key: cord-323666-t7cshj05
authors: Cegolon, L.; Javanbakht, M.; Mastrangelo, G.
title: Nasal Disinfection for the Prevention and Control of COVID-19: A Scoping Review on Potential Chemo-preventive Agents.
date: 2020-08-18
journal: Int J Hyg Environ Health
DOI: 10.1016/j.ijheh.2020.113605
sha: 
doc_id: 323666
cord_uid: t7cshj05

BACKGROUND: Neither pre-exposure nor post-exposure chemo-prophylaxis agents are currently available to prevent COVID-19. On the other hand, high loads of SARS-CoV-2 are shed from the nasal cavity before and after symptoms onset. OBJECTIVE: To conduct a scoping review on the available evidence on tolerable nasal disinfectants with encouraging health outcomes against SARS-CoV-2, i.e., agents effective against at least two different viruses beyond SARS-CoV-2. METHODS: Online databases were searched to identify papers published during 2010–2020. Publications were selected if they were relevant to the scoping review. The review was narrative, describing for each treatment the mechanism(s) of action, tolerability, in vitro and in vivo evidence of the effects against SARS-CoV-2 and whether the product had been marketed. RESULTS: Eight treatments were scrutinized: hypothiocyanite, lactoferrin, N-chlorotaurine, interferon-alpha, povidone-iodine, quaternary ammonium compounds, alcohol-based nasal antiseptics and hydroxychloroquine. In vitro viricidal effect against SARS-CoV-2 was reported for povidone-iodine. Inhibition of other coronaviruses was described for lactoferrin, hydroxychloroquine and quaternary ammonium compound. No treatment has been tested against SARS-CoV-2 in randomized controlled clinical trials thus far. However, interferon-alpha, lactoferrin and hydroxychloroquine were tested in one-arm open label uncontrolled clinical trials. Oxidant activity (hypothiocyanite, N-chlorotaurine and povidone-iodine), enhancement of endocytic and lysosomal pH (quaternary ammonium compounds and hydroxychloroquine) and destruction of the viral capsid (quaternary ammonium compounds, alcohol-based nasal antiseptics) were the main mechanisms of action. Lactoferrin and interferon-alpha had subtle biological mechanisms. With the exception of N-chlorotaurine, the others are products available on the market. CONCLUSIONS: Effective and safe chemo-prophylactic drugs against SARS-CoV-2 do not exist yet but most eligible candidates are already in the market. Whilst the human nasal cavity is the port of entry for SARS-CoV-2, the mouth is involved as exit site through emission of respiratory droplets. The well-known hand-to-nose-to-hand cycle of contamination requires appropriate additional strategies for infection control. To narrow down the subsequent laboratory and clinical investigations, a case-control approach could be employed to compare the use of candidate drugs among individuals testing positive and negative to COVID-19 swabs.

but most eligible candidates are already in the market. Whilst the human nasal cavity is the port of entry for SARS-CoV-2, the mouth is involved as exit site through emission of respiratory droplets.

The well-known hand-to-nose-to-hand cycle of contamination requires appropriate additional strategies for infection control. To narrow down the subsequent laboratory and clinical investigations, a case-control approach could be employed to compare the use of candidate drugs among individuals testing positive and negative to COVID-19 swabs.

J o u r n a l P r e -p r o o f BACKGROUND

The current coronavirus disease 2019 , caused by a novel beta coronavirus (SARS-CoV-2), has been declared a pandemic affecting 213 countries as of 12 th June 2020 [1] .

Unlike SARS-CoV, SARS-CoV-2 seems to replicate efficiently in the upper airways during the incubation period, which is estimated to last up to 14 days [2, 3] . During this prodromal stage, asymptomatic and pre-symptomatic individuals release large amounts of viruses from infected cells [3] . As a result, viral transmission is more effective with SARS-CoV-2 than with SARS-CoV, which conversely was contagious only during the active/critical phase of the disease [3] .

