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A pilot, open labelled, randomised controlled trial of hypertonic saline nasal irrigation and gargling for the common cold

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There are no antivirals to treat viral upper respiratory tract infection (URTI). Since numerous viruses cause URTI, antiviral therapy is impractical. As we have evidence of chloride-ion dependent innate antiviral response in epithelial cells, we conducted a pilot, non-blinded, randomised controlled trial of hypertonic saline nasal irrigation and gargling (HSNIG) vs standard care on healthy adults within 48 hours of URTI onset to assess recruitment (primary outcome). Acceptability, symptom duration and viral shedding were secondary outcomes. Participants maintained a symptom diary until well for two days or a maximum of 14 days and collected 5 sequential mid-turbinate swabs to measure viral shedding. The intervention arm prepared hypertonic saline and performed HSNIG. We recruited 68 participants (2.6 participants/week; November 2014-March 2015). A participant declined after randomisation. Another was on antibiotics and hence removed (Intervention:32, Control:34). Follow up data was available from 61 (Intervention:30, Control:31). 87% found HSNIG acceptable, 93% thought HSNIG made a difference to their symptoms. In the intervention arm, duration of illness was lower by 1.9 days (p = 0.01), over-the-counter medications (OTCM) use by 36% (p = 0.004), transmission within household contacts by 35% (p = 0.006) and viral shedding by ≥0.5 log10/day (p = 0.04). We hence need a larger trial to confirm our findings.
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A pilot, open labelled, randomised
controlled trial of hypertonic saline
nasal irrigation and gargling for the
common cold
Sandeep Ramalingam
1, Catriona Graham2, Jenny Dove1, Lynn Morrice3 & Aziz Sheikh3
There are no antivirals to treat viral upper respiratory tract infection (URTI). Since numerous viruses
cause URTI, antiviral therapy is impractical. As we have evidence of chloride-ion dependent innate
antiviral response in epithelial cells, we conducted a pilot, non-blinded, randomised controlled trial
of hypertonic saline nasal irrigation and gargling (HSNIG) vs standard care on healthy adults within
48 hours of URTI onset to assess recruitment (primary outcome). Acceptability, symptom duration 
and viral shedding were secondary outcomes. Participants maintained a symptom diary until well
for two days or a maximum of 14 days and collected 5 sequential mid-turbinate swabs to measure 
viral shedding. The intervention arm prepared hypertonic saline and performed HSNIG. We recruited
68 participants (2.6 participants/week; November 2014-March 2015). A participant declined after 
randomisation. Another was on antibiotics and hence removed (Intervention:32, Control:34). Follow up 
data was available from 61 (Intervention:30, Control:31). 87% found HSNIG acceptable, 93% thought 
HSNIG made a dierence to their symptoms. In the intervention arm, duration of illness was lower by 
1.9 days (p =0.01), over-the-counter medications (OTCM) use by 36% (p =0.004), transmission within 
household contacts by 35% (p =0.006) and viral shedding by 0.5 log10/day (p =0.04). We hence need a 
larger trial to conrm our ndings.
e common cold is a viral upper respiratory tract infection (URTI). Adults and children get 2-3 and 6-7 attacks
respectively of URTI annually1,2. In 2016 the UK lost 34.0 million work days (33.1% of total) due to minor
illnesses such as URTI3. An episode of URTI cost €266.41, €273.36 in Cardi and Southampton respectively4. In
the US, 72% of respondents had URTI in the past year costing $40 billion annually2. Outbreaks of respiratory tract
infections are common in hospitals and care homes with signicant morbidity and mortality5. URTI can lead to
lower respiratory tract infections (LRTI) such as pneumonia, or cause exacerbations in individuals with asthma,
chronic obstructive pulmonary disease (COPD), and cystic brosis6. Since URTI precedes LRTI, early interven-
tion could prevent these complications.
At present, there are no antiviral agents to treat the common cold. ough rhinovirus is called the “common
cold virus”, a large number of viruses cause URTI7. Hence, specic antiviral treatment is impractical, and we
need an intervention eective against multiple viruses. Jalaneti (cleaning the nasal passages with salt water), an
ancient practice from India is recommended in Yogic texts for the common cold8. A signicant reduction in sore
throats and colds was reported when Australian wood-workers performed Jalaneti for a year9. ree randomised
controlled trials (RCT) report the ecacy of salt water for acute URTI. Adam et al. reported the lack of improve-
ment in symptoms or duration of illness in adults with a common cold or bacterial rhinosinusitis [hypertonic
saline (HS)/normal saline (NS) sprays thrice/day vs. standard care]. However, individuals with a common cold
who received HS sprays said they would use it again (p = 0.007)10. Sea-water sprays (six-times/day) signicantly
reduced sore throat, nasal secretions, decongestant/mucolytic use in children with URTI11. A Cochrane review
1Department of Laboratory Medicine, Royal Inrmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16
4SA, UK. 2Wellcome Trust Clinical Research Facility, University of Edinburgh, Western General Hospital, Crewe Road
South, Edinburgh, EH4 2XU, UK. 3Centre of Medical Informatics, Usher Institute of Population Health Sciences
and Informatics, The University of Edinburgh, Medical School Doorway 3, Teviot Place, Edinburgh, EH8 9AG, UK.
Correspondence and requests for materials should be addressed to S.R. (email: sandeep.ramalingam@nhslothian.
scot.nhs.uk)
Received: 4 May 2018
Accepted: 12 December 2018
Published: xx xx xxxx
OPEN
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concludes that the evidence is very limited12. In a recent report, both NS and sea-water drops (thrice/day) reduced
the severity of URTI symptoms in young children13.
Inhibition of viral replication in the presence of chloride/halide salts was reported in the 1960’s14. We have
recently reported laboratory evidence that non-myeloid cells (e.g. epithelial, broblast and hepatic cells) have an
innate immune mechanism, which is augmented in the presence of salt(NaCl)15. In cell culture models, DNA,
RNA, enveloped and non-enveloped viruses are all inhibited in the presence of NaCl15. e antiviral eect is
dependent on the availability of chloride ions (and not sodium ions)15. In the presence viral infection and the
availability ofNaCl, cells utilise the chloride ions to produce hypochlorous acid (HOCl)15. Since HOCl is the
active ingredient in bleach, which is known to have an antiviral eect, the mechanism could be augmented by sup-
plying chloride ions through NaCl to treat infections. Here, we report the results of the Edinburgh and Lothians
Viral Intervention Study (ELVIS), a pilot RCT of hypertonic saline nasal irrigation and gargling (HSNIG) versus
standard care in adults with URTI to determine if we can recruit and retain participants in Edinburgh and to get
initial information on acceptability, duration of symptoms, and viral shedding.
Results
We recruited 68 participants over 26 weeks between October 2014 and March 2015 (2.6 participants/week: Fig.1).
We excluded two (n = 66) [one declined aer randomisation, and the other was on antibiotics] and randomised
32 to the intervention arm and 34 to the control arm (Fig.2). e majority (76%) were women. Most (76%)
preferred paper forms over online feedback. Most (Intervention: 94%, Control: 91%) returned the daily forms,
end-of-study form (Intervention: 88%, Control: 85%) and swabs (Intervention: 88%, Control: 91%). Of the
sixty-six participants, ve did not return daily forms. Of the sixty-one, four did not return end-of-study forms. Of
the y-seven, three did not return samples. All forms and samples were hence available in y-four individuals.
80% in the intervention arm used 3% HS, while 9% each used 2.5%, 2% HS. All but one used Cornish sea salt.
