Ethanol Inhalation for Respiratory Infections due to Enveloped Viruses

Abstract

Ethanol has demonstrated high efficacy in inactivating enveloped viruses in vitro and in vivo (in animal and human studies). The inhalation route has been a significant method of drug administration for respiratory disorders since ancient times. Infections with enveloped viruses cause many respiratory diseases. This concise review explores the general structural characteristics of enveloped viruses and examines the potential role of inhaled ethanol as a low-cost therapy for respiratory diseases. Current literature data suggest that ethanol inhalation could be beneficial in treating respiratory infections caused by enveloped viruses. However, there is a clear gap in well-designed clinical trials assessing the safety and efficacy of ethanol inhalation in treating respiratory infections from enveloped viruses. This low-cost therapy could become an important therapeutic option, especially for large numbers of patients simultaneously infected, as was the case during the coronavirus disease 2019 (COVID-19) pandemic. In addition, inhaled ethanol could be a successful approach for vulnerable patients such as patients with cancer because it is likely to have no or minimal effects on already established life-saving treatments. Further investigation by national and international institutions is urgently needed to validate these findings and refine treatment protocols.

Full text

Vol.:(0123456789)
Infect Dis Ther
https://doi.org/10.1007/s40121-025-01157-8
REVIEW
Ethanol Inhalation forRespiratory Infections due
toEnveloped Viruses
PietroSalvatori · AliAmoushahi· AldoVenuti· FrancescaPaolini
Received: January 23, 2025 / Accepted: April 7, 2025
© The Author(s) 2025
be benecial in treating respiratory infections
caused by enveloped viruses. However, there is a
clear gap in well-designed clinical trials assessing
the safety and efcacy of ethanol inhalation in
treating respiratory infections from enveloped
viruses. This low-cost therapy could become
an important therapeutic option, especially
for large numbers of patients simultaneously
infected, as was the case during the coronavirus
disease 2019 (COVID-19) pandemic. In addition,
inhaled ethanol could be a successful approach
for vulnerable patients such as patients with
cancer because it is likely to have no or minimal
effects on already established life-saving treat-
ments. Further investigation by national and
international institutions is urgently needed
to validate these ndings and rene treatment
protocols.
Keywords: Respiratory infection; SARS-
CoV-2 and COVID-19; Inuenza A infection;
Enveloped viruses; Ethanol inhalation; Patients
with cancer
ABSTRACT
Ethanol has demonstrated high efcacy in inac-
tivating enveloped viruses invitro and invivo
(in animal and human studies). The inhalation
route has been a signicant method of drug
administration for respiratory disorders since
ancient times. Infections with enveloped viruses
cause many respiratory diseases. This concise
review explores the general structural charac-
teristics of enveloped viruses and examines the
potential role of inhaled ethanol as a low-cost
therapy for respiratory diseases. Current litera-
ture data suggest that ethanol inhalation could
P.Salvatori(*)
ENT Department, Humanitas San Pio X Hospital,
Milan, Italy
e-mail: pietro.salvatori@me.com
A.Amoushahi
Anesthesiology andIntensive Care, Isfahan
University ofMedical Sciences, Isfahan, Iran
A.Venuti
HPV Unit, IRCCS Regina Elena National Cancer
Institute, Rome, Italy
F.Paolini
Biochemical Sciences, IRCCS Regina Elena National
Cancer Institute, Rome, Italy
F.Paolini
Department ofBiochemical Sciences A. Rossi Fanelli,
Sapienza University ofRome, Rome, Italy

Infect Dis Ther
Key Summary Points
Current knowledge on ethanol (EtOH) inha-
lation for enveloped-virus respiratory diseases
is very limited, especially when compared to
the extensive literature on the use of EtOH
for hand and surface disinfection.
This concise clinical review suggests that
EtOH inhalation could potentially play a
benecial role in treating respiratory infec-
tions caused by enveloped viruses.
This low-cost therapy could become an
important therapeutic option, especially for
large numbers of patients simultaneously
infected, as was the case during the COVID-
19 pandemic.
Further investigation by national and inter-
national institutions is urgently needed to
validate these ndings and rene treatment
protocols.
INTRODUCTION
Viruses are categorized into two primary and
widely recognized groups: enveloped viruses
(EV) and non-enveloped viruses (N-EV). This
distinction is based on the presence or absence
of an external lipid bilayer membrane, which
characterizes EV and is absent in N-EV [1].
Ethanol (EtOH) has demonstrated high ef-
cacy in inactivating EV both invitro [2–4] and
invivo (in animal and human studies) [5–7].
The inhalation route has been a signicant
method of drug administration for respiratory
disorders since ancient times. Today, it remains
the preferred approach for treating numer-
ous pulmonary diseases, including asthma,
chronic obstructive pulmonary disease (COPD),
cystic fibrosis, and pneumonia. The pulmo-
nary route enables targeted drug delivery to
the lungs, allowing the drug to directly reach
its site of action. This targeted delivery ensures
a rapid onset of therapeutic effect, with lower
doses required and higher local drug concentra-
tions at the site of pulmonary disease. It also
minimizes systemic bioavailability, thus reduc-
ing the risk of systemic toxicity and bypassing
rst-pass metabolism in the liver [8]. Aerosol
therapy allows for further reduction in drug
dosages, improved access to “hidden” areas and
more precise targeting of specic cells or com-
partments, ultimately enhancing drug bioavail-
ability. The particle size generated—commonly
dened by the mass median aerodynamic diam-
eter (MMAD)—is closely associated with the spe-
cic site of treatment.
This narrative review explores the general
structural characteristics of EV and examines
the potential role of inhaled EtOH in address-
ing respiratory diseases caused by EV.
The search for reference material was carried
out by consulting online databases for existing
work relevant to the topic. PubMed, MEDLINE,
ScienceDirect, Scopus, and Google Scholar (the
latter to identify both published and unpub-
lished information) were searched, utilizing
specific keywords and applying publication
date and other lters. No ethical approval was
required. The search revealed limited data on
this topic, especially when compared with the
extensive literature on the use of EtOH for hand
and surface disinfection. This article is based on
previously conducted studies and does not con-
tain any new studies with human participants or
animals performed by any of the authors.
REVIEW
N‑EV are Typically More Virulent
N-EV, often referred to as naked viruses, are
generally more virulent than EV due to their
tendency to induce host cell lysis. This char-
acteristic represents a fundamental distinction
between the two virus types. The absence of an
external lipid membrane in N-EV means that
cell lysis serves as their primary mechanism of
exiting the host cell. During lysis, the viruses
compromise the integrity of the host cell mem-
brane, leading to cell death and substantial dam-
age to surrounding tissues. Additionally, N-EV
exhibit greater resistance to extreme pH, high
temperatures, dryness, and simple disinfectants,

