Interim analysis of an open‐label randomized controlled trial evaluating nasal irrigations in non‐hospitalized patients with coronavirus disease 2019

Abstract

Response to the coronavirus disease 2019 (COVID-19) pandemic has primarily focused on pharmacologic and medical interventions, including antivirals,1 convalescent sera,2 and vaccinations,3 with each potentially critical in the fight against COVID-19, particularly among high-risk and hospitalized populations. Non-hospitalized patients with mild to moderate disease comprise an estimated 81% of those affected with COVID-19,4 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 (RCT) to evaluate the effect of nasal irrigation with hypertonic saline (HTS) or saline with surfactant on upper respiratory symptoms and viral load. Viral shedding is highest in the nasal cavity and nasopharynx,5 and prior RCTs of saline irrigations for the common cold, including non–severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) coronaviruses, have shown that saline rinses can reduce symptom burden and decrease viral shedding.6 We identified patients diagnosed with a positive qualitative real-time polymerase chain reaction (qRT-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) (Supplementary Fig. 1).7 Patients were randomized to 1 of 3 treatment arms: (1) twice-daily irrigation with 250 mL HTS; (2) twice-daily irrigation with HTS with 1% surfactant (HTSS); and (3) a nonintervention (NI) group (Supplementary 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 healthcare workers.8 Comprehensive details of study methodology and power analysis are provided in the Methods section in the Supplementary Appendix. We performed an interim analysis on the first 45 patients with completed symptom questionnaires, which included 17 patients in the NI group, and 14 each in the HTS and HTSS groups (Supplementary 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 the groups. Study completion was also similar with 3 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 (Fig. 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) (Fig. 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. 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-19.9 Here, we present initial findings from the first RCT 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 to 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, because the impact of HTS and HTSS on symptom resolution was fairly equivalent, and it has been reported that surfactant nasal irrigations are associated with some tolerability issues in a subset of patients.10 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 because 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 time,11 and other types of viruses can be detected in nasal lavage fluid.12 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. Although 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 been reported for some cold viruses,6 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. Figure 1. COVID-19 daily symptom survey (modified from Wisconsin Upper Respiratory Symptom Survey – 212). Figure 2. Consort flow diagram for screening, enrollment, and randomization of study participants. Table 1. Clinical and demographic characteristics of study participants. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.