One participant le without the sea salt and used another brand available at home. An individual in the control
arm reported performing nasal irrigation but provided no further information.
e baseline characteristics, symptom severity and degree of interference with daily life were similar in both
arms (Table1). We identied an aetiology in the baseline sample of 73% (48/66) of participants (TableS1).
Amongst these, 56% were rhinovirus and 31% were coronaviruses (COV), with the rest due to enterovirus, inu-
enza A virus, parainuenza virus type 3 (PIV-3), respiratory syncytial virus (RSV) and human metapneumovirus
(HMPV). We detected dual infections of rhinovirus with an enterovirus/COV HKU1 in two.
Most participants completed the “WURSS-21-Scot” daily until they were well (i.e. a score of 0) on two days
(please see Fig.S1 for daily forms). Intervention and control arms completed the symptom diary for a mean (SD)
of 6.8 (2.2) and 8.7 (3.3) days respectively. e intervention arm hence had a reduction in duration of illness by
1.9 days (95% CI = 0.4 to 3.3) (p = 0.01) (Fig.3). e duration of illness was signicantly lower (p = 0.01) even if
the rst day participants felt well was the end-point [Mean (SD) Intervention: 6.0 (2.4); Control: 8.0 (3.4) days].
Participants performed HSNIG for a median of 5 days (IQR: 3 to 6) and at a median of thrice a day (IQR: 2 to 3)
(Fig.3).
ere was a signicant reduction in the duration of runny nose (1.8 days, 95% CI:0.4 to 3.2, p = 0.01), blocked
nose (2.7 days, 95% CI:1.2 to 4.1, p < 0.001), sneezing (1.5 days, 95% CI:0.3 to 2.9, p = 0.02), cough (2.4 days,
95% CI:0.9 to 4.0, p = 0.003), hoarseness of voice (1.7 days, 95% CI:0.2 to 3.1, p = 0.02) (Fig.3; Supplementary
TableS2).
We could calculate the average WURSS-21 score and EQ-VAS scores from the diaries (please also see sup-
plementary results). e median (IQR) average WURSS 21 score in the intervention group was 13.2 (7.6 to
16.4) [n = 30] and 16.9 (9.9 to 24.7) [n = 31] in the control arm (p = 0.09). e mean (SD) average quality of life
Figure 1. Expected and actual recruitment: Recruitment of participants from the 1st October 2014 till close
of recruitment on 31st March 2015. If we take the full 26-week period, this would result in an average of 2.6
participants per week over the study period. However, if we were to take the rst and last recruitment dates this
give a period of 20 weeks which results in an average of 3.4 participants per week.
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measure (EQ-VAS) over the study duration was higher at 74.3 (12.1) [n = 30] for the intervention and 70.8 (15.5)
[n = 31] in the control arm. e dierence in means of 3.4, 95% CI for dierence (3.7 to 10.6) was not signi-
cant (p = 0.338) (Supplementary TableS3).
Excluding those with no virus detected in the baseline sample [Intervention: 5 (16%); Control: 12 (35%)],
samples on days 1–4 to estimate viral shedding was available in 25 and 20 individuals in intervention and control
arms respectively (Fig.4). In four individuals [a COV and a rhinovirus each per arm], no virus was detectable on
days 1–4. Details of symptom severity, viral shedding and HSNIG are in Fig.4.
e median (IQR) reduction in viral shedding between baseline and end-point sample in the intervention
arm was 2.23 log10 (3.04 to 0.32) [n = 26] and 1.51 log10 (3.30 to 0.55) [n = 21] in the control arm
(p = 0.9). (see supplementary results). We then estimated the proportion of individuals with viral shedding by
0.5 log10/day between arms (see supplementary results). Four individuals in the intervention arm had paramyx-
ovirus infection but none in the control arm. As paramyxoviruses have a longer life cycle16,17, incubation period18,
duration of viral shedding19 and illness19,20 compared to rhinovirus2124, the data was analysed aer removing
these individuals. A higher proportion in the intervention arm had a fall 0.5 log10/day compared to controls
[Intervention 73% [n = 16/22], Control 43% [n = 9/21], dierence 30%, 95% CI for dierence in proportion
(58 to 2) p = 0.04].
End-of-study forms were available from y-seven individuals (Table2). Over-the-counter medications use
(OTCM) use was 36% lower in the intervention arm (95% CI 14 to 59) (p = 0.004). Amongst participants who
were not living alone, 35% fewer individuals in the intervention arm (95% CI 10 to 60) had household contacts
developing URTI aer them (p = 0.006).
Screened prior to eligibility assessment
(n=171)
Assessed for eligibility (n=72)
Excluded (n=99)
Did not meet inclusion criterion (n=76)
Declined to parcipate (n=15)
Other reasons (i.e. unable to aend
within 48 hours(n=8))
Randomized (n=68)
Excluded (n=4)
Did not meet inclusion criterion (n=4)
Allocated to Intervenon (n=33)
Received allocated intervenon (n=32)
Did not receive allocated intervenon
(Declined to perform HSNIG) (n=1)
Allocated to Control (n=35)
Received allocated intervenon (n=34)
Removed (was on anbiocs) (n=1)
Number with follow-up (n=30)
Lost to follow-up, reason unknown (n=2)
Number with follow-up (n=31)
Lost to follow-up, reason unknown (n=3)
Number returned daily form (n=30)
Number returned swabs (n=28)
Number returned end-of-study form (n=28)
Number returned daily form (n=31)
Number returned swabs (n=31)
Number returned end-of-study form (n=29)
Screened
Enrollment
Allocaon
Follow-up
Assessment
Figure 2. Consort Flow diagram: Based on the “CONSORT extension for Pilot and Feasibility Trials Flow
Diagram” (http://www.consort-statement.org/downloads/extensions - Accessed 04/12/2018).
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We received feedback on HSNIG from 28/32 participants (TableS4). 93% said that HSNIG made a dierence
to their symptoms. ey found HS easy to prepare (100%). Most preferred to prepare solution in bulk in a ask
(86%) and preferred using a small bowl to perform HSNIG (75%). Most considered the procedure either com-
fortable or moderately comfortable (89%) and the majority (86%) were happy to perform the procedure outside
home. e most commonly reported eects were that it helped clear the nose/reduced stuness (n = 16), made
it easier to breathe (n = 7), speeded up resolution of symptoms (n = 5), reduced the severity of the illness (n = 3)
and improved sleep (n = 2). 60% of participants were likely to use HSNIG in the future and 25% of participants
were undecided if they would use HSNIG in the future. e gure increased to 86% if the procedure could be
made more convenient. Most (71%) however said they were unlikely to use HSNIG as a prophylactic measure.
Discussion
Our pilot RCT conrms that its 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 inuenza virus) were
compared, 30% more individuals had reduction in viral shedding by 0.5 log10 per day in the intervention arm.
is could explain both the reduction in the duration of illness and transmission to household contacts in the
intervention arm. However, though the dierence between the baseline and end-point samples was larger in the
intervention arm than the control arm, the dierence was not signicant (although this study was not powered
to detect dierences in these measures). In participants who stopped HSNIG before day four, 54% (7/13) had an
increase in viral shedding. ere 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). ese nding 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 signicantly dierent between the two arms, probably a reection in the sample size.