Furthermore, human coronaviruses which may cause common cold are known to cause re-infection regardless of pre-existing humoral immunity [4, 5] . Therefore, there are two issues with COVID- 19: high transmissibility of the virus and variable clinical pattern of the disease, which can range from pre-symptomatic/asymptomatic condition to life threatening pneumonia featured by severe acute respiratory syndrome (SARS) and hypercoagulable state [3, 5] .

The high risk of contagion from SARS-CoV-2 has been tackled so far by infection prevention and control (IPC) measures such as self-isolation, social distancing, quarantine of contacts, use of personal protective equipment (PPE), travel restrictions and other limitations to the freedom of movement of individuals. However, the effect of each intervention in containing the spread of SARS-CoV-2 has not been evaluated yet [6] .

Currently, the World Health Organization and the European Centre for Disease Prevention and Control guidelines recommend testing only symptomatic individuals and close contacts of a confirmed COVID-19 case [7, 8] . Whilst in the initial stage of the epidemic a symptom-based screening strategy was useful with the aim to treat and isolate infected cases, COVID-19 outbreaks in care homes and hospitals suggest that the current IPC measures are inadequate and have failed J o u r n a l P r e -p r o o f [9, 10] . Furthermore, the above IPC measures are not sustainable in the long run, as they would severely ruin the economies of countries heavily affected by COVID-19. The clear need to relax/avoid the lock down measures enforced in many countries prompts for a revised approach to reduce the transmission of SARS-CoV-2 from asymptomatic/pre-symptomatic individuals, until a pharmacological intervention (ideally a vaccine or a chemoprophylaxis) will hopefully become available [9] . As explained above, the problem with COVID-19 is transmission from asymptomatic/pre-symptomatic individuals, a phenomenon particularly critical in care homes and hospitals, where more than half residents testing positive might not develop symptoms [2, 9] . In Los Angeles families have been advised by the Public Health Department to remove their relatives from care homes to reduce health risk of community outbreaks of COVID-19 [11] .

Mass testing has been considered in various countries as a possible strategy to reduce the transmission of SARS-CoV-2 from asymptomatic individuals [9] . Nonetheless, mass testing on defined and contained outbreak clusters (as done in South Korea) may be sensible, not in the current global scenario though, with an ongoing pandemic [12] . Not to mention that mass testing is probably far beyond the capacity of microbiology laboratories even in high-income countries.

However, restricting mass testing to high risk congregate settings, such as care homes, hospitals, mental health facilities and prisons may be appropriate [9] . In an outbreak reported from a care home in Washington State, hosting a total of 76 residents, 27 of the 48 residents testing positive for COVID-19 at real time PCR were asymptomatic during the 14 days preceding the test [10] .

High loads of SARS-CoV-2 are shed from the nasal cavity into the environment also before symptoms onset [2, 9] and transmission of SARS-CoV-2 from asymptomatic individuals has been described [13] [14] [15] . Unnoticed, asymptomatic cases of COVID-19 might therefore constitute an important source of contagion, as endorsed by recent evidence from the China's National Health Commission, reporting that the vast majority of infections (four out of five) were totally J o u r n a l P r e -p r o o f asymptomatic. In particular, 130 out of the total 166 new infections identified in China on 1st April 2020 had no symptoms whatsoever [16] Although asymptomatic individuals testing positive for SARS-CoV-2 are enforced to quarantine for 14 days, mass testing would yet not resolve the endemic presence of the virus in the general population, a condition posing the risk of repeated resurgences of outbreaks, especially with cold weather conditions [17] . There is in fact evidence that the transmissibility and viability of SARS-CoV-2 reduces importantly with hot and humid climate [5, 18, 19] , as confirmed by the diminished spread of the novel coronavirus with increasing relative humidity from 23.33% to 82.67% (p-value = 0.002) and with increased weather temperature from −13.17°C to 19 °C (p-value = 0.003) observed for Chinese cities during January-March 2020 [20] .

Humoral immunity seems not protective against human coronaviruses, and some evidence even points out a potential Antibody Dependent Enhancement (ADE) triggered by re-infections featuring the severe/critical forms of COVID-19, as with other viral diseases such as Dengue, SARS-CoV, MERS-CoV and the West Nile Virus. [5] . Given the potential of reversed and untoward consequences following relaxation of the above IPC measures, especially during cold months, and in absence of a specific registered treatment or vaccine against SARS-CoV-2, there is a clear and urgent need to find alternative solutions to prevent and control the replication of the virus and the spread of COVID-19 among humans [14] .