Infect Dis Ther
contributing to their persistence in various envi-
ronments. Prominent examples of N-EV include
noroviruses, enteroviruses, adenoviruses, and
rhinoviruses.
EV are Generally Less Virulent
EV are less likely to cause direct cell damage,
as they do not always rely on cell lysis for their
exit from host cells, although cell death can still
occur as a consequence of viral replication. The
presence of an outer membrane, or envelope,
surrounding the capsid enables EV to incorpo-
rate portions of the host cell membrane dur-
ing assembly and release [10]. The presence
of a membranous envelope is associated with
reduced resistance to environmental factors such
as desiccation, heat, alcohol, and detergents,
which limits the survival of viral particles out-
side the host.
Despite this limitation, the envelope offers
several distinct advantages to the virus: (i) it
allows viral particles to exit host cells via the cel-
lular exocytosis machinery, minimizing cellular
damage and delaying immune detection; (ii) it
increases the viral particle’s packaging capacity,
enabling the incorporation of additional viral
proteins; (iii) it conceals the capsid’s structurally
xed antigens from circulating antibodies; and
(iv) it offers greater structural exibility to enve-
lope proteins compared with capsid proteins,
enhancing the virus’s ability to evade neutral-
izing immune responses. Most zoonotic viruses
are enveloped, likely due to the adaptability of
envelope proteins, which facilitates their abil-
ity to infect different hosts, although additional
adaptations are also necessary. In addition to
incorporating host cell phospholipids and mem-
brane proteins, the viral envelope contains viral
glycoproteins that are critical for binding to spe-
cic host cell receptors. The fusion of the viral
envelope with the host cell membrane upon
entry allows the capsid to be released into the
cytoplasm, initiating viral genome release, rep-
lication, and the production of progeny virions.
The most prominent EV that cause human dis-
eases are listed in Table1, with a subset of these
viruses specically associated with respiratory
diseases detailed in Table2.
What About Viral Envelopes?
During viral maturation, a process called bud-
ding allows viral envelopes to form from the
membranes of host cells. These membranes
may originate from the plasma membrane or
internal structures such as the nuclear mem-
brane, endoplasmic reticulum, or Golgi com-
plex. The lipids that constitute the viral enve-
lope are sourced directly from the host cell,
whereas the envelope proteins are encoded by
the viral genome.
Two main types of proteins are associated
with the viral envelope. The rst type consists
of glycoproteins, often referred to as peplom-
ers (from peplos, meaning envelope), or spikes.
These structures can frequently be observed as
distinct projections on the surface of the enve-
lope in electron micrographs. The second type,
matrix proteins, are non-glycosylated proteins
located within the envelope of virions in cer-
tain viral families. Matrix proteins provide
structural rigidity to the virion. For example,
the rhabdovirus envelope contains a tightly
packed bullet-shaped matrix protein that sur-
rounds the helical nucleocapsid. In contrast,
arenaviruses, bunyaviruses, and coronaviruses
lack matrix proteins, making their envelopes
more pleomorphic compared with those of
other viruses.
Notably, envelopes are not exclusive to
viruses with helical symmetry; certain icosa-
hedral viruses, including ranaviruses, African
swine fever viruses, herpesviruses, togaviruses,
aviviruses, and retroviruses, also possess an
envelope. For most EV, the integrity of the
envelope is critical for their infectivity. How-
ever, in some cases, such as with certain poxvi-
ruses, the envelope is not essential for the virus
to remain infectious [11].
Types and Functions of the Virus Envelope
Nearly one-quarter of viruses have an envelope
encasing their protein capsid. This envelope
typically consists of a lipid bilayer membrane
obtained from the host, embedded with viral-
encoded glycoproteins. The characteristics of

Infect Dis Ther
the envelope, including its size, composition,
morphology, and complexity, vary widely
among different viral families.
Viral glycoproteins are embedded in the
lipid bilayer and are essential in the virus–host
interactions. In some cases, non-glycosylated
viral proteins may also be incorporated into
the envelope. The number of glycoproteins
differs across viral families. For instance, more
than ten glycoproteins have been identied
in viruses belonging to the Herpesviridae fam-
ily, while simpler viruses such as those in the
Togaviridae and Orthomyxoviridae families pos-
sess only one or two multimeric proteins.
Additionally, some EV encode specialized
glycoproteins known as viroporins. These pro-
teins function as ion channels and possess at
least one transmembrane domain, along with
extracellular regions that interact with host
or viral proteins. Examples of viroporins have
been identied in the inuenza A virus, Hepa-
civirus C (formerly hepatitis C virus), human
immunodeciency virus 1, and coronaviruses.
Table 1 Enveloped viruses
dsDNA double-stranded DNA, ssRNA single-stranded RNA
Virus family Genome Relevant viruses
Herpesviridae dsDNA Herpes simplex viruses 1/2
Varicella zoster virus
Epstein–Barr virus
Cytomegalovirus
Human herpesviruses 6A/B and 7 (HHV 6A/B, HHV 7)
Kaposi’s sarcoma-associated herpesvirus (KSHV )
Poxviridae dsDNA Smallpox virus, vaccinia virus, molluscum contagiosum virus
Hepadnaviridae Circular
partially
dsDNA
Hepatitis B virus
Retroiridae ssRNA HIV 1/2, human T-lymphotropic viruses 1/2 (HTLV 1/2)
Virusoid ssRNA Hepatitis D virus (HDV)
Flaviviridae ssRNA Dengue virus, hepatitis C virus, Japanese encephalitis virus ( JEV), yellow fever virus
(YFV ), West Nile virus, tick born encephalitis virus (TBEV)
Paramyxoiridae ssRNA Measles virus, mumps virus, respiratory syncytial virus, Nipah virus, parainuenza
viruses 1–3, human metapneumovirus (HMPV), Newcastle disease virus (NDV)
Orthomyxoiridae ssRNA Inuenza A/B viruses
Filoiridae ssRNA Ebola virus, Marburg virus
Coronaviridae ssRNA Corona viruses (including SARS-CoV, Middle East respiratory syndrome (MERS)-
CoV, ans SARS-CoV2)
Arenaviridae ssRNA Lymphocytic choriomeningitis virus, Lassa virus
Togaviridae ssRNA Rubella virus, Chikungunya virus, Sindbis virus, etc.
Bunyaviridae ssRNA California encephalitis virus, Hanta virus, Ri Valley fever virus, Toscana virus,
Crimean–Congo hemorrhagic fever virus (CCHFV)
Rhabdoiridae ssRNA Rabies virus