Neither was the EQ VAS score dierent between arms. EQ VAS score is an indicator of how a person feels on a
given day and is not specic 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 ecacy end-points. We hence need a larger trial to conrm our ndings. e lack
of a placebo group is another limitation. Since our hypothesis was that the chloride ion has an antiviral eect, we
were unable to use NS as a control as it could cause a reduction in symptoms. is 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
Intervention (n = 32) n (%) Control (n = 34) n (%)
Age mean(SD) 34.6 (9.3) 39.4 (10.9)
WURSS-21 Score mean (SD) 41.6 (18.2) 43.9 (21.8)
EQ-VAS Score mean(SD) 65.9 (13.6) 63.7 (17.4)
Sex (Female) 24 (75) 25 (74)
Tobacco smoker - current 1 (3) 3 (9)
Tobacco smoker - ex 5 (16) 11 (32)
e-Cigarette smoker - current 0 (1) 1 (3)
e-Cigarette smoker - ex 2 (6) 0 (0)
Adults at home = 1 6 (19) 5 (15)
>126 (81) 29 (85)
Children at home = 0 19 (59) 19 (56)
1 7 (22) 5 (15)
>16 (19) 10 (29)
No one unwell before them at home 19 (59) 21 (62)
Employment status: Full-time 20 (63) 21 (62)
Part-time 7 (22) 5 (15)
Education: Full time 4 (13) 4 (12)
Other 1 (3) 4 (12)
Table 1. Baseline characteristics. WURSS: Wisconsin upper respiratory symptom survey; EQ-VAS: EuroQol-
Visual Analog Scale.
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two-week washout period), twice a day saline sprays signicantly reduced nasal symptoms in military recruits
compared to those with no intervention (p = 0.027). e 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 dierence was just
short of signicance (p = 0.05) 25. Our rationale also seems vindicated by a recent report suggesting that both sea
water drops and saline drops were equally eective 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
Figure 3. Response from participants over the study period: Each line represents response of a participant over
14 days. Data is shown by treatment group. e global severity question was “How unwell do you feel today”.
e responses were graded from 0 (Not unwell), 1 (very mildly), 3 (mildly), 5 (moderately) and 7 (severely
unwell). Likewise, each symptom was graded 0 (no symptom) to 7 (severe).
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experience. Recent evidence suggests that sodium ion also has an antimicrobial eect26,27. Hence, until a safe and
comfortable placebo that contain neither chloride, halide or sodium ion is identied, placebo-controlled trials
cannot be done.
Figure 4. Severity of symptoms, viral shedding and relationship to HSNIG and participant number in each
arm: For each participant, the daily scores for the global question ‘how unwell do you feel today’ over 14
days are represented by the grey background. For the intervention arm (shown on the le), the blue columns
represent the number of times HSNIG was done that day. For both arms, change in viral shedding (as log values;
Red line) is shown for the corresponding days.
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Another aspect that needs to be considered is the potential benets of the simple process of ushing in the
intervention arm. Even in the presence of a placebo arm, this cannot be answered. Further studies with dierent
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. ere 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%). is dierence did not however reach statistical
signicance (p = 0.059) (TableS1). ough 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 oen 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 dicult 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 conven-
ience (no gag reex) 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 o the virus, we collected swabs rst 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 identied a virus in the
baseline sample, we tested all ve samples in the same run to minimise inter-assay variability. To compare viral
shedding, we converted CT values to log10 values. e baseline samples were hence tested on two occasions. e
inter-assay variation between the two results was very low [mean (SD): 0.21 log10 (1.17)]. e cut-o of 0.5 log10
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. is need to be addressed in
future studies.
We detected viruses in 73% of individuals, much higher than 40–55% reported by others3032. is could be
due to sampling within 48 hours of onset of illness. ough rhinoviruses and coronaviruses were the commonest,
our study conrms that numerous viruses cause URTI. e viral load of the initial sample varied between individ-
uals and sequential sampling is important to detect change in viral shedding. A larger study would help determine
the relative ecacy of HSNIG against dierent 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 oen 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.
Intervention Control
pn = 28 % n = 29 %
Took time o work 3 11 7 24 0.297*
Days o work: 1 2 7 2 7
2 1 4 1 3
3 0 4 14
Took over-the-counter medication 14 50 25 86 0.004*
Attended GP 0 2** 7
Attended hospital 1** 4 — 0
Household contact developed
symptoms aer participant 8/26 31 19 66 0.006
Performed procedure 28 100 1 3
Collecting swabs: Easy 19 68 18 62
Moderate 7 25 3 10
Dicult 2 7 8 28
Returning swabs: Easy 26 93 28 97
Diary completion: Easy 25 89 28 97
Form completion: Easy 25 89 27 93
Pre-study information – Useful 27 96 28 97
Instruction pack – Helpful 28 100 27 93
HSNIG video: Helpful 27 96 —
Table 2. Feedback from participants at the end of study. *Using shers exact test due to small counts or
expected counts, **Reason for attending GP/hospital was not available, GP: General practitioner, HSNIG –
Hypertonic saline nasal irrigation and gargling.
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e results of ELVIS are signicantly dierent to that from Adam et al. which had many methodological
issues. ey compared 2% HS spray, NS spray (two squirts, thrice a day) and a control group in individuals with
the common cold or rhinosinusitis10. ough sample size was similar to ELVIS (35–43/arm), individuals were
recruited up to 3 weeks aer 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 signicantly reduced
reported illness, school absence and use of medication11. ough feedback regarding the use of HSNIG as a
prophylactic tool was negative in our population, it may not be reective of a population at high-risk for compli-
cations 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, com-
pliance 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.
e 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 signicantly 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. is is in keeping with the lab evidence that cells utilise NaCl to mount an antiviral eect. A
larger study powered for clinical and virological end-points is urgently needed to conrm these ndings.
Methods
Study Setting and Design. We obtained ethical permission from the South-East Scotland Research Ethics
Committee (13/SS/0079) and carried out the study in accordance with the Declaration of Helsinki (Clinical trials
registration: NCT02438579, May 8, 2015). ELVIS was a pilot unblinded RCT of HSNIG to determine recruitment
in Edinburgh as the primary outcome. Acceptability and compliance with HSNIG, quality of life, duration of
symptoms and viral shedding were secondary outcomes. With a sample size of 27 per group we would be able
to express the proportion of those who return the symptom score diary and samples within that group to within
±19% based on a two-sided 95% condence interval around an expected proportion of 0.5. With the two groups
combined [i.e. a sample size of 54] we would be able to express a proportion to within ±13%. To allow for drop-
outs we planned to recruit up to 80 participants to have at least 30 participants per arm for analysis. e study was
advertised through schools, libraries and general practices in Edinburgh and Midlothian areas, local newspaper
coverage, emails within NHS Lothian, online, social media and the study website (www.elvisstudy.com).
Identication of individuals with a cold. Individuals with URTI were identied as done by Barrett et al.33,36
Volunteers had to (1) answer “Yes” to “do you have a cold?” or “do you think you are coming down with a cold?”;
(2) have at least one of rst four symptoms: nasal discharge, nasal obstruction, sneezing, sore throat, headache,
malaise, chilliness and cough and (3) have a Jackson Score of 2. Onset of URTI >48 hours, concurrent antibiotic
use, pregnancy, known chronic conditions, immunosuppression, allergic rhinitis, inability to perform HSNIG and
taking part in another medical trial were exclusion criterion. Volunteers met a trial nurse at a Clinical Research
Facility at the Royal Inrmary of Edinburgh (RIE) or the Western General Hospital where informed consent was
obtained, and participants were then randomised. Participants were centrally allocated into intervention and
control arms using a minimisation algorithm containing sex and smoking status (current/not a current smoker)
with a built-in random component to ensure allocation concealment.
