprays.
The remaining three studies found no impact on viral load with PVP‐I concentrations varying from 0.5% to 2% at timepoints ranging from 3 min to 7 days post‐intervention. 33 , 34 , 35 The full results for these studies are presented in Table III. Overall, in this review, PVP‐I showed mixed and heterogenous results. No distinguishable pattern for concentration, regimen, or timepoint that showed the greatest efficacy for reduction of SARS‐CoV‐2 NVL was identified.
IMPACT OF NASAL IRRIGATION ON TRANSMISSION OF SARS‐CoV‐2
Four studies investigated the influence of nasal irrigation with either saline or PVP‐I on the transmission of SARS‐CoV‐2. 30 , 36 , 37 The results of these studies are displayed in Table IV. Elsersy et al. (2022) noted a statistically significant reduction in PCR‐positive contacts within household settings. 30 Gutiérrez‐García et al. (2023) utilized nasal irrigation and oral rinse with electrolyzed water as prophylaxis in health care workers, resulting in a lower number of individuals testing positive for COVID‐19 during the study period compared with the control group using PPE alone. 36 Baxter et al. (2022) evaluated the use of saline with either 1% PVP‐I or sodium bicarbonate and found that the combined rate of household transmission was 12.2% which was less than an 18.8% transmission rate reported in a previous meta‐analysis. 37 , 38 Lastly, Balmforth et al. (2022) found that a nasal spray containing saline among other chemical additives used prophylactically in health care workers led to 62% less COVID‐19‐positive participants at the end of their 45‐day study period compared with placebo spray. 39
TABLE IV.
Data Extraction Table for Studies That Assessed the Impact of Nasal Irrigation on SARS‐CoV‐2 Transmission.
Study | Type of Solution and Additives in Intervention Group | Control Group | Irrigation Regimen | Method of Measurement of Transmission | Key Results |
---|---|---|---|---|---|
Elsersy et al. (2022) |
Nasal spray containing 0.5% PVP‐I and 2.5 mg/mL ammonium glycyrrhizate plus oral spray containing same ingredients N = 100 |
Placebo nasal and oral sprays N = 100 |
6x/day | COVID‐19 PCR‐positive household contacts | 4% (8/194) of the intervention group had COVID‐19 PCR‐positive household contacts versus 69% (157/227), p < 0.0001. |
Gutiérrez‐García et al. (2022) |
Nasal irrigation and oral rinse with electrolyzed water, containing NaCl plus PPE N = 84 |
PPE N = 79 |
3x/day for 28 days | COVID‐19‐positive individuals between day 14 and day 28. Study was testing prophylactic effect of nasal irrigation in health care workers. | 12.7% (10/79) individuals in the control group vs. 1.2% (1/84) individuals in the intervention group tested positive for COVID‐19 during the study, p = 0.0039, RR = 0.09405, 95% CI [0.01231–0.7183]. |
Baxter et al. (2022) |
Nasal irrigation with either 1% PVP‐I or sodium bicarbonate N = 79 |
National CDC Case Surveillance Public Use Dataset | 2x/day for 14 days | COVID‐19 PCR‐positive household contacts | 12.2% (10/79) participants in nasal irrigation group had household contacts test positive. This was lower than a 18.8% transmission rate published by a meta‐analysis cited in the article. |
Balmforth et al. (2022) |
Nasal spray containing distilled water with saline plus additives including xylitol, disodium hydrogen phosphate, hydroxypropyl methylcellulose, ginger oil, eucalyptus oil, basil oil, clove oil, sodium hydrogen carbonate, potassium dihydrogen phosphate, ethylenediaminetetraacetic acid, sodium hyaluronate, calcium chloride dihydrate, benzalkonium chloride, magnesium chloride hexahydrate, potassium chloride, glycerol, and zinc chloride N = 275 |
Placebo nasal spray N = 281 |
3x/day for 45 days | COVID‐19‐positive individuals defined by those who test positive for IgGS on day 45. Study tested the prophylactic effect of the nasal spray in health care workers. | 36 (13.1%) cases in the intervention group had subjects test positive on day 45 versus 97 (34.5%) cases in the placebo group [OR 0.40, (95% CI; 0.27–0.59), p < 0.0001]. Overall, 62% fewer infections were seen in the intervention group compared with placebo. |
Abbreviations: CDC = Center for Disease Control; N = Number of participants in study arm; PCR = polymerase chain reaction; PPE = personal protective equipment; PVP‐I = povidone iodine.