Infect Dis Ther
A structural layer of proteins known as the
matrix may be found between the envelope
and the capsid in some EV (e.g., Orthomyxoviri-
dae and Retroviridae). In other cases, the capsid
may directly interact with the internal tails of
membrane proteins, as observed in Togaviridae
and Bunyavirales. The envelope and associated
proteins primarily function in processes such
as recognition, attachment, and entry into host
cells through fusion with host membranes.
The envelope also plays a signicant role in
helping viruses evade the mammalian host’s
immune response, conferring an evolutionary
advantage.
From an evolutionary perspective, viral enve-
lope proteins have been co-opted into vertebrate
genomes, playing signicant roles in biological
processes. A notable example is the syncytin
genes, which originate from retroviral enve-
lope proteins and have been adapted for critical
functions in placental morphogenesis. This rep-
resents a striking case of convergent evolution,
where viral-derived genes have been repurposed
to enable placentation in several species [12].
Respiratory Viruses
As presented in Table2, most respiratory
viruses are enveloped. These are among the
most prevalent causes of disease in humans
and have a signicant global impact, particu-
larly on children. Acute respiratory infections
(ARI) are responsible for about one-fth of all
childhood deaths worldwide, with the burden
being disproportionately higher in impov-
erished tropical regions compared with tem-
perate areas. This disparity is due to higher
ARI case–fatality ratios in these regions. The
severe acute respiratory syndrome coronavi-
rus 2 (SARS-CoV-2) pandemic has underscored
the profound impact that human respiratory
viruses can have on global health.
Respiratory viruses from various families
have evolved to efciently transmit from per-
son to person and are found circulating glob-
ally. Community-based studies conrm that
these viruses are the leading causes of ARI. The
most commonly circulating respiratory viruses,
Table 2 Common respiratory viruses, their classication, and principal syndromes
Enveloped viruses are in bold
PCF pharyngoconjunctival fever, SARS severe acute respiratory syndrome, URI upper respiratory infection, COPD chronic
obstructive pulmonary disease
Virus Classication Principal syndromes
Inuenza virus Groups A, B, and C Flu
Human respiratory syncytial virus
(RSV)
Groups A and B URI, bronchiolitis, croup, bronchitis,
pneumonia
Human parainuenza virus (HPIV) Types 1, 2, 3, 4 URI, croup, bronchiolitis, bronchitis,
pneumonia
Human rhinovirus (HRV) Species A, B, and C with more than 160
genotypes
URI; asthma and COPD exacerbation
Adenovirus (ADV) 51 serotypes URI, PCF, bronchitis, pneumonia
Human coronavirus (HCoV) Types OC43, 229E, NL(NH), HKU1,
MERS-CoV, SARS CoV-1, SARS
CoV-2
URI, bronchitis, pneumonia SARS,
COVID-19
Human metapneumovirus (HMPV) Groups A and B URI, bronchitis, pneumonia
Human bocavirus (HBoV) 2 lineages URI, bronchiolitis, asthma exacerbation,
bronchitis, pneumonia

Infect Dis Ther
endemic or epidemic, include inuenza viruses,
respiratory syncytial virus (RSV), parainflu-
enza viruses, metapneumovirus, rhinovirus,
coronaviruses, adenoviruses, and bocaviruses
(Table2).
Given the prevalence and impact of these
viruses, this review focuses particularly on envel-
oped respiratory viruses, such as coronaviruses.
The viral envelope, derived from the host cell
membrane, is vulnerable to specic disruptions.
Unlike host membranes, viral envelopes lack
metabolic turnover and cannot repair them-
selves once the virus has budded. This inherent
vulnerability has long been exploited by disin-
fectants to inactivate EV.
Moreover, this review highlights new thera-
peutic possibilities, such as the use of nebulized
EtOH solutions to interfere with the transmis-
sion and infectivity of enveloped respiratory
viruses. This approach provides an innovative
avenue for limiting the spread of these patho-
gens, particularly in healthcare and community
settings where ARI poses a signicant risk [13].
What is EtOH?
Ethanol, or ethyl alcohol, known simply as alco-
hol, is a linear alkyl chain alcohol. Its condensed
structural formula is CH3CH2OH. In chemistry,
it can also be found abbreviated with the acro-
nym EtOH or C2H6O.
How does EtOH Work on EV?
EtOH most likely inactivates EV by disrupting
their structural components, as viruses lack a
metabolism, unlike bacteria. EV are structured
with a genomic core encased in a protein shell,
further surrounded by an outer lipid bilayer.
According to Watts etal. [2], EtOH can inter-
act with all three of these components: it can
denature protein, uidize and overall reorganize
the structures of the lipid bilayers through the
modication of the lipid packing by its cosur-
factant actions, and aggregate DNA and RNA;
they also noted that the detailed nano-structural
and surface-chemical effects of EtOH on EV had
not been fully explored. To address this, they
used the Phi6 bacteriophage as a model. Phi6
is an 85nm-diameter enveloped bacteriophage
that infects Pseudomonas bacteria and serves as
a surrogate for enveloped human viruses such
as inuenza, Ebola, and SARS-CoV-2. The Phi6
envelope is composed of a lipid bilayer derived
from the plasma membrane of its bacterial host,
containing a high density of viral membrane
proteins (however, a caveat should be added: the
EtOH sensitivity of the bacterial plasma mem-
brane may differ from that of eukaryotic mem-
branes, which are rich in cholesterol). The most
abundant of these is the major envelope protein
P9, which facilitates vesicle formation from the
plasma membrane and associates with the nucle-
ocapsid. The nucleocapsid, located beneath the
membrane, contains the virus’s three double-
stranded RNA segments. Their research revealed
that EtOH’s primary disruptive effect is on the
envelope structure rather than the protein cap-
sid. However, envelope proteins and their inter-
actions with the nucleocapsid play a critical role
in stabilizing the bilayer structure. This nding
suggests that destabilizing the lipid envelope is
a key mechanism through which EtOH inac-
tivates EV. No signicant modications in the
lipid envelope were observed up to EtOH 20%.
At 50% EtOH concentration, the lipid bilayer
of the EV separates from the nucleocapsid and
loses its bilayer structure. This structural disin-
tegration correlates directly with a complete loss
of viral infectivity at the same EtOH concentra-
tion, highlighting EtOH’s unspecic but effec-
tive mode of action in destroying the lipid mem-
brane. This broad-spectrum activity is thought
to extend to human pathogenic EV such as
Ebola, inuenza, and coronaviruses [2].
Manning etal. [14] further explored EtOH’s
mechanism of action, focusing on its interac-
tion with protein structures. EtOH interferes
with intramolecular hydrogen bonds between
the side chains of proteins. These bonds are
crucial for maintaining the tertiary structure
of proteins, which in turn is essential for their
function [15]. EtOH’s hydroxyl group (–OH)
competes as a hydrogen bond donor or acceptor,
disrupting these bonds and destabilizing protein
structures. While other alcohols such as metha-
nol and propanol can act similarly, their higher
toxicity limits their use invivo. They then
addressed the challenges of translating invitro

