Interim Analysis of an Open-label Randomized Controlled Trial Evaluating Nasal Irrigations in Non-hospitalized Patients with COVID-19

Quanhu Sheng, Ph.D.,3 Li Ching Huang, Ph.D.,3 Kate Von Wahlde, M.J.,1 Suman Das, Ph.D.,4 Naweed I. Chowdhury, M.D.,1 and Justin H. Turner, M.D., Ph.D1

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Introduction

Response to the Covid-19 pandemic has primarily focused on pharmacologic and medical interventions, including antivirals1, convalescent sera2, and vaccinations3, with each potentially critical in the fight against Covid-19, particularly among high risk and hospitalized populations. Non-hospitalized patients with mild-moderate disease comprise an estimated 81% of those affected with Covid-194 and there are currently no widely available interventions with proven ability to hasten symptom resolution or reduce viral shedding. We started an open-label randomized controlled trial to evaluate the effect of nasal irrigation with hypertonic saline or saline with surfactant on upper respiratory symptoms and viral load. Viral shedding is highest in the nasal cavity and nasopharynx5, and prior RCTs of saline irrigations for the common cold, including non-SARS-CoV-2 coronaviruses, have shown that saline rinses can reduce symptom burden and decrease viral shedding6.

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Methods

We identified patients diagnosed with a positive qualitative RT-PCR SARS-CoV-2 diagnostic test obtained from Vanderbilt University Medical Center and affiliated testing centers. Patients were enrolled in the study within 24 hours of testing and were given swabs, viral preservation media, and a symptom diary incorporating a modified version of the validated Wisconsin Upper Respiratory Symptom-21 Survey (WURSS-21) (Supp. Fig. 1)7. Patients were randomized to one of three treatment arms: 1) twice daily irrigation with 250cc hypertonic saline (HTS), 2) twice daily irrigation with hypertonic saline with 1% surfactant (HTSS) and 3) a non-intervention (NI) group (Supp. Fig. 2). Participants performed scheduled mid-turbinate swabs and recorded daily temperatures and symptom scores over the 21-day study duration. A prior cross-sectional study found equivalent sensitivity and high correlation between patient-performed mid-turbinate swabs and nasopharyngeal swabs performed by health care workers8. Comprehensive details of study methodology and power analysis are provided in the Methods section in the Supplementary Appendix.

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Results

We performed an interim analysis on the first 45 patients with completed symptom questionnaires, which included 17 patients in the no intervention group, and 14 each in the hypertonic saline and saline + surfactant groups (Supp. Table 1). The groups were similar with respect to age, sex, comorbidities, and other demographic and/or clinical factors. The median number of symptomatic days before diagnosis ranged from 2.0 to 2.5 and did not differ between groups. Study completion was also similar with three patients lost to follow-up in each treatment arm.

The global symptom score for the question ‘How sick do you feel today’, continually declined during the study duration for all treatment groups (Figure 1A), with a trend toward earlier time to symptom resolution in the intervention groups (median 14 days for NI, 10 days for HTS and HTSS; p=0.16). There was a significant difference in median days to symptom resolution for nasal congestion (NI 14 days; HTS 5 days; HTSS 7 days; p=0.04) and headache (NI, 12 days; HTS, 3 days; HTSS, 5 days; p=0.02) (Figure 1B, Table 1). Additionally, there was a trend toward differences between groups for cough (p=0.19), and fatigue (p=0.17). Comparison of viral load between groups is awaiting batch analysis and is pending completion of study enrollment.

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Days until symptom resolution in COVID-19 patients. (A) Daily reported symptom scores for individual participants during the 21-day study duration for the question ‘How sick do you feel today’. (B) Daily median symptom scores for participants during the 21-day study duration for cough, nasal congestion, headache, and fatigue.

Table 1.

Days until symptom resolution obtained from modified WURSS-21 questionnaire. Data presented as medians with interquartile range. BOLD indicated p < 0.05 by Kruskal-Wallis test.