COVID-19 is a rapidly evolving pandemic. Asymptomatic individuals testing positive for SARS-CoV-2 and asked to self-isolate at home were in Italy about 40% of all positive individuals at the beginning of the epidemic, then becoming >80% following the end of full lockdown [21] . Figure 1 reports the corresponding changes as percentage or odds; the latter detects the improvement of the index score better than the former because it is able to overcome the ceiling effects J o u r n a l P r e -p r o o f Therefore, in addition to an effective treatment for symptomatic patients, there is an urgent need to abate the carriage of SARS-CoV-2 in the human nasal cavity of asymptomatic/pre-symptomatic individuals, in order to contain the transmission of the novel coronavirus within the community.

To find tolerable topical nasal disinfectants featured by encouraging efficacy against SARS-CoV-2, e.g. drugs effective against at least two different viruses beyond SARS-CoV-2, with similar viral/molecular structure.

PubMed was investigated using "Anti-Infective Agents, Local" and "Anti-Infective Agents, Nasal"

as key words and applying the filters "Age: 19+ years", "Humans" and "English" to identify papers published during 2010-2020. The 254 publications returned by the system were scrutinized by inspection of title and abstract. The majority of papers dealt with drugs against methicillin resistant Staphylococcus aureus (generally, mupirocin in nose associated with either chlorhexidine or J o u r n a l P r e -p r o o f hexachlorophene body wash). The pharmacological agents relevant for the present scoping review were: povidone-iodine solution (reported by 7 papers), alcohol-based nasal antiseptics (2 papers), quaternary ammonium compounds (1 paper) and N-chlorotaurine (1 paper). Furthermore, "nasal disinfection" was used as search term in three online repositories of preliminary not peer-reviewed reports. The treatments found were: povidone-iodine solution and interferon-alpha (2 papers from MedRxiv), hypothiocyanite (2 papers, of which 1 from SSRN) and alcohol-based nasal antiseptics (1 paper from arXiv).

Every cited treatment was used as key term to find additional information from different electronic databases. The abstracts of the original articles were explored for the following terms: mechanism(s) of action, tolerability and any evidence of toxic effects or selection of resistant strains, whether the treatment was tested in vitro (in particular against SARS-CoV-2), or reached the clinical trials stage, or is currently marketed/promoted/sold. In Figure 2 , R-SH is a peptide or protein with a thiol moiety essential for the activity of numerous enzymes and proteins. Sulphydryl oxidation of R-SH by OSCN − or OI − generates sulfenyl thiocyanate (R-S-SCN) or sulfenyl iodide (R-S-I), determining inhibition of bacterial glycolysis, respiration and glucose transport. Inhibition of the pentose phosphate pathway was also observed only for OI − , with sulfenic acid (R-S-OH) as well as SCN − or I − formed at the end of the cycle.

Either SCN − or I − reacts with native LPO and the cycle restarts. The anti-microbial activity of the entire system (enzyme plus substrates) is known to be more effective than hypothiocyanite or hypoiodite alone and has been explained by the production of short-lived, highly reactive intermediates [22] . Furthermore, the activity of the I − peroxidase system is more effective against E.

coli than the SCN − system, in that lower I − concentrations are necessary. The I − peroxidase system deserves to be tested in vitro against the new coronavirus [22] . Additionally, OSCN − seems able to alter the surface proteins of different respiratory viruses, probably by oxidizing free thiol radicals and creating disulfide bonds [23] , thus contrasting the J o u r n a l P r e -p r o o f binding of viruses with the human airways mucosae. OSCN − may also arguably hamper the synthesis and assemblance of viral proteins and nucleic acids, thus interfering with the release of viruses from infected cells [16, 24, 25] .