Feedback. Participants had to maintain a daily form (Fig.S1) until they recorded “not unwell” (i.e. score of 0) on
two consecutive days or for a maximum of 14 days or until the individual needed further treatment for URTI and
then lled the end-of-study form (Fig.S2). e short form of the Wisconsin Upper Respiratory Symptom Survey
(WURSS-21) was used to collect daily symptom data33. For use in the Scottish context, and with the authors con-
sent, the words “sick” and “plugged” were replaced with “unwell” and “blocked”, respectively (WURSS-21-Scot)
(Fig.S1). Participants were asked to answer the global severity question: “How unwell do you feel today?” which
was scored from 0 (not unwell) to 7 (severely unwell). If they scored >0, then symptoms and functional ability
were graded 0–7. ey then answered the global change question “Compared to yesterday, I feel my cold is” which
was scored from 0 (very much better) to 6 (very much worse). Total WURSS-21 score was calculated by adding
the scores for all except the rst and last question. To calculate the mean WURSS-21 score, the scores for each
participant were added and divided by 14. A mean value of EQ-VAS was calculated for each participant over the
time questionnaires were returned as it was possible that participants may not score 100 even when a person’s cold
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9
SCIENTIFIC REPORTS | (2019) 9:1015 | https://doi.org/10.1038/s41598-018-37703-3
symptoms have completely resolved. Both arms documented OTCM use and if they contacted the general prac-
titioner (GP)/nurse for further management of their URTI. Feedback about trial procedures, acceptability, health
service use, costs to the patient and suggestions for improving the study and information on symptomatic house-
hold contacts were collected at the end of the study. Participants had the option to ll the daily and end-of-study
forms online or on paper and return them to the laboratory.
Study Procedures. Intervention arm were taught to prepare the hypertonic saline, perform HSNIG and doc-
umented the number of times/day and side-eects. ey could either prepare 100 ml of hypertonic saline for
a single use or prepare in bulk in a clean ask for use during the day. Instructions on how to make the solution
and perform HSNIG are in Supplementary Methods and in www.elvisstudy.com. Control arm managed URTI
as they normally did. As the hypothesis was chloride ion mediated antiviral eect, normal saline could not be
used as a placebo. As sodium bicarbonate was uncomfortable in the authors personal experience, we opted for
not including a placebo arm. e rationale for not including a saline placebo arm is elaborated in the discussion.
Participants documented OTCM use and were asked to contact to their GP if unwell. e trial nurse helped
participants in the intervention arm identify the highest concentration of HS they were comfortable with (from
3%, 2.5%, 2.0% and 1.5%). Intervention arm were taught how to prepare HS and perform HSNIG with vid-
eos (www.elvisstudy.com) and given the opportunity to perform HSNIG under supervision. Cornish sea salt,
digital-measuring spoon, bowls and ask were provided with instructions to perform HSNIG as many times as
required (expected frequency up to 6 times/day for the rst two days, reducing in frequency from day 3 as symp-
toms improved).
Mid-turbinate swab collection. e trial nurse collected a mid-turbinate swab (day 0) and taught partic-
ipants on how to collect samples rst thing in the morning on days 1–4 (before HSNIG was performed that day
in the intervention arm). Flocked mid-turbinate swabs and eNAT transport medium (Copan, Italy) and Royal
Mail Safebox were provided with instructions to package and return the samples to the Department of Laboratory
Medicine, RIE for testing. Instructions on how to collect and return mid-turbinate swabs are in Supplementary
Methods.
Virological testing and quantication. Mid-turbinate swabs were tested by an in-house polymerase chain reac-
tion (PCR). e panel included, inuenza virus A&B, respiratory syncytial virus (RSV), parainuenza viruses
(PIV) 1–3, human metapneumovirus (HMPV), adenovirus, rhinovirus, enterovirus, parechovirus, bocavirus,
coronaviruses (COV) OC43, NL63, 229E, HKU1, and mycoplasma. Day 0 samples were initially tested. Where an
agent was identied, all samples (day 0 – day 4) were tested in parallel and the cycle threshold value (CT value)
converted to log10 to estimate change in viral shedding. CT was capped at 40 as samples with CT values above this
level was unlikely to be positive on repeat testing. CT values were converted to log10 using this formula (40-CT of
sample)/3.3 (a CT of 3.3 represents a log change in viral load by PCR). Since the baseline sample was tested on two
separate occasions, reproducibility of testing was assessed by comparing the two results. Inter-assay variation was
expected to be <0.5 log10. Where consecutive samples had undetectable virus, the rst sample that was undetect-
able was treated as the end-point for viral shedding analysis. For the intervention arm, since NaCl could have an
antiviral eect, the day with the lowest shedding when HSNIG was being performed was treated as the end-point.
Where HSNIG was stopped earlier than 4 days, since swabs were collected rst thing in the morning, the day
aer HSNIG was stopped was considered the end-point. Hence for the intervention arm, the end-point was day 4
[apart from participant numbers 1, 5, 7, 13, 16, 17, 18 and 19 where it was day 3; 2 (rhinovirus), 14, and 15 where
it was day 2; and 11 and 12 where it was day 1]. Two individuals had dual viral infections in their specimen. Both
viruses were included for viral shedding analysis.
To determine if there was reduction in viral shedding, the log10 value of the day 0 sample was subtracted from
the log10 value of the end-point. Negative values indicate a reduction in viral shedding and positive values indicate
an increase in viral shedding. To determine the reduction in viral shedding per day, these values were divided by
the number of days of follow-up. e proportion of individuals with reduction in viral shedding by 0.5 log10/
day was then calculated.
Statistical analysis. We used SAS v9.4 soware for statistical analysis. For categorical data, we present num-
bers and percentages. For continuous data, we present mean (standard deviation) or median (interquartile range
(IQR)) as appropriate. Binomial test for the comparisons of proportions was used to examine dierences in pro-
portions and presented along with 95% CI for dierences in proportions or chi-square tests depending on the
number of groups. To compare dierences between treatment arms, two-sample t-tests or Mann-Whitney tests
were used, as appropriate.
Participants were considered in the groups to which they were randomised irrespective of treatment received
for analysis. Due to the way the data were collected, baseline information was available for all participants. Any
subsequent information was the result of participants returning the diary card, potential non-return of diary
cards was accounted for by increasing our sample size to allow for drop-outs. In the cases where diary cards were
not returned, we do not have any information beyond baseline and therefore we have not used any methods to
impute any missing data.
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Acknowledgements
We would like to acknowledge the Edinburgh Clinical Research Facility where recruitment was done. We would
like to thank the trial nurses particularly Jill Steven, Audrey Kuchnowski for helping with the study, Allan Walker
and David Buchanan from Edinburgh Clinical Trials Unit for designing and maintain the database, Glen Merrit
from the nance department, Philip Tanswell (Cornish Sea Salt Co.) for providing the sea-salt, and Santina
Castriciano from Copan, Italy for providing us with mid-turbinate swabs and eNAT transport medium. Our
thanks to Midlothian and Edinburgh councils and schools and NHS Lothian for helping us advertise the study
and most importantly, the participants for taking part in the study. Sandeep Ramalingam is nancially supported
by NHS Research Scotland (NRS) and the Scottish Chief Scientist Oce (CSO). Aziz Sheikh is supported by the
FARR institute, which is funded by a consortium of funders led by the MRC. is work was supported by the
Edinburgh and Lothians Health Foundation [Reference 10-303 to S.R.].
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Author Contributions
S.R. Principle Investigator. Was involved in designing, conducting, analysing and writing the manuscript.
C.G. Involved in designing, analysing and writing the manuscript. J.D. Involved in testing and reviewing the
manuscript. L.M. Involved in designing and reviewing the manuscript. A.S. Involved in designing and writing
the manuscript.
Additional Information
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-37703-3.
Competing Interests: e authors declare no competing interests.