Infect Dis Ther
ndings into effective invivo treatments. In the
human respiratory system, sputum and mucus
on the respiratory epithelium may impede a
molecule’s access to its viral target, even if the
molecule demonstrates efcacy invitro. Using
Lipinski’s rules and quantitative structure–activ-
ity relationship (QSAR) models, they developed
the penetration score (PS), a metric that esti-
mates the likelihood of a molecule penetrating
a mucus layer. PS values are calculated relative
to water, the most abundant molecule invivo.
A low PS indicates a better candidate for invivo
applications. EtOH, with a very low PS, is thus
a promising candidate for treating conditions
such as COVID-19, where mucus accumula-
tion in the lungs is common. This low PS helps
explain why some invitro effective drugs, such
as remdesivir, may fail to achieve the same ef-
cacy invivo. EtOH’s ability to penetrate mucus
layers, combined with its broad-spectrum activ-
ity against EV, makes it a strong candidate for
therapeutic use in respiratory infections.
Manning et al. [16] also calculated the
amount of alcohol needed to clear the SARS-
CoV-2 estimated viral load affecting the lungs:
153µg of EtOH or 122.4µL.
Studies suggest that viral loads in the lungs,
often higher than in other parts of the respira-
tory tract, are correlated with the severity of
COVID-19 [17]. Therefore, a direct treatment
targeting the infection from the mouth to the
alveoli could be the most effective approach.
Tamai etal. [5] investigated the effect of EtOH
(20% v/v) on Inuenza A virus (IAV)-infected
mice. Their findings indicate that EtOH not
only directly inactivates extracellular IAV, but
also suppresses progeny virus production in
the respiratory tract. Interestingly, the virucidal
efcacy of low-concentration EtOH solutions in
the respiratory tract was observed to be higher
than that on environmental surfaces, likely due
to temperature effects. While the inactivation of
extracellular IAV by EtOH is attributed to its abil-
ity to disrupt viral envelopes, the mechanism by
which EtOH suppresses progeny virus produc-
tion remains unclear. They also noted that IAV-
induced expression of type I interferon-related
genes was not affected by EtOH, suggesting that
further research is needed to determine whether
EtOH enhances antiviral immunity. This is
particularly relevant because EtOH is known to
modulate several immune-related pathways [18].
Additionally, they recommended investigat-
ing EtOH’s effects on viral proteins or the cellu-
lar metabolism of virus-infected epithelial cells,
given its previously reported activities [19].
Recently, Hancock etal. [7] conrmed the ef-
cacy of inhaled EtOH (40/60/80% ethanol v/v in
water) for three 30-min periods, with a 2-h break
between exposures, in another inuenza-infec-
tion mouse model, both in terms of lowering
the viral load and increasing the macrophagic
response.
Nomura etal. [20] examined the effect of
various EtOH concentrations on SARS-CoV-2
infectivity in culture cells. They found that a
99% reduction in infectious titers occurred at
an EtOH concentration of 24.1% (w/w) [29.3%
(v/v)]. For comparison, ETOH was tested against
other EV, including inuenza virus, vesicular sto-
matitis virus (Rhabdoviridae), and Newcastle dis-
ease virus (Paramyxoviridae). The 99% inhibitory
concentrations were 28.8% (w/w) [34.8% (v/v)],
24.0% (w/w) [29.2% (v/v)], and 13.3% (w/w)
[16.4% (v/v)], respectively. Some differences
from SARS-CoV-2 were observed, but the differ-
ences were not signicant. It was concluded that
EtOH at a concentration of 30% (w/w) [36.2%
(v/v)] almost completely inactivates SARS-CoV-2.
Recently, Jia etal. [21] discovered that high
expression of oleoyl-acyl-carrier-protein (ACP)
hydrolase (OLAH) is a key factor in life-threat-
ening respiratory viral diseases, including avian
A (H7N9) inuenza, seasonal inuenza, COVID-
19, RSV, and multisystem inammatory syn-
drome in children (MIS-C). OLAH is an enzyme
involved in fatty acid production, primarily oleic
and palmitic acids, which are known for their
proinammatory activity. Due to EtOH’s action
on solving lipids, it is also possible to hypoth-
esize its benecial effect on lowering inamma-
tory status connected with these diseases, via the
reduction of the abundant fatty acids deriving
from the OLAH high expression.
How does EtOH Work on N‑EV?
N-EV lack lipid membranes, then are expected
to be less susceptible to EtOH. Indeed, for N-EV

Infect Dis Ther
with and without organic matter, ≥ 77.50% and
≥ 65% ethanol with an extended contact time of
≥ 2min were required for a 4 log10 viral reduc-
tion, respectively, while EV required around
≥ 35% ethanol with an average contact time of
at least 1min, which reduced the average viral
load by 4 log10 [22].
EtOH Inhalation Toxicity
Three major considerations must be taken into
account:
• Firstly, there is a notable distinction between
EtOH that is ingested and EtOH that is
inhaled. Inhaled EtOH bypasses the initial
metabolic step required for ingested EtOH
and instead directly reaches the left ventricle
of the heart and the brain.
• Secondly, the chronic use of EtOH differs
from chronic EtOH abuse, which can lead to
lung damage, including alveolar macrophage
dysfunction and an increased risk of bacte-
rial pneumonia and tuberculosis [23].
• Finally, chronic intoxication has to be differ-
entiated from the acute one.
The inhalation/absorption rate, i.e., the
amount of EtOH that passes from the alveoli to
the bloodstream, is 62% [24].
EtOH is eliminated from the body at a rate
of 120–300mg/L/h [25]. Approximately 95%
of consumed (or inhaled) EtOH is metabolized
by alcohol dehydrogenase, while the remaining
5% is excreted unchanged through exhaled air,
urine, perspiration, saliva, and tears.
The EtOH clinical effects are related to the
blood levels:
1. Blood levels below 184.2mg/L (4mmol/L):
asymptomatic.
2. Blood levels up to 460.6mg/L (10mmol/L):
associated with behavioral and cognitive
changes.
3. Blood levels exceeding 460.6 mg/L
(10mmol/L): considered toxic.
4. Blood levels above 2763.7mg/L (60mmol/L):
may result in coma or death.
The serum concentrations observed follow-
ing EtOH inhalation are signicantly lower than
those linked to toxicity or fatal outcomes [26].
It is worth noting that regulations concern-
ing acute EtOH exposure vary across nations or
states, with legal limits on blood alcohol con-
centration (BAC) generally ranging between
500mg/L and 800mg/L. Additionally, work-
place regulations impose restrictions on maxi-
mum levels of chronic EtOH exposure.
Regarding acute EtOH inhalation, Besson-
neau [24] demonstrated that during 90s of
hand disinfection using a gel with an EtOH con-
centration of 700g/L, the cumulative inhaled
dose of EtOH was approximately 328.9 mg
(~65.78mg/L).
Healthcare workers may disinfect their hands
as many as 30 times per day [27], resulting in
an estimated daily inhaled EtOH dose of 9.86g.
Clinically, this repetitive exposure could lead to
a state of subacute, rather than acute, intoxi-
cation, and such occupational practices could
contribute to chronic EtOH exposure over time.
Clinically, this repetitive exposure could lead to
a state of subacute, rather than acute, intoxi-
cation, and such occupational practices could
contribute to chronic EtOH exposure over time.
For workers in the alcohol production indus-
try in the United Kingdom, the occupational
exposure limit (OEL) for EtOH is set at 1000
parts per million (ppm) or 1910mg/m3 dur-
ing an 8-h work shift. This exposure is roughly
equivalent to the daily consumption of 10g of
EtOH, approximately the amount in one glass
of alcohol [28]. These ndings align closely with
Bessonneau’s analysis [24] and exceed the theo-
retical amount needed to reduce viral loads in
the respiratory tract, as estimated by Manning
etal. [16].
Furthermore, multiple studies suggest that
industrial EtOH exposure does not pose signi-
cant issues in oncology [28] or in reproductive
medicine [29], despite the known toxicity associ-
ated with chronic EtOH inhalation.
Sisson’s work [30] demonstrated that EtOH’s
effect on respiratory ciliary cells follows a
bimodal pattern depending on both exposure
time and dosage. Specifically, low quantities
of EtOH (10mM) were found to enhance cili-
ary beat frequency, potentially facilitating the