The products of LPO extracellular oxidative complex is part of the human natural protective system of central airways against pathogen threats [16, [23] [24] [25] . Due to the need of maximizing gas exchange, alveolar epithelial cells cannot contain strong protective structures. The latter cells are fragile and vulnerable to infectious agents, as shown by the diffuse alveolar damage discovered in two patients undergoing surgical resections for lung adenocarcinoma, later discovered to be affected also by COVID-19 pneumonia [26] . Bronchi were not reported to be as vulnerable as alveoli in the same study [26] .

The lack of LPO/H2O2/SCN − system in nasal and eye secretions of humans may explain the survival and proliferation of bacteria and respiratory viruses in the mucosae of conjunctiva and nose and their subsequent shedding in the environment [27] [28] [29] [30] [31] [32] . At micromolar concentration, the reactive mixture LPO/H 2 O 2 /OSCN − proved cidal activity against a range of bacteria (Gram positive and negative), fungi (Candida albicans and Candida krusei) and viruses as HIV, herpes-simplex virus (HSV-1), adenovirus, echovirus, respiratory syncytial virus (RSV) and influenza virus [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] .

In a recent experiment in-vitro, OSCN − produced by the oxidase/LPO/ H 2 O 2 /thiocyanate system rapidly and effectively inactivated A/swine/Illinois/02860/09 (swH1N2) influenza A virions, successfully preventing the infection of both primary human and male Sprague-Dawley rat tracheabronchial epithelial cells [43] .

In a more recent in-vitro cell-free experiment, all 12 different strains of influenza A and B viruses (the major circulating serotypes and species causing epidemics) were effectively inactivated by the LPO/H 2 O 2 /(SCN − /I − ) system [39] . Considering the strain-independent effect, the authors of the J o u r n a l P r e -p r o o f latter study encouraged a pharmaceutical application of the LPO/H 2 O 2 /(SCN − /I − ) system in vivo to contribute to the clearance of influenza virus [39] .

Another laboratory experiment also challenged enzyme free OSCN − against A/H1N1 2009 pandemic influenza virus in-vitro, showing an evident dose-dependent viricidal activity, without cell toxicity [24] . Considering a demonstrated wide spectrum cidal effect [17, 39] , not targeting specific proteins, it could be reasonably argued that OSCN − may be effective also against SARS-CoV-2 and would therefore deserved to be tested in vitro [24, 25] . Since it is already naturally present in human airways secretion and considering its large spectrum of action, a low level of resistance due to viral mutations and limited adverse reactions can be predicted with OSCN − Due to its similarities to transferrin, LF possesses iron binding capabilities; its iron is not released even at pH 3.5. This property ensures iron sequestration in infected tissues where the pH is typically acidic, preventing the utilization of iron by pathogenic bacteria [45] .

LF is a constituent of the innate immune response and during viral infections the expression of genes encoding LF was elevated by approximately 150 fold in SARS-CoV patients compared with healthy controls [46] . LF possesses strong antiviral activity against a broad spectrum of RNA and DNA viruses, such as HIV, Zika virus, Chikungunya, hepatitis C virus, cytomegalovirus, rotavirus, among others [47] [48] [49] [50] [51] [52] [53] [54] .

The antiviral activity of LF takes place particularly when the virus attacks the host cell, since LF prevents the virus from anchoring and then entering the host cell [56] . It has been reported that LF binds to heparan sulfate proteoglycans (HSPGs), which are cell-surface and extracellular matrix macromolecules that are composed of a core protein decorated with covalently linked glycosaminoglycan chains [45] . HSPGs could be the preliminary docking sites on the host cell membrane and play an important role in the process of entry of SARS-CoV into the cell [56] . As shown in figure 3 , LF blocks the infection of SARS-CoV by competing with the virus for HSPGs [56] . This mechanism could prevent the viral concentration on the cell surface, as well as to the specific entry receptors (ACE2). It is not presently known whether LF binds to ACE2 [56] . It is likely that LF can inhibit SARS-CoV-2 invasion at micromolar concentrations and in a dose dependent fashion, just as for SARS-CoV [56] . However, there is no current confirmed information that SARS-CoV-2 binds to HSPGs. Whether SARS-CoV-2 also enters host cells via HPSGs in the same way clearly warrants further investigation. LF is available as an oral supplement and is widely used as a nutritional additive for infants at doses ranging from 100 mg to 4.5g a day for various indications without apparent toxicities [55] . There is a list of 24 commercial products available by the American corporation Amazon.