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Discussion

Nasal saline irrigation is a commonly accepted and inexpensive therapy with proven efficacy as a treatment for viral upper respiratory infections and has been proposed as a potentially beneficial treatment for COVID-199. Here we present initial findings from the first randomized controlled trial evaluating nasal irrigations in non-hospitalized patients with COVID-19. The effect of nasal irrigation on symptom resolution was substantial, with nasal congestion and headache resolving a median of 7-9 days earlier in the intervention groups. Our analysis suggests that nasal irrigations may shorten symptom duration and may have potential as a widely available and inexpensive intervention to reduce disease burden among those affected. The additive effects of surfactant remain unclear as the impact of HTS and HTSS on symptom resolution were fairly equivalent, and it has been reported that surfactant nasal irrigations are associated with some tolerability issues in a subset of patients10. However, the addition of surfactant may have beneficial effects on viral shedding and/or maturation given their reported ability to rapidly induce membrane dissolution and lysis of many viruses and other microorganisms.

A note of caution is indicated when considering use of nasal saline irrigations in patients with confirmed COVID-19 as irrigation could potentially disperse viral particles or contaminate surfaces in the immediate vicinity. The SARS-CoV-2 virus can remain on plastic and metal surfaces for extended periods of time11, and other types of viruses can be detected in nasal lavage fluid12. Given these concerns, the current study only enrolled patients who could self-isolate and perform irrigation in a bathroom separate from other household contacts. Similar precautions would need to be taken by any COVID-19 patient considering this intervention.

While the current study provides evidence to suggest that topical saline irrigation can reduce symptom burden in patients with COVID-19, we are not yet able to determine whether irrigations affect viral load and/or shedding. We hypothesize that both HTS and HTSS will reduce viral shedding as has previously been reported for some cold viruses6, and will present these findings after batch qRT-PCR analysis of nasal swabs from all study participants. In the interim, we would advocate the use of hypertonic nasal saline irrigations in non-hospitalized COVID-19 patients as a safe and inexpensive intervention to reduce symptom burden.

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Supplementary Material

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Acknowledgments

This project was supported by NIH R21 AI142321 (to J.H.T. and S.D.). Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Institutes of Health.

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Footnotes

Disclosure of potential conflicts of interest: N.I. Chowdhury is a consultant for Optinose, Inc. J.H. Turner has received grant support from the NIH/National Institute of Allergy and Infectious Diseases (NIAID) and NIH/National Institute on Aging (NIA). The remaining authors declare that they have no relevant conflicts of interest.

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References

1. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report. The New England journal of medicine 2020. [PubMed] [Google Scholar]

2. Valk SJ, Piechotta V, Chai KL, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. The Cochrane database of systematic reviews 2020;5:CD013600. [PMC free article] [PubMed] [Google Scholar]

3. Corbett KS, Flynn B, Foulds KE, et al. Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. The New England journal of medicine 2020. [PMC free article] [PubMed] [Google Scholar]

4. Coronavirus Disease 2019 (COVID-19). 2020. (Accessed August 3, 2020, at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html.)

5. Zou L, Ruan F, Huang M, et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. The New England journal of medicine 2020;382:1177–9. [PMC free article] [PubMed] [Google Scholar]

6. Ramalingam S, Graham C, Dove J, Morrice L, Sheikh A. A pilot, open labelled, randomised controlled trial of hypertonic saline nasal irrigation and gargling for the common cold. Scientific reports 2019;9:1015. [PMC free article] [PubMed] [Google Scholar]

7. Barrett B, Brown R, Mundt M, et al. The Wisconsin Upper Respiratory Symptom Survey is responsive, reliable, and valid. Journal of clinical epidemiology 2005;58:609–17. [PMC free article] [PubMed] [Google Scholar]

8. Tu YP, Jennings R, Hart B, et al. Swabs Collected by Patients or Health Care Workers for SARS-CoV-2 Testing. The New England journal of medicine 2020;383:494–6. [PMC free article] [PubMed] [Google Scholar]

9. Farrell NF, Klatt-Cromwell C, Schneider JS. Benefits and Safety of Nasal Saline Irrigations in a Pandemic-Washing COVID-19 Away. JAMA otolaryngology-- head & neck surgery 2020. [PubMed] [Google Scholar]

10. Turner JH, Wu J, Dorminy CA, Chandra RK. Safety and tolerability of surfactant nasal irrigation. International forum of allergy & rhinology 2017;7:809–12. [PubMed] [Google Scholar]

11. Jin Y, Yang H, Ji W, et al. Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses 2020;12. [PMC free article] [PubMed] [Google Scholar]

12. Lee SB, Yi JS, Lee BJ, et al. Human rhinovirus serotypes in the nasal washes and mucosa of patients with chronic rhinosinusitis. International forum of allergy & rhinology 2015;5:197–203. [PubMed] [Google Scholar]