Infect Dis Ther
elimination of viral loads (either after they have
been theoretically inactivated by EtOH’s phys-
icochemical properties, or not). On the other
hand, exposition to 1M of EtOH lowered the
ciliary beat frequency.
Concerns regarding EtOH inhalation and
potential damage to the respiratory tract were
addressed by the detailed study of Castro-Bal-
ado etal. [6]. This research examined possible
mucosal or structural harm in the lungs, trachea,
and esophagus of rodents exposed to 65% v/v
EtOH for 15min every 8h (three times daily)
over 5 consecutive days, at a ow rate of 2L/
min. Importantly, histological analysis revealed
no signs of damage in the treated animals or the
control group. The absorbed EtOH dosage in this
experiment was calculated to be 1.2g/kg/day.
Translating this dosage to humans would cor-
respond to an exposure of 151g per day.
Tamai etal. [5] conducted a study on mice
treated with EtOH vapor twice daily, beginning
the day before intranasal administration of the
Inuenza A virus (IAV). The treatment group
showed signicantly less weight loss compared
with the control group. On day 10 post-infec-
tion, 63% of untreated mice (17 of 27) reached
the humane endpoint (20% body weight loss),
while only 11% of treated mice (3 of 27) reached
the same point. EtOH vapor treatment was
shown to reduce viral titers in the lungs, but not
in the nasal cavity, on day3 after infection. Fur-
thermore, the treatment also led to a reduction
in leukocyte inltration and lung damage, with
a decrease in monocytes and macrophages in the
bronchoalveolar lavage uid (BALF). Despite this
reduction, the viability of these cells was some-
what preserved. Additionally, EtOH vapor treat-
ment signicantly decreased the expression of
genes associated with innate immunity, such as
Irf7, in lung tissues.
Overall, the study suggests that inhalation of
EtOH vapor can reduce viral load in the lungs
and protect mice from lethal IAV infection, with
no detectable adverse effects.
As regards humans, Hancock etal. [31] con-
ducted a phase I, single-center, open-label clini-
cal trial in healthy adult volunteers assessing
the safety, tolerability, and pharmacokinetics of
inhaled EtOH. Three groups were studied: indi-
viduals with stable asthma, individuals with
stable cystic brosis, and individuals actively
smoking. A dose-escalating design was used,
with participants receiving three dosing cycles of
40%, 60%, and then 80% ethanol v/v in water,
2h apart, in a single visit. EtOH was nebulized
using a standard jet nebulizer, together with
a closed-circuit reservoir system. No serious
adverse events were reported, with only small
transient increases in heart rate, blood pressure,
and blood neutrophil levels. They concluded
that concentrations up to 80% of inhaled EtOH
are safe and efcacious, suggesting further stud-
ies for assessing its use as a treatment for respira-
tory infections.
In this view, we consider it wise that patient
selection should exclude individuals with certain
conditions or circumstances, such as infancy,
alcoholism, or a history of adverse reactions to
EtOH, drug addiction or previous treatment for
alcoholism/drug addiction, currently on disul-
ram or cimetidine, nondrinkers of alcohol (no
absolute criteria), any liver disease, uncontrolled
diabetes, acute or chronic pancreatitis, serious
respiratory diseases, tuberculosis or other myco-
bacterial infections, confirmed or suspected
pregnancy, active psychosis, or inability to give
legally valid informed consent.
Although EtOH could theoretically exert a
negative impact on the respiratory microbiome,
no evidence supporting this has been found in
the current literature. On the contrary, some
insights may suggest otherwise. For instance,
Sulaiman etal. [17] observed that poor clinical
outcomes were associated with the enrichment
of the lower respiratory tract microbiota by an
oral commensal, the Mycoplasma salivarium,
and with an increased SARS-CoV-2 viral load in
a group of intubated patients with COVID-19.
Similarly, Rueca etal. [32] reported a complete
depletion of Bidobacterium and Clostridium
in the nasal/oropharyngeal microbial ora of
intensive-care patients with SARS-CoV-2. Com-
parable ndings have been recently corrobo-
rated by Chu etal. [33].
It is worth noting that Mycoplasma salivar-
ium is fully inactivated by EtOH at 70% con-
centration [34]. Additionally, certain strains of
Clostridium are known to produce endogenous
EtOH [35], raising the possibility that their
absence could deprive the host of a potential

Infect Dis Ther
defense mechanism. A somewhat complemen-
tary finding has been reported by Tong and
Salvatori [36], who conducted a cross-sectional
study within a social community. Despite the
methodological limitations, they found a statis-
tically signicant association between increased
alcohol consumption and a lower likelihood of
contracting SARS-CoV-2. One possible explana-
tion for these ndings was the dual action of
inhaled and ingested EtOH acting as a disinfect-
ant for the naso-oropharyngeal mucosa and the
respiratory tract through exhaled EtOH. How-
ever, the authors strongly cautioned against
drawing misleading conclusions and explicitly
advised against using the ingestion of EtOH as
a medical treatment. The study instead high-
lighted the potential role of inhaled EtOH in
combating SARS-CoV-2.
Lastly, Kramer etal. [37] reported that fre-
quent use of alcohol-based antiseptics had no
adverse effects on the hand microbiome of
healthcare workers.
EtOH in Medicine
In addition to its widespread industrial and rec-
reational applications (e.g., spirits, cosmetics,
fuel), EtOH is recognized as a medicinal agent
and is listed in both the European and US Phar-
macopeias. Medically, EtOH is primarily utilized
as an antidote for methanol and ethylene glycol
poisoning, as an excipient in numerous medi-
cations, as a sclerosant agent, and as a highly
effective disinfectant for both skin and surfaces.
Historically, EtOH inhalation was demon-
strated to be both safe and effective for the treat-
ment of coughs and pulmonary edema [38–41].
Moreover, EtOH is commonly used as an excipi-
ent in inhalation treatments for asthma and
chronic obstructive pulmonary disease (COPD),
with doses as high as 9mg per actuation [42].
Current Knowledge of EtOH Inhalation for
EV Respiratory Diseases
Shintake, on 17 March 2020 [43, preprint], then
Amoushahi and Padmos, on 25 May 2020 [44,
guest editorial] and Manning etal., on 30 Sep-
tember 2020 [16, letter to editor] are credited for
rst hypothesizing EtOH treatment to prevent
or eradicate SARS-Cov-2 infection.Castro-Balado
etal., on 5 March 2021 [6], then Salvatori, on
4 December 2021 [45], published the rst peer-
reviewed articles on this topic.
Within the context of prevention, Hossein-
zadeh etal. [46] conducted a randomized con-
trolled trial involving healthcare workers from
medical centers at the frontline of the COVID-19
pandemic. This study aimed to assess the ef-
cacy of combining EtOH (at unspecied con-
centration) with dimethyl sulfoxide (DMSO) in
a nasal spray format for preventing COVID-19.
The results indicated that the incidence rates of
COVID-19 were 0.07 in the control group and
0.008 in the intervention group. The relative risk
was calculated at 0.12 (95% CI 0.02–0.97), lead-
ing the authors to conclude that the combined
use of DMSO and EtOH can signicantly reduce
the incidence of COVID-19 among healthcare
providers. Interestingly, no collateral effects
were reported, likely due to their absence or
their minimal and tolerable nature.
In the treatment domain, Castro-Balado
etal. [47] conducted the ALCOVID-19 trial,
aimed at evaluating the safety and efcacy of
inhaled EtOH (65% v/v) in older adults during
the early stages of infection. The study found
no signicant difference in disease progression
between treatment and control groups. How-
ever, a reduction in viral load was observed in
the treatment group, though not statistically sig-
nicant. Importantly, inhaled EtOH was deemed
safe, as no plasma EtOH was detected, and no
electrocardiographic, analytical, or respiratory
issues were noted. It is worth mentioning that
the trial was terminated early due to difculties
in participant recruitment.
Stogner [48] conducted an RCT on 306
patients with COVID-19. The treatment group
inhaled EtOH 47.5% v/v, given continuously via
face mask over approximately 60–75min, using
a standard large-volume nebulizer driven by
wall oxygen or air (determined by the patient’s
pretreatment supplemental oxygen require-
ment) at a ow rate of 10L/min, for a 3-day
regimen (three total doses). Each daily dose
was weight-based (actual body weight): female
patients = 0.31g/kg, and male patients = 0.33g/
kg. The control group did not receive EtOH.