A randomized, open-label, parallel-group clinical trial was conducted to examine the effectiveness of sucking tablets containing LF and LPO (LF+LPO) in alleviating symptoms of the common cold and/or influenza infection. Treatment and non-treatment groups (overall 407 subjects) were further classified into subgroups habitually wearing a face mask, washing their hands, or gargling [58] . The incidence and duration of common cold, influenza infection and gastrointestinal symptoms were not statistically different between treatment and non-treatment groups. (LF+LPO) tablets were moderately effective in significantly reducing the duration of fever higher than 38°C in the subgroup that did not wear a protective face mask [58] .

LF in its free form is degraded within the stomach by the action of hydrochloric acid and hydrolytic enzymes. Newer formulations of LF including encapsulation and liposomalization have been explored. Another interesting observation is that zinc saturated lactoferrin can apparently exert a A. In presence of Lactoferrin B. In absence of Lactoferrin more potent antiviral effect. This is of particular relevance in COVID-19 as zinc supplementation has been proposed as a possible intervention for the disease [58] . An oral supplement combining a liposomal bovine lactoferrin (LLF) syrup (32 mg of LF/10 ml plus 12 mg of ascorbic acid) and a Zinc solution 10 mg/10 ml 2-3 times a day and 4-6 times/day was administered for 10 days to 75

symptomatic COVID-19 patients tested positive for IgM/IgG rapid test and self-isolated at home. A control group was treated only with LLF. All patients, who were followed up for one month, resolved their symptoms within 4-5-days since treatment inception and a half dose of LLF on 256 household contacts was effective to prevent the infection [48] . Last but not least, out of seven authors, six worked for Sesderma Laboratories, the producer of all treatments used in the trial [48] .

As mentioned above, LF, alone or in combination with OSCN − , is already being tested in a phase 1 clinical trial (RCT02598999) on healthy volunteers and patients affected by cystic fibrosis [23, 25] .

N-chlorotaurine (NCT) is a natural oxidant part of the human defense system which is produced in the body (HOCl + taurine → NCT + H 2 O) by the strongly toxic hypochlorous acid and the aminoacid taurine [59] . Recently NCT was obtained by synthesis and large quantities were available. This compound revealed an optimal compromise between sufficient disinfecting power and good tissue tolerability. NCT can be stored long-term at low temperatures, and has killing activity against bacteria, fungi, parasites and viruses (Herpes simplex virus type 1; Herpes simplex virus type 2;

Adenovirus; Influenza virus A and HIV-1). NCT can be applied to sensitive body regions as an endogenous antiseptic. Tolerability was very good in the eye, skin, mucous membranes and paranasal sinuses. The ciliary beat frequency of epithelial cells of the nasal mucosa, a very sensitive parameter for toxicity, was decreased only moderately and reversibly by 1% NCT [60] . A special field of application of NCT is inhalation for treatment of various infections. A phase I double-blind randomized clinical study with test group (inhalation of 1% NCT) and a parallel control group (0.9% NaCl as placebo) was carried out in two Austrian centers. The forced expiratory volume in J o u r n a l P r e -p r o o f the first second (FEV1), was not reduced and blood analyses showed no abnormalities compared to the baseline and compared to the control arm [60] . Overall, there is no evidence of efficacy of NCT to clear the nasopharynx from SARS-CoV-2.

The interferon, discovered by virologists in 1957, is part of the human anti-viral innate defenses and plays a critical role in anti-viral immunity, interfering with the viral replication and spread with different mechanisms, including inhibition of the cell metabolism and downregulating the secretion of cytokines which stimulate the adaptive immunity [61] . An in vitro test confirmed the efficacy of IFN-α against SARS-like coronavirus infections [62] . Animal tests have confirmed that IFN-α nasal spray can effectively block or reduce SARS-CoV infection-related damage in monkeys [63, 64] .