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Supplementary resource (1)

... Ten RCTs 4,26-34 and 1 meta-analysis 35 In adult patients, 5 RCTs assessed nasal saline vs no-saline treatment. 26,27,30,31,33 Duration of treatment ranged from 1 to 4 weeks. There were no differences in symptom reduction, 26,30,31,33 QoL improvement, 30,31,33 and STT. ...
... 26,27,30,31,33 Duration of treatment ranged from 1 to 4 weeks. There were no differences in symptom reduction, 26,30,31,33 QoL improvement, 30,31,33 and STT. 27 However, a post hoc analysis of an RCT showed that the common cold subgroup benefited from saline irrigation on symptom reduction and QoL. 31 The duration of illness after saline treatment showed mixed results. ...
... 26,27,30,31,33 Duration of treatment ranged from 1 to 4 weeks. There were no differences in symptom reduction, 26,30,31,33 QoL improvement, 30,31,33 and STT. 27 However, a post hoc analysis of an RCT showed that the common cold subgroup benefited from saline irrigation on symptom reduction and QoL. 31 The duration of illness after saline treatment showed mixed results. ...
Article
Full-text available
Objective This review aimed to systematically determine the optimal nasal saline regimen for different types of sinonasal diseases. Data Sources PubMed, Embase, SCOPUS, Cochrane Library, Web of Science, ClinicalTrials.gov. The last search was on December 6, 2021. Review Methods Study selection was done by 2 independent authors. Randomized controlled trials and meta-analyses were included. The effects of nasal saline treatment through various devices, saline tonicities, and buffer statuses were evaluated in patients with allergic and nonallergic rhinitis, acute and chronic rhinosinusitis (CRS), CRS with cystic fibrosis, and postoperative care, including septoplasty/turbinoplasty and endoscopic sinus surgery. Results Sixty-nine studies were included: 10 meta-analyses and 59 randomized controlled trials. For allergic rhinitis, large-volume devices (≥60 mL) were effective for treating adults, while low-volume devices (5-59 mL) were effective for children. Isotonic saline was preferred over hypertonic saline due to fewer adverse events. For acute rhinosinusitis, saline irrigation was beneficial in children, but it was an option for adults. Large-volume devices were more effective, especially in the common cold subgroup. For CRS, large-volume devices were effective for adults, but saline drop was the only regimen that had available data in children. Buffered isotonic saline was more tolerable than nonbuffered or hypertonic saline. The data for CRS with cystic fibrosis and nonallergic rhinitis were limited. For postoperative care, buffered isotonic saline delivered by large-volume devices was effective. Conclusion Nasal saline treatment is recommended for treating most sinonasal diseases. Optimal delivery methods for each condition should be considered to achieve therapeutic effects of saline treatment.
... Nasopharyngeal washes could prevent the virus from inhabiting and replicating in the nasal and pharyngeal mucosa and has been suggested as a potential method to reduce symptoms, transmission, and viral shedding in various acute respiratory tract viral infections [5]. Ct values obtained from Real-time PCR (RT-PCR) testing on consecutive specimens collected from the same patient and performed using the same assay, in the same microbiology laboratory can provide a relative measure of viral quantity in the different respiratory specimens. ...
... In a recent randomized open labeled trial, adults with acute upper respiratory tract infection in the last 48 h (56% from rhinovirus and 31% from coronaviruses) were randomized to perform oral gargles and nasal wash with hypertonic saline (n � 32) versus no intervention (n � 34). ere was a significant reduction in the duration of illness, use of symptomatic medication, transmission of household contacts, and viral shedding measured by sequential nasal swabs (p < 0.05) in the hypertonic saline group [5]. In COVID-19 patients, apart from case reports [17], there is only one study by Poulas who observed a reduction of SARS-CoV-2 viral load in hospitalized patients with COVID-19 after nasopharyngeal washes with hypertonic water [18]. ...
... Another interesting observation was that significantly more patients from the normal saline group had a negative test at follow-up. is was an expected finding considering the significant decrease in viral load in this group, and is in accordance with previous studies with non-COVID-19 patients [5]. Moreover, the possible reduction in high flow nasal cannula use, ICU admission, and death seen in our study, suggest that nasal washes could potentially reduce serious complications of COVID-19. ...
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Background. Although great progress has been made over the past 2 years in the scientific understanding of the biology, epidemiology, and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), case morbidity and fatality rates remain a great concern and continue to challenge the healthcare resources worldwide as novel variants emerge. There is therefore an urgent need for affordable and readily available strategies to reduce viral transmission. Previous studies in non-COVID-19 patients have demonstrated that administration of low-salt (isotonic but 0.0375% Na) and isotonic saline (0.9% Na) solutions has been associated with an immediate, significant reduction in the microbial antigens and a related decline of microbial burden. The aim of the present study was to determine the effect of nasal washes with normal saline 0.9% on nasopharyngeal viral load and outcome in hospitalized patients with COVID-19 pneumonia. Methods. We performed a prospective, randomized, pilot, controlled trial in 50 patients with confirmed COVID-19 disease. Patients were randomized into two groups, the normal saline group (received normal saline 0.9% solution for nasopharyngeal wash) and the control group (no treatment). In the normal saline group, nasopharyngeal wash was performed every 4 hours for a 16-hour period. Twenty-four hours after the baseline nasopharyngeal swab (and 8 hours after the last wash in the normal saline group), a second nasopharyngeal swab was collected for the semiquantitative estimation of the SARS-CoV-2 viral load as determined by cycle threshold (Ct) values. Results. In the normal saline group, mean N gene Ct values increased significantly 24 hours after the baseline measurement [ΔCtday2−day1 = 1.87 ± 3.11 cycles, p = 0.007 (95% CI: 0.55 to 3.18)], indicating a decline in SARS-CoV-2 nasopharyngeal viral load by 8.9%. A significant decrease in mean N gene Ct values was observed in the control group, indicating an increase in viral load [ΔCtday2-day1 = −2.12 ± 2.66, p < 0.001 (95% CI: −3.20 to −1.05)] by 9.7%. The difference between the two groups 24 hours after admission and nasopharyngeal wash was 3.09 cycles ( p = 0.005 , 95% CI: 0.97 to 5.20). Conclusion. Nasal washes with normal saline effectively decreased the viral load during hospitalization and at follow-up.
... Nasal irrigation under pressure, or "nasal lavage," has been demonstrated to safely reduce the duration and severity of both Coronaviridae and illnesses like flu with shorter incubation periods. [4][5][6][7] Repeated irrigation should be most effective for pathogens with prolonged incubation, local nonhematogenous spread, and variolation where viral load impacts severity. ...
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Objective To determine whether initiating saline nasal irrigation after COVID-19 diagnosis reduces hospitalization and death in high-risk outpatients compared with observational controls, and if irrigant composition impacts severity. Methods Participants 55 and older were enrolled within 24 hours of a + PCR COVID-19 test between September 24 and December 21, 2020. Among 826 screened, 79 participants were enrolled and randomly assigned to add 2.5 mL povidone-iodine 10% or 2.5 mL sodium bicarbonate to 240 mL of isotonic nasal irrigation twice daily for 14 days. The primary outcome was hospitalization or death from COVID-19 within 28 days of enrollment by daily self-report confirmed with phone calls and hospital records, compared to the CDC Surveillance Dataset covering the same time. Secondary outcomes compared symptom resolution by irrigant additive. Results Seventy-nine high-risk participants were enrolled (mean [SD] age, 64 [8] years; 36 [46%] women; 71% Non-Hispanic White), with mean BMI 30.3. Analyzed by intention-to-treat, by day 28, COVID-19 symptoms resulted in one ED visit and no hospitalizations in 42 irrigating with alkalinization, one hospitalization of 37 in the povidone-iodine group, (1.27%) and no deaths. Of nearly three million CDC cases, 9.47% were known to be hospitalized, with an additional 1.5% mortality in those without hospitalization data. Age, sex, and percentage with pre-existing conditions did not significantly differ by exact binomial test from the CDC dataset, while reported race and hospitalization rate did. The total risk of hospitalization or death (11%) was 8.57 times that of enrolled nasal irrigation participants (SE = 2.74; P = .006). Sixty-two participants completed daily surveys (78%), averaging 1.8 irrigations/day. Eleven reported irrigation-related complaints and four discontinued use. Symptom resolution was more likely for those reporting twice daily irrigation ( X ² = 8.728, P = .0031) regardless of additive. Conclusion SARS-CoV-2+ participants initiating nasal irrigation were over 8 times less likely to be hospitalized than the national rate.