Infect Dis Ther
The treatment group versus controls had a sta-
tistically signicant decreased average length of
stay, an improved inpatient and overall surviv-
als, a higher return home rate, and a decreased
need for transfer to another facility for ongo-
ing post-acute care. They also experienced an
improvement in hypoxemia, decreased intuba-
tion rate, and lower need for transfer to inten-
sive care, even with a nonstatistically signicant
difference.
This regimen proved safe and was well tol-
erated in the great majority (89%) of patients
who were known to have been offered the treat-
ment. No severe adverse or untoward events
were reported or discovered on review of the
medical records. No patient reported a feeling
of intoxication, and none became noticeably
intoxicated during observance by medical per-
sonnel. All patients had onset of a temporary
minor cough and/or burning sensation in the
nasopharynx and throat, which lasted about
2min, but these were the reasons given by those
who initially gave consent to try the nebulized
EtOH but refused subsequent treatments. No
patient who received any or all of the 3-day
regimen was found to have physical evidence
of naso-oropharyngeal mucosal inammation.
Amoushahi etal. [49] conducted a rand-
omized clinical trial (RCT) involving 99 symp-
tomatic, reverse transcription-polymerase chain
reaction (RT-PCR)-positive patients hospital-
ized and receiving remdesivir-dexamethasone.
Patients were randomly assigned to either the
control group (CG), receiving distilled water
spray, or the intervention group (IG), which
received a 35% v/v EtOH spray. The primary out-
come was the global symptomatic score (GSS),
measured at the rst visit and on days 3, 7, and
14. Secondary outcomes included the clinical
status scale (CSS) and readmission rates.
The results showed no signicant difference
in the GSS or CSS at admission. However, by
day14, both the GSS and CSS improved sig-
nicantly in the IG (p = 0.016 and p = 0.001,
respectively). Additionally, the readmission
rate was considerably lower in the IG (0%
versus 10.9%; p = 0.02). On the basis of these
ndings, the authors concluded that inhaled-
nebulized EtOH is effective in rapidly improv-
ing clinical status and reducing the need for
further treatment. They noted only a few mild
and bearable adverse events.
Due to its low cost, availability, and mini-
mal adverse effects, they recommended it as an
adjunctive treatment for moderate COVID-19.
CONCLUSIONS
The research data suggest that EtOH inhala-
tion could potentially play a benecial role in
treating respiratory infections caused by EV.
On the basis of the above ndings, a 50% v/v
EtOH concentration appears to be a reason-
able option for inhalation therapy. As viruses
might affect every airway site, (either simul-
taneously or spreading over time), the best
delivery method would likely involve an aero-
sol device capable of generating particles with
an MMAD of around 5µm to ensure effective
deposition in the respiratory tract, as different
MMAD particles have a different target site:
specifically, the upper airways—if < 5µm—
and the alveolar bed—if > 5µm [9]. In terms
of treatment schedule, delivering EtOH every
8h (as suggested by many papers, namely [46,
47, 49]) for 1–2weeks seems to be a promising
regimen, offering adequate therapeutic effects
with minimal or no side effects, though further
research is needed to conrm the optimal tim-
ing and frequency.
Despite the promising preliminary results,
there is a clear gap in well-designed clinical
trials assessing the efcacy of EtOH inhala-
tion in treating respiratory infections. There-
fore, conducting carefully structured studies is
essential. This low-cost therapy could become
an important therapeutic option, especially
for large numbers of patients simultaneously
infected, as was the case during the COVID-19
pandemic. In addition, inhaled EtOH could be
a successful approach for vulnerable patients,
such as patients with cancer, because it is likely
to have no or minimal effects on already estab-
lished life-saving treatments. Further investiga-
tion by national and international institutions
is urgently needed to validate these ndings
and rene treatment protocols.