SARS-CoV-2 can inhibit the endogenous secretion of IFN by host cells, thus in turn reducing their ability to suppress viral infections. Therefore, the use of exogenous IFN is critical with the severe form of COVID-19 [65] . A recent open-label prospective study tested nasal drops of recombinant human interferon alpha (rhIFN-α) on 2,944 health care workers in China during SARS-CoV-2 epidemics as follows [66] :

• 2,415 subjects (997 doctors and 1,418 nurses with average ages of 37.38 and 33.56 years respectively) included in a "low-risk group" were administered 2-3 drops/nostril/time of rhIFNα, 4 times/day for 28 days.

• 529 subjects (122 doctors and 407 nurses with average ages of 35.24 and 32.16 years respectively) were included in a "high-risk group" and administered 2-3 drops/nostril/time of rhIFN-α, 4 times/day for 28 days, in addition to thymosin-α 11.6 mg hypodermic injection once a week.

At day 28 no study subject was positive for COVID-19 and nobody developed respiratory symptoms [66] . The study was not a clustered, randomized study. The control group used was J o u r n a l P r e -p r o o f medical staff with COVID-19 pneumonia in the epidemic area during the same period reported in the literature, rather than a strictly parallel, placebo-controlled group. In addition, the paper in its current form is a preliminary report which has not been certified by peer review.

Although IFN is seemingly effective to disinfect the upper airways from COVID-19, its use may be more appropriate for front-line individuals such as health care staff, especially considering its likely high cost. Since the protocol entails also the injection of thymosin-α 11.6 mg once a week, IFN

does not seem of practical use in the general population.

Polyvinylpyrrolidone polymer with iodine (PVP-I), also known as povidone iodine, was discovered and marketed as disinfectant since 1955.

The air-liquid interface of human nasal epithelial cells cultures collected from patients affected by chronic rhinosinusitis were recently exposed in vitro to a 0.5% solution of PVP-I (Nasodine ® licensed by Firebrick Pharma) [67] . No cell toxicity was observed on paracellular permeability or cilia beat frequency. The trans epithelial electrical resistance of cultured cells was significantly reduced only after 30 minutes exposure to Nasodine ® [66] . Consequently, PVP-I could be considered as a safe therapy when used as a mouthwash or taken nasally or used during ophthalmic surgeries.

The viricidal activity in-vitro of topical and oral PVP-I products against SARS-CoV-2 was recently reported [68] . A phase III clinical trial (ACTRN12619000764134) is ongoing to assess the safety and efficacy of povidone-iodine nasal spray (Nasodine®) in the treatment of subjects affected by common cold, potentially caused by human coronaviruses [69] . PVP-I awaits clinical trial data confirming an effective activity of drug against SARS-CoV-2.

Although it is an effective antiseptic, PVP-I may not be optimal for pregnant women and children though. Hypothyroidism has been reported with povidone-iodine antiseptics in neonates. Transient hyper-thyrotropinemia can occurs in neonates whose mothers had been exposed to povidone-iodine as a skin disinfectant during and after labour [70] .

Hydroxychloroquine (HCQ), a less toxic derivative of chloroquine (CQ), at micromolar concentration proved anti-viral activity against SARS-CoV-2 in vitro [71] , and its mechanism of action entails the increase of pH of intracellular organelles, such as endosomes/lysosomes, essential for membrane fusion [72] . In addition, CQ could inhibit SARS-CoV entry through changing the glycosylation of ACE2 receptor and spike protein [73] . Along with the derivative HCQ, CQ has even entered multiple clinical trials. The evidence on the efficacy of HCQ to clear the nasopharynx from SARS-CoV-2 is relatively low, being founded only on one small open-label non-randomized clinical trial, which did not confirm clinical improvement of COVID-19 patients though [74] .

