Carrageenan nasal spray may double the rate of recovery from coronavirus and influenza virus infections: Re‐analysis of randomized trial data
Harri Hemilä, Elizabeth Chalker
Pharmacology Research & Perspectives, doi:10.1002/prp2.810
In this individual patient data meta-analysis we examined datasets of two randomized placebo-controlled trials which investigated the effect of nasal carrageenan separately on children and adults. In both trials, iota-carrageenan was administered nasally three times per day for 7 days for patients with the common cold and follow-up lasted for 21 days. We used Cox regression to estimate the effect of carrageenan on recovery rate. We also used quantile regression to calculate the effect of carrageenan on colds of differing lengths. Nasal carrageenan increased the recovery rate from all colds by 54% (95% CI 15%-105%; p = .003). The increase in recovery rate was 139% for coronavirus infections, 119% for influenza A infections, and 70% for rhinovirus infections. The mean duration of all colds in the placebo groups of the first four quintiles were 4.0, 6.8, 8.8, and 13.7 days, respectively. The fifth quintile contained patients with censored data. The 13.7-day colds were shortened by 3.8 days (28% reduction), and 8.8-day colds by 1.3 days (15% reduction). Carrageenan had no meaningful effect on shorter colds. In the placebo group, 21 patients had colds lasting over 20 days, compared with six patients in the carrageenan group, which corresponds to a 71% (p = .003) reduction in the risk of longer colds. Given that carrageenan has an effect on diverse virus groups, and effects at the clinical level on two old coronaviruses, it seems plausible that carrageenan may have an effect on COVID-19. Further research on nasal iota-carrageenan is warranted.
AUTH O R CO NTR I B UTI O N S HH planned the study, measured the published survival curves, 28 entered the data into a spreadsheet and carried out the statistical analysis, and wrote the draft manuscript. EC checked that the entered data were consistent with the published survival curves and participated in the critical revision of the manuscript. Both authors read and approved the final manuscript.
References
Baba, Snoeck, Pauwels, De Clercq, Sulfated polysaccharides are potent and selective inhibitors of various enveloped viruses, including herpes simplex virus, cytomegalovirus, vesicular stomatitis virus, and human immunodeficiency virus, Antimicrob Agents Chemother,
doi:10.1128/aac.32.11.1742Carfì, Bernabei, Landi, Gemelli, Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19, JAMA,
doi:10.1001/jama.2020.12603Carlucci, Scolaro, Noseda, Cerezo, Damonte, Protective effect of a natural carrageenan on genital herpes simplex virus infection in mice, Antiviral Res,
doi:10.1016/j.antiviral.2004.07.001Core, R: a language and environment for statistical computing
Eccles, Meier, Jawad, Weinmüllner, Grassauer et al., Efficacy and safety of an antiviral iota-carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold, Respir Res,
doi:10.1186/1465-9921-11-108Eccles, Winther, Johnston, Robinson, Trampisch et al., Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial, Respir Res,
doi:10.1186/s12931-015-0281-8Fazekas, Eickhoff, Pruckner, Lessons learned from a double-blind randomised placebo-controlled study with a iota-carrageenan nasal spray as medical device in children with acute symptoms of common cold, BMC Complement Altern Med,
doi:10.1186/1472-6882-12-147Fergusson, Aaron, Guyatt, Hébert, Demets et al., Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis, JAMA,
doi:10.1001/jama.2018.19192Figueroa, Lombardo, Dogliotti, Trial, Efficacy of a nasal spray containing iota-carrageenan in the prophylaxis of COVID-19 in hospital personnel dedicated to patients care with COVID-19 disease: a pragmatic multicenter, randomized, double-blind, placebo-controlled trial (CARR-COV-02,
doi:10.1101/2021.04.13.21255409Girond, Crance, Van Cuyck-Gandre, Renaudet, Deloince, Antiviral activity of carrageenan on hepatitis A virus replication in cell culture, Res Virol,
doi:10.1016/0923-2516(91)90011-qGonzález, Alarcón, Carrasco, Polysaccharides as antiviral agents: antiviral activity of carrageenan, Antimicrob Agents Chemother,
doi:10.1128/aac.31.9.1388Graf, Bernkop-Schnürch, Egyed, Koller, Prieschl-Grassauer et al., Development of a nasal spray containing xylometazoline hydrochloride and iota-carrageenan for the symptomatic relief of nasal congestion caused by rhinitis and sinusitis, Int J Gen Med,
doi:10.2147/ijgm.s167123Grassauer, Weinmuellner, Meier, Pretsch, Prieschl-Grassauer et al., Iota-Carrageenan is a potent inhibitor of rhinovirus infection, Virol J,
doi:10.1186/1743-422x-5-107Hemilä, Carr, Chalker, Vitamin C may increase the recovery rate of outpatient cases of SARS-CoV-2 infection by 70%: Reanalysis of the COVID A to Z randomized clinical trial, Frontiers in Immunology,
doi:10.3389/fimmu.2021.674681Hemilä, Chalker, Carrageenan nasal spray may double the rate of recovery from coronavirus and influenza virus infections: reanalysis of randomized trial data,
doi:10.21203/rs.3.rs-108775/v1Hemilä, Chalker, The effectiveness of high dose zinc acetate lozenges on various common cold symptoms: a meta-analysis, BMC Family Pract,
doi:10.1186/s12875-015-0237-6Hemilä, Do vitamins C and E affect respiratory infections?