Infect Dis Ther
Author Contributions. Pietro Salvatori
ideated, partly reviewed the literature, wrote
the manuscript, and co-edited the draft; Ali
Amoushahi provided clinical consultancy and
co-edited the draft; Aldo Venuti reviewed part
of the literature, wrote the manuscript, and co-
edited the draft; and Francesca Paolini reviewed
part of the literature and co-edited the draft.
Funding. This study and the journal’s
publication fee was funded by ENEA grant
21/18/R/53.
Data Availability. Data sharing is not appli-
cable to this article as no datasets were generated
or analyzed during the current study.
Declarations
Conict of Interest. In compliance with
the ICMJE uniform disclosure form, all authors
declare that there are no other relationships
or activities that could appear to have inu-
enced the submitted work.Pietro Salvatori, Ali
Amoushahi, Aldo Venuti, and Francesca Paolini
conrm that they have no conicts of interest
to declare.
Ethical Approval. This article is based on
previously conducted studies and does not con-
tain any new studies with human participants or
animals performed by any of the authors.
Open Access. This article is licensed under
a Creative Commons Attribution-NonCommer-
cial 4.0 International License, which permits
any non-commercial use, sharing, adaptation,
distribution and reproduction in any medium
or format, as long as you give appropriate credit
to the original author(s) and the source, pro-
vide a link to the Creative Commons licence,
and indicate if changes were made. The images
or other third party material in this article are
included in the article’s Creative Commons
licence, unless indicated otherwise in a credit
line to the material. If material is not included
in the article’s Creative Commons licence and
your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will
need to obtain permission directly from the cop-
yright holder. To view a copy of this licence, visit
http:// creat iveco mmons. org/ licen ses/ by- nc/4. 0/.
REFERENCES
1. Kuhn RJ, Strauss JH. Enveloped viruses. Adv Pro-
tein Chem. 2003;64:363–77. https:// doi. org/ 10.
1016/ s0065- 3233(03) 01010-6.
2. Watts S, Ramstedt M, Salentinig S. Ethanol inacti-
vation of enveloped viruses: structural and surface
chemistry insights into Phi6. J Phys Chem Lett.
2021;7:9557–63. https:// doi. org/ 10. 1021/ acs. jpcle
tt. 1c023 27.
3. Kampf G. Efcacy of ethanol against viruses in
hand disinfection. J Hosp Infect. 2018;98:331–8.
https:// doi. org/ 10. 1016/j. jhin. 2017. 08. 025.
4. Kratzel A, Todt D, V’kovski P, etal. Inactivation
of severe acute respiratory syndrome coronavirus
2 by WHO-recommended hand rub formulations
and alcohols. Emerg Infect Dis. 2020;26:1592–5.
https:// doi. org/ 10. 3201/ eid26 07. 200915.
5. Tamai M, Taba S, Mise T, Yamashita M, Ishikawa
H, Shintake T. Effect of ethanol vapor inhalation
treatment on lethal respiratory viral infection with
inuenza A. J Infect Dis. 2023;20:1720–9. https://
doi. org/ 10. 1093/ infdis/ jiad0 89.
6. Castro-Balado A, Mondelo-García C, Barbosa-
Pereira L, etal. Development and characterization
of inhaled ethanol as a novel pharmacological
strategy currently evaluated in a phase II clinical
trial for early-stage SARS-CoV-2 infection. Phar-
maceutics. 2021;13:342. https:// doi. org/ 10. 3390/
pharm aceut ics13 030342.
7. Hancock DG, Berry L, Scott NM, Mincham KT,
Ditcham W, Larcombe AN, Clements B. Treatment
with inhaled aerosolised ethanol reduces viral
load and potentiates macrophage responses in an
established inuenza mouse model. Exp Lung Res.
2024;50:118–26. https:// doi. org/ 10. 1080/ 01902
148. 2024. 23463 20.
8. Eedara BB, Alabsi W, Encinas-Basurto D, Polt R,
Ledford JG, Mansour HM. Inhalation delivery for
the treatment and prevention of COVID-19 infec-
tion. Pharmaceutics. 2021;13:1077. https:// doi.
org/ 10. 3390/ pharm aceut ics13 071077.
9. Sheth P, Stein SW, Myrdal PB. Factors inuenc-
ing aerodynamic particle size distribution of sus-
pension pressurized metered dose inhalers. AAPS
PharmSciTech. 2015;16:192–201. https:// doi. org/
10. 1208/ s12249- 014- 0210-z.

Infect Dis Ther
10. Louten J. Virus structure and classication. In:
Essential human virology; 2016. p. 19–29. https://
doi. org/ 10. 1016/ B978-0- 12- 800947- 5. 00002-8.
11. Fenner F, Bachman PA, Gibbs EPJ, Murphy FA,
Studdert MJ, White DO. Structure and composi-
tion of viruses. In: Veterinary virology; 1987. p.
3–19. https:// doi. org/ 10. 1016/ B978-0- 12- 253055-
5. 50005-0.
12. Tennant P, Fermin G, Foster JE: Viruses: molecu-
lar biology, host interactions, and applications to
biotechnology. New York: Academic Press; 2018.
eBook. https:// doi. org/ 10. 1016/ C2015-0- 05650-7.
13. Boncristiani HF, Criado MF, Arruda E. Respiratory
viruses. In: Encyclopedia of microbiology; 2009. p.
500–18. https:// doi. org/ 10. 1016/ B978- 01237 3944-
5. 00314-X.
14. Manning TJ, Livingston T, Persaud C, et al.
Ethanol inhalation as a method to denature
the spike protein of SARS-CoV-2. Adv Exp Med
Biol. 2024;1457:45–77. https:// doi. org/ 10. 1007/
978-3- 031- 61939-7_3.
15. Pace CN, Fu H, Lee Fryar K, etal. Contribution
of hydrogen bonds to protein stability. Protein
Sci. 2014;23:652–61. https:// doi. org/ 10. 1002/ pro.
2449.
16. Manning TJ, Thomas-Richardson J, Cowan M,
Thomas-Richardson G. Should ethanol be consid-
ered a treatment for COVID-19? Rev Assoc Med
Bras. 2020;66:1169–71. https:// doi. org/ 10. 1590/
1806- 9282. 66.9. 1169.
17. Sulaiman I, Chung M, Angel L, etal. Microbial
signatures in the lower airways of mechanically
ventilated COVID-19 patients associated with poor
clinical outcome. Nat Microbiol. 2021;6:1245–58.
https:// doi. org/ 10. 1038/ s41564- 021- 00961-5.
18. Goral J, Choudhry MA, Kovacs EJ. Acute ethanol
exposure inhibits macrophage IL-6 production:
role of p38 and ERK1/2 MAPK. J Leukoc Biol.
2004;75:553–9. https:// doi. org/ 10. 1189/ jlb. 07033
50.
19. Hoek JB, Cahill A, Pastorino JG. Alcohol and mito-
chondria: a dysfunctional relationship. Gastroen-
terology. 2002;122:2049–63. https:// doi. org/ 10.
1053/ gast. 2002. 33613.
20. Nomura T, Nazmul T, Yoshimoto R, Higashiura
A, Oda K, Sakaguchi T. Ethanol susceptibility of
SARS-CoV-2 and other enveloped viruses. Biocon-
trol Sci. 2021;26:177–80. https:// doi. org/ 10. 4265/
bio. 26. 177.
21. Jia X, Chase J, Crawford C, etal. High expression
of oleoyl-ACP hydrolase underpins life-threatening
respiratory viral diseases. Cell. 2024;187:4586–
4604.e20. https:// doi. org/ 10. 1016/j. cell. 2024. 07.
026.
22. Wanguyun AP, Oishi W, Sano D. Sensitivity evalu-
ation of enveloped and non-enveloped viruses
to ethanol using machine learning: a systematic
review. Food Environ Virol. 2024;16:1–13. https://
doi. org/ 10. 1007/ s12560- 023- 09571-2.
23. Yeligar SM, Chen MM, Kovacs EJ, Sisson JH, Burn-
ham EL, Brown LA. Alcohol and lung injury and
immunity. Alcohol. 2016;55:51–9. https:// doi. org/
10. 1016/j. alcoh ol. 2016. 08. 005.
24. Bessonneau V, Thomas O. Assessment of exposure
to alcohol vapor from alcohol-based hand rubs.
Int J Environ Res Public Health. 2012;9:868–79.
https:// doi. org/ 10. 3390/ ijerp h9030 868.
25. Winek CL, Murphy KL. The rate and kinetic
order of ethanol elimination. Forensic Sci Int.
1984;25:159–66. https:// doi. org/ 10. 1016/ 0379-
0738(84) 90189-0.
26. Peng SH, Hsu SY, Kuo PJ, Rau CS, Cheng YA,
Hsieh CH. Inuence of alcohol use on mortal-
ity and expenditure during hospital admission: a
cross-sectional study. BMJ Open. 2016;1: e013176.
https:// doi. org/ 10. 1136/ bmjop en- 2016- 013176.
27. Boyce JM, Pittet D. Guideline for hand hygiene
in health-care settings: recommendations of the
healthcare infection control practices advisory
committee and the HICPAC/SHEA/APIC/IDSA
hand hygiene task force. Morb Mortal Wkly Rep.
2002;51:1–44. https:// pubmed. ncbi. nlm. nih. gov/
12418 624/.
28. Bevan RJ, Slack RJ, Holmes P, Levy LS. An assess-
ment of potential cancer risk following occupa-
tional exposure to ethanol. J Toxicol Environ
Health Part B. 2009;12:188–205. https:// doi. org/
10. 1080/ 10937 40090 28941 60.
29. Irvine LFH. Relevance of the developmental tox-
icity of ethanol in the occupational setting: a
review. J Appl Toxicol. 2003;23:289–99. https://
doi. org/ 10. 1002/ jat. 937.
30. Sisson JH, Pavlik JA, Wyat TA. Alcohol stimu-
lates ciliary motility of isolated airway axonemes
through a nitric oxide, cyclase and cyclic nucleo-
tide- dependent kinase mechanism. Alcohol Clin
Exp Res. 2009;33:610–6. https:// doi. org/ 10. 1111/j.
1530- 0277. 2008. 00875.x.
31. Hancock DG, Ditcham W, Ferguson E, Karpiev-
itch YV, Stick SM, Waterer GW, Clements BS. A
phase I clinical trial assessing the safety, tolerabil-
ity, and pharmacokinetics of inhaled ethanol in
humans as a potential treatment for respiratory