Furthermore, HCQ if featured by risk of side effects in terms of QTc prolongation and haemolysis associated with deficiency of glucose-6-phosphate dehydrogenase [75] . On this note, the Mayo clinic recommended baseline electrocardiogram monitoring before commencing treatment of COVID-19 patients with HCQ [76] . The efficacy of hydroxychloroquine, also in combination with azithromycin has been questioned too, since it was not associated with a significantly reduced J o u r n a l P r e -p r o o f mortality among 1,428 randomly sampled COVID-9 patients admitted to 25 hospitals of the New York City Metropolitan region [77] .

Lastly, nasal antimicrobials such as HCQ are typically not used on a regular basis to reduce subclinical colonization in individuals because this strategy might lead to increased development of resistant bacteria/viruses.

SARS-CoV-2, SARS-CoV and MERS-CoV are lipophilic enveloped viruses relatively easy to inactivate by exposure to alcohols. Ethanol 62-71% is among the reagents already proven effective to disinfect fomites from SARS-CoV-2 within 1 minute [78] . Shintake recently proposed a controlled inhalation of ethanol vapor obtained from readily available alcoholic beverages (whisky or Japanese sake), to disinfect the human airways from SARS-CoV-2 [79] .

Two additional studies tested the effectiveness of alcohol-based antiseptic in reducing nasal bacterial carriage in health care professionals at an urban hospital center [80] or in colonized patients [81] . Further clinical research is however necessary to investigate the preventive and protective effects against SARS-CoV-2 because the above papers were not peer-reviewed. A commercially available, non-prescription product, Nozin Nasal Sanitizer antiseptic was used as test agent in both studies. The safety-tested formulation is composed of 70% ethanol active combined with a mixture of natural oil emollients and the preservative benzalkonium chloride. Sterile phosphate-buffered saline with 0.017% peppermint oil as a masking agent was used as placebo treatment control. CoV-2. The amounts of QACs used in households (including detergents for personal care, soaps and liquid hand washes), workplace, and industry settings has likely increased a lot, and their usage will continue to be elevated considering the trend of COVID-19 pandemic [82] .

Inactivation of SARS-CoV-2 by formulated detergents is believed to occur as a result of disruption of the virally modified, host-cell-derived, phospholipid bilayer glycoproteinaceous envelope, and the associated spike glycoproteins that interact with the ACE2 receptor for infection of host cells.

Another mechanism entails raising the endocytic and lysosomal pH [82] .

Using a text mining approach, Baker [83] identified the following three classes of QACs having a possible antiviral activity against coronaviruses.

• Ammonium chloride. Various uses, including metabolic acidosis. Viral activity against murine coronavirus and hepatitis C.

• Cetylpyridinium chloride. Used as antiseptic, mouthwash, personal care products, cleaning agents etc. It is also being used as an antimicrobial agent for meat and poultry products. It was tested in a clinical trial as a treatment against respiratory infections [84] . Cetylpyridinium chloride has anti-viral activity against Influenza, hepatitis B, poliovirus 1.

• Miramistin. Used as antiseptic, has antiviral activity against HIV, influenza, herpes and SARS-CoV.

QACs such as cetylpyridinium chloride and miramistin have not been tested yet against SARS-CoV-2 in vitro or in clinical trials.

The clear and severe threat posed by COVID-19 prompts an elevated use of QACs as a reasonable strategy to mitigate and contain the spread of the infection. It is important, however, to assess the potential environmental impact of elevated QAC use, which may include disruption of wastewater treatment unit operations, proliferation of antibiotic resistance, formation of nitrosamine J o u r n a l P r e -p r o o f disinfection byproducts, and negative effects on biota of surface waters. Exploration of potential technologies to minimize the environmental releases of QACs is also warranted [82] .

The viricidal effect in vitro against SARS-CoV-2 has been described for povidone-iodine only. In vitro inhibition of other coronaviruses was reported for LF, HCQ and AQCs. No treatment was tested against SARS-CoV-2 in randomized controlled clinical trials. The lack of effective and safe drugs against SARS-CoV-2 implies primarily that the relevant literature on this topic does not exist.

Most drug candidates are already in the market. A pointed out by Baker et al. "As simple as it sounds, it is entirely possible that we should be looking in our bathroom cupboards for potential remedies against COVID-19" [83] .