RISK OF BIAS ASSESSMENT
The results for the ROB assessment are displayed in Figure 2. The domains of “randomization process,” “measurement of the outcome,” and “selection of the reported result” were generally low risk, with the majority of studies showing low risk in these domains. However, there were some concerns with the domain “deviation from intended interventions,” as 7 out of 13 studies suggested some concerns for bias. Additionally, the “missing outcome” domain had one study, Wang et al. (2023), show high risk bias as this study did not report the time to negative PCR in the control group. 23 The overall risk of bias assessment highlighted a mixed quality studies for this review, with five studies showing no concerns, eight studies showing some concerns, and one study showing high risk of bias. Six studies could not undergo ROB assessment due to the face that they were non‐randomized. 21 , 22 , 23 , 27 , 28 , 35
FIGURE 2.
Results from Cochrane risk of bias assessment for randomized control trials (Version 2). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
DISCUSSION
This systematic review investigated the efficacy of nasal irrigation with saline, PVP‐I, or INCS for reducing SARS‐CoV‐2 NVL. In this review, SNI was the best studied intervention and showed the greatest efficacy for reducing SARS‐CoV‐2 NVL. Benefits of SNI manifested as an earlier time to a negative COVID‐19 test (either molecular or antigenic) ranging from approximately 2–11 days and greater proportional decline in NVL during early study time points, suggesting an immediate effect. Both isotonic and hypertonic SNI were shown to be effective, with slightly more positive studies using hypertonic saline. Six out of seven positive SNI studies utilized either hypertonic or isotonic saline without additives. 19 , 20 , 21 , 22 , 23 , 24 Studies using sodium bicarbonate solution are included, as bicarbonate is frequently found in saline nasal irrigations. Of the SNI studies incorporating chemical additives into saline solutions, 3 out of 4 showed a reduction in viral load. 25 , 26 , 27 , 28 However, the specific contribution of these additives remains unclear, and the observed effects may predominantly be attributed to the act of irrigation. Only one study in our review did not observe a significant reduction in viral load with saline irrigation. 28 This study compared hypertonic saline with surfactant versus hypertonic saline alone versus no intervention. 28
Overall, although most of the saline studies reported a positive impact of SNI on reduction of SARS‐CoV‐2 NVL, the study designs were heterogenous, which prevented pooling of data for meta‐analysis. As such, this review could not determine the exact degree of viral clearance achieved with SNI or the exact time frame for which viral clearance could be achieved faster. Nonetheless, this review still showed that most studies published on this topic report a benefit for reduction of SARS‐CoV‐2 NVL with SNI. Given that SNI is generally well‐tolerated, safe, inexpensive, and easy to use, this review supports SNI for reduction of SARS‐CoV‐2 NVL. 10
In addition to facilitating mechanical clearance and hydration of the nasal cavity, SNI has also been shown to have specific anti‐SARS‐CoV‐2 effects relating to saline. Sodium chloride has been shown to inhibited of host protease furin, which is required for cleavage and activation of the SARS‐CoV‐2 S protein and restores host ENaC sodium channel functioning, which is involved in normal mucociliary clearance and is dysregulated by SARS‐CoV‐2. 40 Also, as mentioned previously, SNI is a well‐established treatment for symptomatic relief in URTIs and CRS. 9 , 10 , 41 The most common side effects reported by <10% of users are nasal irritation and rarely epistaxis; however, compliance in the literature remains high and most find it tolerable. 41 Hypertonic saline has been found to achieve greater symptomatic relief but is associated with more adverse effects such as nasal irritation and burning. 42 Multiple trials have been published, including some that were included in this review, that have also shown benefit of SNI for symptomatic relief in COVID‐19. 20 , 43 Enhanced NVL clearance is hypothesized to assist in the reduction in symptom severity and disease mortality. 8 , 44 Thus, our findings complement the emerging literature that SNI may be beneficial for COVID‐19 symptoms.