... Sodium chloride solution (particularly in hypertonic concentrations) has been found to have a potential effect against a variety of DNA/RNA viruses, including coronaviruses. 2,3 In vitro investigations also revealed that NaCl (at 1.5% Conc.) inhibits the severe acute respiratory syndrome coronavirus 2 completely (SARS-CoV-2). 4 In nonhospitalized coronavirus disease-2019 (COVID-19) patients, a more recent interim analysis revealed that hypertonic saline causes symptom alleviation (nasal congestion and headache). ...
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Saline nasal irrigation (SNI) is a clinically established treatment that has been used to manage upper respiratory infections and allergies; there is also some indication that it may be effective in the setting of coronavirus disease-2019 (COVID-19). The possible advantages of SNI include the following benefits due to the well-known antiviral impact of sodium chloride (NaCl) and the mechanical cleansing effect arising from the irrigation method. First, there will most likely be a decrease in COVID-19 infection rates; second, illness severity will be lowered; and third, community transmission will be mitigated. Despite the need for more concentrated research into these aspects, public health organizations should emphasize alternate infection mitigation measures such as SNI in light of the ongoing COVID-19 problem, low global vaccine supply, and the rapid introduction of SARS-CoV-2 variants. Keywords: Community transmission, COVID-19, Pandemic, Prevention, Saline, SARS-CoV-2.
... Patients with a known history of immunosuppressive disorders, thyroid disorders, pregnant and lactating women, nasal polyps, recurrent nasal bleeding, known allergy to iodine and its compounds, and on lithium therapy were excluded. The sample size was calculated based on similar study, [11] at 95% significance level and 90% power with expected difference of 3 days in symptoms recovery between intervention and control groups. The total sample size calculated was 80 (20 in each group). ...
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Context: In the absence of any specific treatment available for COVID-19, people started practicing traditional nonpharmacological preventive home remedies such as salt water gargling and steam inhalation. The available research evidence on some of these measures opines that steam inhalation, saline gargling, and povidone-iodine gargling does have virucidal properties and do provide symptomatic relief. Aims: The aim is to test this hypothesis, and the present trial was undertaken with an objective to assess the effect of steam inhalation, saline gargling, and povidone-iodine gargling among the COVID-19-positive patients with respect to early test negativity and clinical recovery. Methodology: Open-labeled, parallel, randomized controlled trial was conducted among asymptomatic or mild COVID-19-positive patients in Bangalore from September 2020 to February 2021. In each group of steam inhalation, saline gargling, povidone-iodine gargling, and control, twenty participants were allocated. Daily follow-up was done for 21 days to assess early test negativity and clinical recovery. Trial Registry Number: Clinical Trial Registry India/2020/09/027687. Results: Among 80 participants recruited, 65 (81.3%) were symptomatic. Early test negativity was seen in povidone-iodine gargling group of 6 days (KaplanMeier survival curve, BreslowGeneralized Wilcoxon test P = 0.7 as per the intention-to-treat and as per-protocol P = 0.8). Significant clinical recovery was seen in saline gargling group (4 days, P = 0.01). Conclusion: Povidone-iodine gargling was effective in providing early test negativity, whereas saline gargling was effective in early clinical recovery.
... Although no study is reported on the repurposing of corticosteroids that act directly on SARS-CoV2 encoded proteins to kill them, some in vitro and in vivo studies showed the effective role of ciclesonide, fluticasone propionate, etc. via suppressing ACE2 expression, and thus preventing the SARS-CoV2 cell entry in the nasal mucosa [26,27]. In a previous study, oxymetazoline and xylometazoline displayed the reduction of rhinovirus infections as shown in a study [28]. Moreover, povidone iodine-containing nasal spray to reduce the nasopharyngeal viral load in patients with COVID-19 is under clinical trials [29,30]. ...
Article
The recent outbreak "Coronavirus Disease 2019 (COVID-19)" is caused by fast-spreading and highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). This virus enters into the human respiratory system by binding of the viral surface spike glycoprotein (S-protein) to an angiotensin-converting enzyme2 (ACE2) receptor that is found in the nasal passage and oral cavity of a human. Both spike protein and the ACE2 receptor have been identified as promising therapeutic targets to develop anti-SARS-CoV2 drugs. No therapeutic drugs have been developed as of today except for some vaccines. Therefore, potent therapeutic agents are urgently needed to combat the COVID-19 infections. This goal would be achieved only by applying drug repurposing and computational approaches. Thus, based on drug repurposing approach, we have investigated 16 bioactive components (1-16) from different nasal spray solutions to check their efficacies against human ACE2 and SARS-CoV2 spike proteins by performing molecular docking and molecular dynamic (MD) simulation studies. In this study, three bioactive components namely ciclesonide (8), levocabastine (13), and triamcinolone acetonide (16) have been found as promising inhibitory agents against SARS-CoV2 spike and human ACE2 receptor proteins with excellent binding affinities, comparing to reference drugs such as nafamostat, arbidol, losartan, and benazepril. Furthermore, MD simulations were performed (triplicate) for 100 ns to confirm the stability of 8, 13, and 16 with said protein targets and to compute MM-PBSA-based binding-free energy calculations. Thus, bioactive components 8, 13, and 16 open the door for researchers and scientist globally to investigate them against SARS-CoV2 through in vitro and in vivo analysis.
... 15 In children, nasal irrigation using normal salt water and seawater spray was found to be useful in preventing upper respiratory tract infections. 16,17 Salt water nasal irrigation and gargling proved to protect against common cold and is often used as a home treatment measure for many years. 19 The work ofEdinburgh and Lothians Viral Intervention Study (ELVIS) 19 proved that salt water nasal irrigation and gargling was very effective against the alpha and beta variants of coronavirus. ...
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Introduction: The infection caused by COVID-19 ranges from mild to moderate infection, but it can also cause severe infection and death in some people mostly in people who are old, or immunocompromisedSARS-CoV-2 has shown evidence of having higher capacity of binding to human cells and can settle in upper and lower portion of the respiratory tract it being the two important hotspots. Symptoms localized to the upper respiratory tract are mild which usually includes anosmia/hyposmia, ageusia/ dysgeusia, rhinitis along with sore throat. Material and methods: This study included individuals who were diagnosed with COVID-19 having mild symptoms of the disease which could be managed at their homes.Random assignment (50/50 chance) of subjects was done into two groups (A and B) for this study. Participants in group A were asked to perform the nasal washing and gargling with salt water up to 10 times a day for 14 days or until they felt better.Results:The leading cause for hospitalization for 15 (53.57%) people was that the oxygen saturation fell to below 93. Some scores compared between the two groups showed significant results in parameters of headache, postnasal drip, anosmia, sinusitis, sore throat, body ache, dry cough by unpaired two tailed P test. The age groups of 26 to 35, and 56 to 65 had comparatively higher values of adherence as compared to different age groups.Conclusion:The study demonstrates the hypothesis that nasal irrigation and saline gargling can have promising results to reduce the severity of COVID-19 infection when initiated within 24 hours of a positive test.
