Our pilot RCT confirms that it’s possible to recruit and retain participants for a full trial of HSNIG with 3% HS. HSNIG reduced the duration of illness (22%), OTCM use (36%) and illness in household members (35%). When individuals infected with similar viruses (rhinovirus, coronavirus, enterovirus and influenza virus) were compared, 30% more individuals had reduction in viral shedding by ≥0.5 log 10 per day in the intervention arm. This could explain both the reduction in the duration of illness and transmission to household contacts in the intervention arm. However, though the difference between the baseline and end-point samples was larger in the intervention arm than the control arm, the difference was not significant (although this study was not powered to detect differences in these measures). In participants who stopped HSNIG before day four, 54% (7/13) had an increase in viral shedding. There was also an increase/stabilisation of symptoms in 50% (8/16) before symptoms resolved. In fact, four individuals felt the need to restart HSNIG for one or more days (Fig. 4). These finding along with the lower rate of symptomatic household contacts in the intervention arm suggest that HSNIG helps reduce viral replication. Since viruses are shed during breathing and speaking7, measure that helps reduce viral shedding would help reduce transmission.

Recruitment was relatively easy though it involved regular email reminders. Advertising through social media could potentially help in future studies. A major concern was whether the population in Edinburgh would be happy to perform HSNIG. Surprisingly, only one individual declined to participate having met the trial nurse. Patient reported compliance with HSNIG was excellent. Participants performed HSNIG more times in the earlier part of the URTI and fewer times as symptoms improved, a trend which was in keeping with the severity of illness (Fig. 3). A surprisingly high proportion (86%) reported performing HSNIG outside their homes. 93% found HSNIG useful and 61% said they would perform HSNIG again if they had a cold, with a higher uptake if the procedure was more convenient. Alternatives such as nasal sprays are options, though they would not have the physical rinsing component of nasal irrigation. Hence a study to compare the two methodologies would be useful.

WURSS 21 score was not significantly different between the two arms, probably a reflection in the sample size. Neither was the EQ VAS score different between arms. EQ VAS score is an indicator of how a person feels on a given day and is not specific to URTI. It is hence probably not suitable for studies on URTI.

Our study has limitations. As a pilot with a primary outcome of establishing if a trial using HSNIG is viable, the study is not powered for efficacy end-points. We hence need a larger trial to confirm our findings. The lack of a placebo group is another limitation. Since our hypothesis was that the chloride ion has an antiviral effect, we were unable to use NS as a control as it could cause a reduction in symptoms. This is supported by results from earlier studies. For e.g. in a cross over trial (10 weeks twice daily nasal spray and 10 weeks without sprays with a two-week washout period), twice a day saline sprays significantly reduced nasal symptoms in military recruits compared to those with no intervention (p = 0.027). The number of episodes of URTI was lower in the period when saline sprays were used compared to the period when sprays were not used. However, the difference was just short of significance (p = 0.05)25. Our rationale also seems vindicated by a recent report suggesting that both sea water drops and saline drops were equally effective in treating children <2 years of age with URTI compared to symptomatic controls13. Sodium bicarbonate, though commonly used, is uncomfortable in the author’s personal experience. Recent evidence suggests that sodium ion also has an antimicrobial effect26,27. Hence, until a safe and comfortable placebo that contain neither chloride, halide or sodium ion is identified, placebo-controlled trials cannot be done.

Another aspect that needs to be considered is the potential benefits of the simple process of flushing in the intervention arm. Even in the presence of a placebo arm, this cannot be answered. Further studies with different methodologies for supplying NaCl (e.g. hypertonic saline sprays, or aerosolised NaCl) may help answer this question.

In the absence of a placebo, we focused on viral shedding as an objective measure of antiviral activity due to HSNIG. There were more individuals without a detectable virus in the baseline sample in the control arm (12/34:35%) compared to the intervention arm (5/32:16%). This difference did not however reach statistical significance (p = 0.059) (Table S1). Though allergic rhinitis (history of allergy with current eye/nose itching or sneezing) was an exclusion criterion, it is possible that some of these individuals could have allergic rhinitis. Or, the infective aetiology might not have been detected in the nose swab. For e.g. sore throat was often recorded by those who did not have a detectable virus. As we collected a nose swab, it is possible that the aetiology could be picked up by including a throat swab along with a nose swab.