Infect Dis Ther
tract infections. Front Med (Lausanne). 2024;5:11.
https:// doi. org/ 10. 3389/ fmed. 2024. 13246 86.
32. Rueca M, Fontana A, Bartolini B, etal. Investiga-
tion of nasal/oropharyngeal microbial community
of COVID-19 patients by 16S rDNA sequencing.
Int J Environ Res Public Health. 2021;18(4):2174.
https:// doi. org/ 10. 3390/ ijerp h1804 2174.
33. Chu X-J, Song D-D, Zhou M-H, etal. Perturbations
in gut and respiratory microbiota in COVID-19
and inuenza patients: a systematic review and
meta-analysis. Front Med. 2024;11:1301312.
https:// doi. org/ 10. 3389/ fmed. 2024. 13013 12.
34. Eterpi M, McDonnell G, Thomas V. Decontamina-
tion efcacy against mycoplasma. Lett Appl Micro-
biol. 2011;52:150–5. https:// doi. org/ 10. 1111/j.
1472- 765x. 2010. 02979.x.
35. Ruuskanen MO, Åberg F, Mannistö V, etal. Links
between gut microbiome composition and fatty
liver disease in a large population sample. Gut
Microbes. 2021;13:1–22. https:// doi. org/ 10. 1080/
19490 976. 2021. 18886 73.
36. Tong NH, Salvatori P. Positive correlation between
heavy alcoholic drinking and SARS-Cov-2 non-
infection rate. Cureus. 2023;8:15. https:// doi. org/
10. 7759/ cureus. 40130.
37. Kramer A, Borg Dahl M, Bengtsson MM, etal. No
detrimental effect on the hand microbiome of
health care staff by frequent alcohol-based anti-
sepsis. Am J Infect Control. 2024;15:0196–6553.
https:// doi. org/ 10. 1016/j. ajic. 2024. 11. 006.
38. Burnham PJ. A new rapid treatment for the useless
cough in the postoperative patient. Q Bull North-
west Univ Med Sch. 1954;28:76–78. https:// pmc.
ncbi. nlm. nih. gov/ artic les/ PMC38 03219/.
39. Calesnick B, Vernick HQ. Antitussive activity of
ethanol. J Stud Alcohol. 1971;32:434–41. https://
pubmed. ncbi. nlm. nih. gov/ 49322 55/.
40. Luisada AA, Weyl R, Goldmann MA. Alcohol vapor
by inhalation in the treatment of acute pulmonary
edema. Circulation. 1952;5(3):363–9. https:// doi.
org/ 10. 1161/ 01. cir.5. 3. 363.
41. Gootnick A, Lipson HI, Turbin J. Inhalation of
ethyl alcohol for pulmonary edema. N Engl J Med.
1951;245:842–3. https:// doi. org/ 10. 1056/ nejm1
95111 29245 2202.
42. Ethanol content of inhalers—What is the signi-
cance? (2019). https:// www. studo cu. com/ en- gb/
docum ent/ unive rsity- of- bradf ord/ clini cal- pharm
acolo gy/ ukmi- qa- ethan ol- in- inhal ers- nal/ 42729
847.
43. Shintake T. Possibility of disinfection of SARS-
CoV-2 (COVID-19) in human respiratory tract by
controlled ethanol vapor inhalation. 2020. https://
doi. org/ 10. 48550/ arXiv. 2003. 12444.
44. Amoushahi A, Padmos AA. Suggestion on ethanol
therapy in COVID-19?. EC Anaesthesia. 2020;6:1–
2. https:// ecron icon. net/ assets/ ecan/ pdf/ ECAN- 06-
00229. pdf.
45. Salvatori P. The rationale of ethanol inhalation for
disinfection of the respiratory tract in SARS-CoV-
2-positive asymptomatic subjects. Pan Afr Med J.
2021;40:201. https:// doi. org/ 10. 11604/ pamj. 2021.
40. 201. 31211.
46. Hosseinzadeh A, Tavakolian A, Kia V, etal. Com-
bined application of dimethyl sulfoxide and
ethanol nasal spray during COVID-19 pandemic
may protect healthcare workers: a randomized
controlled trial. Iran Red Crescent Med J. 2022.
https:// doi. org/ 10. 32592/ ircmj. 2022. 24.8. 1640.
47. Castro-Balado A, Novo-Veleiro I, Vázquez-Agra
N, etal. Efcacy and safety of inhaled ethanol in
early-stage SARS-CoV-2 infection in older adults: a
phase II randomized clinical trial. Pharmaceutics.
2023;15:667. https:// doi. org/ 10. 3390/ pharm aceut
ics15 020667.
48. Stogner SW. Nebulized ethanol: an old treatment
for a new disease. In: Ethanol and glycerol chem-
istry—production, modelling, applications, and
technological aspects. IntechOpen Ed. (2023).
https:// doi. org/ 10. 5772/ intec hopen. 111695
49. Amoushahi A, Moazam E, Tabatabaei AR, Ghasimi
G, Grant-Whyte I, Salvatori P, Ezz AR. Efcacy
and safety of inhalation of nebulized ethanol in
COVID-19 treatment: a randomized clinical trial.
Cureus. 2022;14: e32218. https:// doi. org/ 10. 7759/
cureus. 32218.
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