... A randomized controlled trial (RCT) also reported the efficiency of HS (3, 2.5, 2.0, and 1.5%; nasal irrigation and gargle versus standard care) as therapy on adults within 48 h of the upper respiratory tract infection (URTI) onset. The authors found a reduction in the time of illness, transmission within household contacts, over-thecounter medications use, and viral shedding (51). Accordingly, the analysis from the Edinburgh and Lothians Viral Intervention Study RCT demonstrated that HS (gargling and nasal irrigation) decreases the time of URTI by an average of two-and-a-half days (52), however, since the results are a post hoc secondary analysis of data from a pilot RCT, they need to be interpreted with caution. ...
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Coronavirus disease 2019 (COVID-19) features hyper-inflammation, cytokine storm, neutrophil function changes, and sodium chloride (NaCl) homeostasis disruption, while the treatment with NaCl hypertonic solutions (HS) controls electrolytic body homeostasis and cell functions. HS treatment is a simple, popular, economic, and feasible therapy to regulate leukocyte function with a robust anti-inflammatory effect in many inflammatory diseases. The purpose of this narrative review is to highlight the knowledge on the use of HS approaches against viral infection over the past years and to describe the mechanisms involved in the release of neutrophil extracellular traps (NETs) and production of cytokine in severe lung diseases, such as COVID-19. We reported the consequences of hyponatremia in COVID-19 patients, and the immunomodulatory effects of HS, either in vitro or in vivo. We also described the relationship between electrolyte disturbances and COVID-19 infection. Although there is still a lack of clinical trials, hypertonic NaCl solutions have marked effects on neutrophil function and NETs formation, emerging as a promising adjuvant therapy in COVID-19.
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Phagocytes destroy ingested microbes by producing hypochlorous acid (HOCl) from chloride ions (Cl-) and hydrogen peroxide within phagolysosomes, using the enzyme myeloperoxidase. HOCl, the active ingredient in bleach, has antibacterial/antiviral properties. As myeloperoxidase is needed for HOCl production, non-myeloid cells are considered incapable of producing HOCl. Here, we show that epithelial, fibroblast and hepatic cells have enhanced antiviral activity in the presence of increasing concentrations of sodium chloride (NaCl). Replication of enveloped/non-enveloped, DNA (herpes simplex virus-1, murine gammaherpesvirus 68) and RNA (respiratory syncytial virus, influenza A virus, human coronavirus 229E, coxsackievirus B3) viruses are inhibited in a dose-dependent manner. Whilst treatment with sodium channel inhibitors did not prevent NaCl-mediated virus inhibition, a chloride channel inhibitor reversed inhibition by NaCl, suggesting intracellular chloride is required for antiviral activity. Inhibition is also reversed in the presence of 4-aminobenzoic hydrazide, a myeloperoxidase inhibitor, suggesting epithelial cells have a peroxidase to convert Cl- to HOCl. A significant increase in intracellular HOCl production is seen early in infection. These data suggest that non-myeloid cells possess an innate antiviral mechanism dependent on the availability of Cl- to produce HOCl. Antiviral activity against a broad range of viral infections can be augmented by increasing availability of NaCl.
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Background Incomplete adherence to tuberculosis (TB) treatment increases the risk of delayed culture conversion with continued transmission in the community, as well as treatment failure, relapse, and development or amplification of drug resistance. We conducted a systematic review and meta-analysis of adherence interventions, including directly observed therapy (DOT), to determine which approaches lead to improved TB treatment outcomes. Methods and findings We systematically reviewed Medline as well as the references of published review articles for relevant studies of adherence to multidrug treatment of both drug-susceptible and drug-resistant TB through February 3, 2018. We included randomized controlled trials (RCTs) as well as prospective and retrospective cohort studies (CSs) with an internal or external control group that evaluated any adherence intervention and conducted a meta-analysis of their impact on TB treatment outcomes. Our search identified 7,729 articles, of which 129 met the inclusion criteria for quantitative analysis. Seven adherence categories were identified, including DOT offered by different providers and at various locations, reminders and tracers, incentives and enablers, patient education, digital technologies (short message services [SMSs] via mobile phones and video-observed therapy [VOT]), staff education, and combinations of these interventions. When compared with DOT alone, self-administered therapy (SAT) was associated with lower rates of treatment success (CS: risk ratio [RR] 0.81, 95% CI 0.73–0.89; RCT: RR 0.94, 95% CI 0.89–0.98), adherence (CS: RR 0.83, 95% CI 0.75–0.93), and sputum smear conversion (RCT: RR 0.92, 95% CI 0.87–0.98) as well as higher rates of development of drug resistance (CS: RR 4.19, 95% CI 2.34–7.49). When compared to DOT provided by healthcare providers, DOT provided by family members was associated with a lower rate of adherence (CS: RR 0.86, 95% CI 0.79–0.94). DOT delivery in the community versus at the clinic was associated with a higher rate of treatment success (CS: RR 1.08, 95% CI 1.01–1.15) and sputum conversion at the end of two months (CS: RR 1.05, 95% CI 1.02–1.08) as well as lower rates of treatment failure (CS: RR 0.56, 95% CI 0.33–0.95) and loss to follow-up (CS: RR 0.63, 95% CI 0.40–0.98). Medication monitors improved adherence and treatment success and VOT was comparable with DOT. SMS reminders led to a higher treatment completion rate in one RCT and were associated with higher rates of cure and sputum conversion when used in combination with medication monitors. TB treatment outcomes improved when patient education, healthcare provider education, incentives and enablers, psychological interventions, reminders and tracers, or mobile digital technologies were employed. Our findings are limited by the heterogeneity of the included studies and lack of standardized research methodology on adherence interventions. Conclusion TB treatment outcomes are improved with the use of adherence interventions, such as patient education and counseling, incentives and enablers, psychological interventions, reminders and tracers, and digital health technologies. Trained healthcare providers as well as community delivery provides patient-centered DOT options that both enhance adherence and improve treatment outcomes as compared to unsupervised, SAT alone.
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Background/aim: The effectiveness of isotonic and hypertonic saline solutions used to open the nasal passage and improve clinical symptoms was compared in children under 2 years of age admitted with the common cold. Materials and methods: The study was performed as a randomized, prospective, and double-blind study. The study included 109 children. The children using saline (0.9%) and seawater (2.3%) as nasal drops (the patient group) and the control group (in which nasal drops were not administered) were compared. Seventy-four patients received nasal drops from package A (seawater) in single days and from package B (physiological saline) in double days. Results: The mean age of the patients was 9.0 ± 3.9 months and the numbers of boys and girls were 65 (59.6%) and 44 (40.4%), respectively. There was no significant difference between Groups A and B in terms of nasal congestion (P > 0.05). However, a significant difference was found between the control group and Groups A and B (P < 0.05). Conclusion: Relief was seen in nasal congestion, weakness, sleep quality, and nutrition with the use of both saline and seawater in children with the common cold. Seawater or saline drops may be added to standard treatment protocols.