Hemilä, Duration of the common cold and similar continuous outcomes should be analyzed on the relative scale: a case study of two zinc lozenge trials, BMC Med Res Methodol,
doi:10.1186/s12874-017-0356-yHemilä, Fitzgerald, Petrus, Prasad, Zinc acetate lozenges may improve the recovery rate of common cold patients: an individual patient data meta-analysis, Open Forum Infect Dis,
doi:10.1093/ofid/ofx059Hemilä, Vitamin, the placebo effect, and the common cold: a case study of how preconceptions influence the analysis of results, J Clin Epidemiol,
doi:10.1016/0895-4356(96)00189-8Hemilä, Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage, JRSM Open,
doi:10.1177/2054270417694291Hong, Christiani, Li, Quantile regression for survival data in modern cancer research: expanding statistical tools for precision medicine, Precis Clin Med,
doi:10.1093/pcmedi/pbz007Jang, Shin, Lee, Antiviral activity of lambdacarrageenan against influenza viruses and severe acute respiratory syndrome coronavirus 2, Sci Rep,
doi:10.1038/s41598-020-80896-9Koenighofer, Lion, Bodenteich, Carrageenan nasal spray in virus confirmed common cold: individual patient data analysis of two randomized controlled trials, Multidiscip Respir Med,
doi:10.1186/2049-6958-9-57Koenker, Quantile treatment effects. Quantile Regression
Koenker, Quantreg, Quantile regression
Lee, Carrageenans as broad-spectrum microbicides: current status and challenges, Mar Drugs,
doi:10.3390/md18090435Louhiala, Hemilä, Can CAM treatments be evidence-based? Focus, Altern Complement Ther,
doi:10.1111/fct.12110Ludwig, Enzenhofer, Schneider, Efficacy of a carrageenan nasal spray in patients with common cold: a randomized controlled trial, Respir Res,
doi:10.1186/1465-9921-14-124Mckim, Willoughby, Sr, Blakemore, Weiner, Clarifying the confusion between poligeenan, degraded carrageenan, and carrageenan: a review of the chemistry, nomenclature, and in vivo toxicology by the oral route, Crit Rev Food Sci Nutr,
doi:10.1080/10408398.2018.1481822Morokutti-Kurz, Graf, Prieschl-Grassauer, Amylmetacresol/2,4-dichlorobenzyl alcohol, hexylresorcinol, or carrageenan lozenges as active treatments for sore throat, Int J Gen Med,
doi:10.2147/ijgm.s120665Morokutti-Kurz, König-Schuster, Koller, The intranasal application of Zanamivir and carrageenan is synergistically active against influenza A virus in the murine model, PLoS One,
doi:10.1371/journal.pone.0128794Nakazawa, Fmsb, Functions for medical statistics Book
Schütz, Conzelmann, Fois, Carrageenan containing over-the-counter nasal and oral sprays inhibit SARS-CoV-2 infection of airway epithelial cultures, Am J Physiol Lung Cell Mol Physiol,
doi:10.1152/ajplung.00552.2020Shao, Guo, Wp, Li, Tt, Specific inhibitory effect of κ-carrageenan polysaccharide on swine pandemic 2009 H1N1 influenza virus, PLoS One,
doi:10.1371/journal.pone.0126577Shi, Wang, Lu, Qin, Hu et al., Overview on the antiviral activities and mechanisms of marine polysaccharides from seaweeds, Carbohydr Res,
doi:10.1016/j.carres.2017.10.020Therneau, A package for survival analysis in R
Veiga, Martins, Riediger, Mazetto, Debur et al., More than just a common cold: endemic coronaviruses OC43, HKU1, NL63, and 229E associated with severe acute respiratory infection and fatality cases among healthy adults, J Med Virol,
doi:10.1002/jmv.26362Weiner, Parameters and pitfalls to consider in the conduct of food additive research, Carrageenan as a case study, Food Chem Toxicol,
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'of nasal carrageenan separately on children and adults. In both trials, iota‐carrageenan was '
'administered nasally three times per day for 7\xa0days for patients with the common cold and '
'follow‐up lasted for 21\xa0days. We used Cox regression to estimate the effect of carrageenan '
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'colds of differing lengths. Nasal carrageenan increased the recovery rate from all colds by '
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