Viral shedding is difficult to quantify due to the variability in sampling and as most routine respiratory PCR’s are qualitative assays. We used self-collected mid-turbinate swabs (Copan, Italy) both for participants convenience (no gag reflex) and as the swabs are designed with a stop which increases safety and should help reduce variation in sampling28. Since nasal irrigation could physically wash off the virus, we collected swabs first thing in the morning before HSNIG. We used eNAT, a transport medium that inactivates viruses and in which samples are stable at room temperature for at least two weeks. In our hands, samples in eNAT were stable for at least a week at room temperature and could be posted back to the laboratory for testing29. Where we identified a virus in the baseline sample, we tested all five samples in the same run to minimise inter-assay variability. To compare viral shedding, we converted CT values to log 10 values. The baseline samples were hence tested on two occasions. The inter-assay variation between the two results was very low [mean (SD): 0.21 log 10 (1.17)]. The cut-off of ≥0.5 log 10 per day used to determine reduction in viral shedding is more than double that of the inter-assay variation seen and hence is unlikely to be an artefact of the testing process. All these measures together have helped produce viral shedding data that could be compared between arms. In four individuals with a positive baseline sample, follow-up samples were negative. In two individuals a sample with a low CT (i.e. high viral copy) were followed by samples with undetectable virus. Since our consent did not include human DNA testing, we could not test for housekeeping genes and cannot be certain if these samples were properly collected. This need to be addressed in future studies.

We detected viruses in 73% of individuals, much higher than 40–55% reported by others30,31,32. This could be due to sampling within 48 hours of onset of illness. Though rhinoviruses and coronaviruses were the commonest, our study confirms that numerous viruses cause URTI. The viral load of the initial sample varied between individuals and sequential sampling is important to detect change in viral shedding. A larger study would help determine the relative efficacy of HSNIG against different viruses.

At baseline, those infected with a virus other than rhinovirus had more individuals with runny nose and blocked nose (data not shown). Sore throat was often recorded in those without a viral aetiology. Hence a baseline throat swab for both bacteria and viruses may help determine the aetiology in these individuals.

The results of ELVIS are significantly different to that from Adam et al. which had many methodological issues. They compared 2% HS spray, NS spray (two squirts, thrice a day) and a control group in individuals with the common cold or rhinosinusitis10. Though sample size was similar to ELVIS (35–43/arm), individuals were recruited up to 3 weeks after illness onset. Very few had the common cold (12–17/arm), most had bacterial rhinosinusitis and 98% of them were treated with antibiotics. Despite these shortcomings, individuals with the common cold who received HS sprays said they would use it again (p = 0.007). To avoid these shortcomings, we selected only those with a common cold within 48 hours of onset, and who were not on antibiotic therapy.

Strengths of the study are the use of WURSS-21, a validated symptom score diary33, for up to two weeks, and sequential sampling over 5 days in otherwise healthy adults. With positive results in a controlled population, we can also look at more challenging population groups in subsequent studies. An alternative strategy would be to use HSNIG as a prophylactic tool. Wood workers who performed nasal irrigation twice a day for a year had fewer episodes of sore throat and colds9. Sea water sprays thrice a day, for 12 weeks in children significantly reduced reported illness, school absence and use of medication11. Though feedback regarding the use of HSNIG as a prophylactic tool was negative in our population, it may not be reflective of a population at high-risk for complications such as those with asthma/COPD.

Compliance was excellent in our study. We had online videos for preparation of hypertonic saline, performing HSNIG and collection of swabs both for providing instruction to participants and as a handy reminder if needed later on. Participants were all encouraged to prepare the solution and perform HSNIG in the presence of the trial nurse which we believe helped with compliance. Participants were also trained to collect the nose swab by the trial nurse. Hence a pragmatic approach (i.e. patient reported compliance) can be taken to reduce the burden to the participant and the cost of the study. However, in patient groups where compliance might be an issue, compliance could be improved by using video monitoring of the procedures (HSNIG and collecting nasal swabs) via smart phones with support from the clinical team similar to the approach used for tuberculosis treatment34,35. The amount of salt used could also be measured at the end of the study. Tests for human DNA could be done to determine if swabs were actually collected before being introduced into the transport medium. Online data entry could be encouraged which would help reduce missing/incorrect data. Reminder messages (by text or email) could be sent to prompt regular data entry and return of samples. However, these decisions would need to be taken considering the population, the burden to the participant and the cost involved.

In this pilot, HSNIG significantly reduced the duration of URTI, OTCM use and illness within the household. A greater fall in viral shedding possibly explains the reduction in duration of symptoms and in symptomatic household contacts. This is in keeping with the lab evidence that cells utilise NaCl to mount an antiviral effect. A larger study powered for clinical and virological end-points is urgently needed to confirm these findings.