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Iota-carrageenan (I-C) is active against respiratory viruses in vitro and was effective as nasal spray in three previous clinical trials. The current trial served to further investigate I-C in patients with early common cold symptoms. Methods This randomized, placebo-controlled, double-blind phase IV trial was conducted in 200 adult patients with self-diagnosed colds of <48 h’ duration that were confirmed by baseline cold symptom scores. Patients were to self-administer 0.12 % I-C or placebo spray (NaCl 0.5 %) four times daily for four to ten days and record symptom information for ten days. Common respiratory viruses were quantified by RT-PCR during pretreatment and on Day 3 or 4. The primary endpoint was the mean total symptom score (TSS) of eight cold symptoms on Days 2–4 (TSS2–4). Results Patients in both treatment groups had similar baseline TSSs (mean TSS: 6.75 for I-C and 6.79 for placebo). Viruses were detected in baseline samples from 53 of 98 I-C patients (54.1 %) and 54 of 97 placebo patients (55.7 %). Mean ± SE for TSS2–4 was 5.78 ± 0.25 for I-C patients and 6.39 ± 0.25 for placebo (p = 0.0895). Exploratory analyses after unblinding (TSS2–4 excluding a patient with aberrantly high symptom scores [TSS2–4, ex 1pt]; mean of TSS over Days 1–4 [TSS1–4]; change in TSS1–4 relative to baseline [TSS1–4, rel]) demonstrated treatment differences in favor of I-C (p = 0.0364, p = 0.0495 and p = 0.0421, respectively). For patients with quantifiable rhinovirus/enterovirus at baseline, there was a trend towards greater reduction of virus load at Day 3 or 4 (p = 0.0958; I-C: 90.2 % reduction in viral load; placebo: 72.0 %). Treatments were well tolerated with no differences in adverse event rates. Conclusions The primary endpoint did not demonstrate a statistically significant difference between I-C and placebo but showed a trend towards I-C benefit. Exploratory analyses indicated significant reduction of cold symptoms in the I-C group relative to placebo during the first four days when symptoms were most severe, and also substantiated I-C’s activity against rhinovirus/enterovirus. Trial registration NCT01944631 (clinicaltrials.gov)
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The highest incidence of childhood acute lower respiratory tract infection (ALRI) is in low- and middle-income countries. Few studies examined whether detection of respiratory viruses predicts ALRI outcomes in these settings. We conducted prospective cohort and case-control studies of children 1-23 months of age in Botswana. Cases met clinical criteria for pneumonia and were recruited within six hours of presentation to a referral hospital. Controls were children without pneumonia matched to cases by primary care clinic and date of enrollment. Nasopharyngeal specimens were tested for respiratory viruses using polymerase chain reaction. We compared detection rates of specific viruses in matched case-control pairs. We examined the effect of respiratory syncytial virus (RSV) and other respiratory viruses on pneumonia outcomes. Between April 2012 and August 2014, we enrolled 310 cases, of which 133 had matched controls. Median ages of cases and controls were 6.1 and 6.4 months, respectively. One or more viruses were detected from 75% of cases and 34% of controls. RSV and human metapneumovirus were more frequent among cases than controls, but only enterovirus/rhinovirus was detected from asymptomatic controls. Compared with non-RSV viruses, RSV was associated with an increased risk of treatment failure at 48 hours [risk ratio (RR): 1.85; 95% confidence interval (CI): 1.20, 2.84], more days of respiratory support [mean difference (MD): 1.26 days; 95% CI: 0.30, 2.22 days], and longer duration of hospitalization [MD: 1.35 days; 95% CI: 0.20, 2.50 days], but lower in-hospital mortality [RR: 0.09; 95% CI: 0.01, 0.80] in children with pneumonia. Respiratory viruses were detected from most children hospitalized with ALRI in Botswana, but only RSV and human metapneumovirus were more frequent than among children without ALRI. Detection of RSV from children with ALRI predicted a protracted illness course but lower mortality compared with non-RSV viruses.
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Curing tuberculosis (TB) entails adhering to a multidrug regimen for ≥6 months [1]. Failure to take the medications as prescribed can lead to treatment failure, drug resistance and further spread of TB, resulting in morbidity and death for the patient and a threat to public health. Treatment failure is the most important cause of drug-resistant TB, which is much more long, expensive and toxic to treat, and the outcomes of which are still unsatisfactory [2–4]. The public health consequences of nonadherence to TB treatment led to directly observed therapy (DOT) becoming the universal standard of care [5–8]. While DOT is a best practice model for TB treatment, it is labour intensive and can itself be a barrier to effective therapy because of its inconvenience for patients. The expense may be prohibitive for cash-strapped public healthcare systems [9]. A video-based approach is a novel, patient-oriented strategy for TB treatment The authors would like to thank Golnaz Ebrahimi (University of Illinois at Chicago, Chicago, IL, USA) and Marybeth Allen (University of Louisville, Louisville, KY, USA) for their editorial assistance.
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Lower respiratory tract infection is a leading cause of death in the United States. Advances in diagnostic testing have improved our ability to detect pathogens. Viral pathogens are important causal pathogens in immunocompetent patients. As the number of elderly adults and those with chronic medical conditions increases, the burden of viral respiratory infections will increase. Clinicians must be familiar with the characteristics of rhinovirus, human adenoviruses, respiratory syncytial virus, and human metapneumovirus. Major challenges include distinguishing true infection from asymptomatic carriage and characterizing patients admitted with severe lower respiratory tract infection who do not have a causative pathogen identified.
Article
Background: Acute upper respiratory tract infections (URTIs), including the common cold and rhinosinusitis, are common afflictions that cause discomfort and debilitation and contribute significantly to workplace absenteeism. Treatment is generally by antipyretic and decongestant drugs and sometimes antibiotics, even though most infections are viral. Nasal irrigation with saline is often employed as an adjunct treatment for URTI symptoms despite a relative lack of evidence for benefit in this clinical setting. This review is an update of the Cochrane review by Kassel et al, which found that saline was probably effective in reducing the severity of some symptoms associated with acute URTIs. Objectives: To assess the effects of saline nasal irrigation for treating the symptoms of acute URTIs. Search methods: We searched CENTRAL (2014, Issue 7), MEDLINE (1966 to July week 5, 2014), EMBASE (1974 to August 2014), CINAHL (1982 to August 2014), AMED (1985 to August 2014) and LILACS (1982 to August 2014). Selection criteria: Randomised controlled trials (RCTs) comparing topical nasal saline treatment to other interventions in adults and children with clinically diagnosed acute URTIs. Data collection and analysis: Two review authors (DK, BM) independently assessed trial quality with the Cochrane 'Risk of bias' tool and extracted data. We analysed all data using the Cochrane Review Manager software. Due to the large variability of outcome measures only a small number of outcomes could be pooled for statistical analysis. Main results: We identified five RCTs that randomised 544 children (three studies) and 205 adults (exclusively from two studies). They all compared saline irrigation to routine care or other nose sprays, rather than placebo. We included two new trials in this update, which did not contribute data of sufficient size or quality to materially change the original findings. Most trials were small and we judged them to be of low quality, contributing to an unclear risk of bias. Most outcome measures differed greatly between included studies and therefore could not be pooled. Most results showed no difference between nasal saline treatment and control. However, one larger trial, conducted with children, did show a significant reduction in nasal secretion score (mean difference (MD) -0.31, 95% confidence interval (CI) -0.48 to -0.14) and nasal breathing (obstruction) score (MD -0.33, 95% CI -0.47 to -0.19) in the saline group. However, a MD of -0.33 on a four-point symptom scale may have minimal clinical significance. The trial also showed a significant reduction in the use of decongestant medication by the saline group. Minor nasal discomfort and/or irritation was the only side effect reported by a minority of participants. Authors' conclusions: Nasal saline irrigation possibly has benefits for relieving the symptoms of acute URTIs. However, the included trials were generally too small and had a high risk of bias, reducing confidence in the evidence supporting this. Future trials should involve larger numbers of participants and report standardised and clinically meaningful outcome measures.