Whilst the nasal cavity is the port of entry for SARS-CoV-2, the mouth is also relevant as exit site of the virus through emission of saliva droplets. The well-known hand-to-nose-to-hand cycle of contamination requires appropriate additional methods for infection control.

The present scoping review identified knowledge gaps more than available evidence on the topic of chemoprevention of COVID-19. Since speed is essential in responding to the COVID-19 pandemic [85] , undertaking clinical trials on all the candidate agents identified could be too demanding and requires too much time.

Taking everything into account, these data suggest that the search for convenient non-antibiotic drug(s) could be pursued with a case-control study, comparing the use of candidate drugs among individuals positive and negatives to coronavirus swab tests. The results of such study could help in narrowing down the subsequent laboratory and clinical investigations.

None to declare.

J o u r n a l P r e -p r o o f

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Lactoferrin-a multifunctional protein with antimicrobial properties

The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria

Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome

A nutritional supplement containing lactoferrin stimulates the immune system, extends lifespan, and reduces amyloid β peptide toxicity in Caenorhabditis elegans. Sci Nutr

Liposomial lactoferrin as Potential Preventive and Cure for COVOD-19 -Int

Bovine lactoferrin activity against Chikungunya and Zika viruses

Antiviral properties of lactoferrin-A Natural Immunity Molecule

Oral lactoferrin prevents body weight loss and increases cytokine responses during herpes simplex virus type 1 infection of mice

Effect of lactoferrin on taste and smell abnormalities induced by chemotherapy: A proteome analysis

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Cellular entry of the SARS coronavirus

Viral infections: lactoferrin, a further arrow in the quiver of prevention

Inhibition of SARS Pseudovirus Cell Entry by Lactoferrin Binding to Heparan Sulfate Proteoglycans

Effects of orally administered lactoferrin and lactoperoxidase on symptoms of the common cold

Potential interventions for novel coronavirus in China: A systematic review

N-chlorotaurine, a natural antiseptic with outstanding tolerability

N-chlorotaurine, a promising future candidate for topical therapy of fungal infections

Interferon  for multiple sclerosis. Cold Spring Harb

Characterization of the antiviral effects of interferon-alpha against a SARS-like coronavirus infection in vitro

SARS treatment: Interferon Shows Promise in Monkeys

Preventive and therapeutic effects of recombinant IFN-alpha2b nasal spray for SARS-CoV infection in Macaca mulata

Interferon-α2b Treatment for COVID-19. Front Immunol

An experimental trial of recombinantX human interferon alpha nasal drops to prevent coronavirus disease 2019 in medical staff in an epidemic area

S In Vitro Safety Evaluation of a Povidone-Iodine Solution Applied to Human Nasal Epithelial Cells. Int Forum Allergy Rhinol

Rapid In-Vitro Inactivation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Using Povidone-Iodine Oral Antiseptic Rinse

Trial Registration ACTRN12619000764134. Australian-New Zealand Clinical Trial Registry

Transient neonatal hypothyroidism during breastfeeding after post-natal maternal topical iodine treatment

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Lysosomotropic agents as HCV entry inhibitors

New insights into the antiviral effects of chloroquine

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Hydroxychloroquine prophylaxis for high-risk COVID-19 contacts in India: a prudent approach

Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19)

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents

Possibility of Disinfection of SARS-CoV-2 (COVID-19) in Human Respiratory Tract by Controlled Ethanol Vapor Inhalation. ArXiv -Cornell University

Reduction of nasal Staphylococcus aureus carriage in health care professionals by treatment with a nonantibiotic, alcohol-based nasal antiseptic

Evaluation of an alcohol-based antiseptic for nasal decolonization of methicillin-resistant Staphylococcus aureus in colonized patients

Increased Use of Quaternary Ammonium Compounds during the SARS-CoV-2 Pandemic and Beyond: Consideration of Environmental Implications. Environmental Science & Technology Letters

Repurposing Quaternary Ammonium Compounds as Potential Treatments for COVID-19

Randomized, double-blind, placebo controlled clinical trial to assess the safety and effectiveness of a nove dual-action oral topical formulation against upper respiratory infections

Moving quickly in pandemics