PVP‐I is a broad‐spectrum antiseptic with virucidal activity which has shown in‐vitro efficacy against SARS‐CoV‐2. 15 , 16 Assessing the impact of PVP‐I on viral load, four studies found that PVP‐I could achieve greater viral clearance compared with controls, with two finding an immediate effect with a single application and two finding improved viral clearance over the course of their study with prolonged use. Conversely, three studies showed no impact of PVP‐I sprays (concentrations 0.4%–2.0%) on SARS‐CoV‐2 NVL. Notably, in this review, higher concentrations of PVP‐I did not necessarily translate to better viral clearance. Overall, the results for PVP‐I were mixed and heterogenous, and as such, its impact on SARS‐CoV‐2 NVL is inconclusive.
PVP‐I can be administered as a nasal spray or irrigation. Arefin et al. (2021) showed that irrigation with 0.5% PVP‐I is more effective than a spray at the same concentration in reducing viral load. 30 Previous studies have concluded that nasal irrigation administered via nasal douche or neti‐pot shows greater efficacy for treating symptoms of CRS compared with nasal sprays, which is attributed to greater penetration of the paranasal structures. 45 Additionally, high‐volume irrigation (>50 mL) has shown to improve penetration of the nasal cavities and maxillary sinuses, and lead to greater shear stress and contact time in simulated models. 46 , 47 The majority of the studies on PVP‐I administered it as a nasal spray which are low volume formulations that may not achieve effective delivery of PVP‐I to all areas of the nasal mucosa. This is one reason that could explain its varied efficacy in this review. Notably, the two studies that tested PVP‐I as an irrigation were both successful; however, it is uncertain how much of this is attributed to the virucidal activity of PVP‐I versus the irrigation itself.
A chemical additive that was employed in three positive SNI studies, two studying viral load and one studying transmission, was xylitol. 26 , 27 , 39 Xylitol is a sugar alcohol that has anti‐inflammatory and anti‐microbial properties. 48 Preliminary data during the pandemic showed that xylitol demonstrated in‐vitro virucidal efficacy against SARS‐CoV‐2. 49 Imaging results from electron microscopy within this study suggest that xylitol may be involved in a mechanism that produces decoy carbohydrate molecules that SARS‐CoV‐2 will bind to in place of ACE2 receptors. 49 Xylitol‐based nasal sprays have already been shown in two different studies, an RCT and a case series of three patients, to improve viral symptoms of COVID‐19, particular olfactory dysfunction. 50 , 51 While not a primary outcome, the data from our review support that intranasal xylitol employed in saline‐based mediums can also contribute to the reduction of NVL and transmission of SARS‐CoV‐2. Xylitol was one of many different additives employed in nasal irrigation mediums studied in this review. There is potential for synergistic benefit with additives employed in nasal irrigation, and future work could involve a scoping review to understand the various additives available and their efficacy against SARS‐CoV‐2.
INCS have been hypothesized to prevent COVID‐19 progression if used early in the disease, via inhibition of viral entry and suppression of the anti‐inflammatory cascade. 52 Specifically, INCS have been shown to reduce expression of the ACE2 receptor in the nasal mucosa, the main route of entry for SARS‐CoV‐2, and to reduce pro‐inflammatory cytokines such as IL‐6. 52 , 53 This review found no studies investigated the efficacy of INCS for reduction of SARS‐CoV‐2 NVL. However, a retrospective cohort study by Strauss et al. (2021) found that INCS usage before COVID‐19 infection was associated with lower risk for hospitalization, ICU admission, and in‐hospital mortality. 54 This highlights the need for a RCT in this area.
This study is limited by the overall heterogeneous data and various methods for measuring viral load or transmission across these trials, which prevented meta‐analysis and made direct comparisons of these studies difficult. Additionally, many of the trials used in this study had relatively small sample sizes and were lower quality based on the ROB assessment.
CONCLUSIONS
In this review, SNI was the best studied intervention and had the best evidence for reducing SARS‐CoV‐2 NVL. The data surrounding the use of PVP‐I present mixed results, and it remains unclear if the benefit is from potential virucidal activity or from irrigation alone. This study did not yield any evidence for the use of INCS for reducing viral load in patients with COVID‐19, and future clinical trials are warranted.
ACKNOWLEDGEMENTS
Thank you to all authors for their tireless contributions to this manuscript.
Editor's Note: This Manuscript was accepted for publication on August 28, 2024.
The authors have no funding, financial relationships.
Since 2022, Dr. Sowerby received royalties from the company NeilMed for a product called SmellRestore. This project is unrelated to nasal irrigation.
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