Nebulized Ethanol: An Old Treatment for a New Disease

Abstract

Ethyl alcohol (ethanol) is known to inactivate SARS-CoV-2, and therefore, direct delivery to the upper and lower respiratory tracts hypothetically would inhibit the progression of COVID-19. After informed consent, nebulized EtOH was given to inpatients admitted with COVID-19, and outcomes were retrospectively compared to randomly selected controls. Benefits of nebulized EtOH included decreased average length of stay, improved inpatient survival, decreased intubation rate and need for transfer to intensive care, improvement in hypoxemia, and decreased need for transfer to another facility for ongoing post-acute care. Also, fewer patients required supplemental home oxygen after discharge to home. Interpretation: Nebulized EtOH is beneficial in the treatment of COVID-19. Further study is warranted.

1. Introduction

The virus that causes COVID-19 Disease (designated SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2) has caused severe morbidity and mortality around the world. In addition to the human toll of disease, the pandemic triggered stark social as well as economic disruption around the world, affecting a global recession [1]. Supply shortages (including food), travel restrictions, business restrictions and closures, workplace hazard controls, quarantines, testing systems, and tracing contacts of the infected has been costly in not only financial terms as governments attempted to control the pandemic but also in societal customs and “norms” as well. Near-global lockdowns of educational institutions and other entities were partially or completely closed in many areas, as well as the postponement of needed surgeries placed major stress on communities across the globe, often resulting in a political uproar. In truth, the world has not experienced a similar pandemic and its results since the 1918 Flu Pandemic (February 1918 until April 1920 in four successive waves affecting 500 million people) [2, 3].

As of August 2022, COVID-19 has infected more than 600 million people and caused almost 6.5 million confirmed deaths worldwide—one of the deadliest in history [3]. First identified in Wuhan, China, in December 2019, the COVID-19 virus outbreak was identified by the World Health Organization (WHO) as a public health emergency of international concern on January 30, 2020, and the astronomical trajectory continued with it being declared a global pandemic only 2 weeks later [4]. In March of that year, hospitals and outpatient clinics alike found themselves overwhelmed with astonishing volumes of patients which stressed healthcare resources to the edge, to the point of having to contemplate the rationing of care [5], including intensive care beds and mechanical ventilators.

In addition to inadequate resources at the onset of the pandemic—other than standard treatment measures for respiratory failure, including ARDS—specific treatment for the COVID-19 virus did not exist. Healthcare workers found themselves having to care for critically ill and dying patients who were most often isolated from their loved ones. Saddled with the grim fact of no specific treatment, the apprehension of becoming infected themselves and transmission of the virus to their own loved ones at home, and the emotional (and ethical) nightmarish thoughts which occurred as the potential of rationing healthcare loomed, it is no shock the common burn-out of healthcare workers that ensued [6].

2. COVID-19: the disease

The degree of disease caused by COVID-19 ranges from undetectable to lethal, but most commonly includes fever, nonproductive cough, fatigue, and loss of taste and/or smell in 40 percent of cases [7]. While severe illness such as organ failure occurs most frequently in elderly patients, it is also seen in younger patients with certain comorbidities such as chronic obstructive pulmonary disease, heart failure, malignancy, obesity, chronic steroid or immunosuppressive use, etc. [8]. Transmission occurs when people inhale droplets of airborne particles containing the virus, but also when viral-contaminated fluids reach the eyes, nose, mouth, and even contaminated objects (i.e. hands, etc.).

3. Pathogenesis: a clue for an effective treatment

The COVID-19 virus contains genetic material (RNA) packaged in a protein coat which is surrounded by an envelope composed of a lipid bilayer derived from the host cell membrane [9, 10, 11]. SARS-CoV-2 affects the upper and lower respiratory tracts, where its entry genes are highly expressed in epithelial cells of the nasal cavity and into the alveolar cells. Thus, the portal of entry of SARS-CoV-2 is the upper respiratory tract where the acute infection begins, then subsequently travels to the alveoli by viral aspiration. A “cytokine storm” can then ensue, likely due to an interleukin-6 amplifier resulting in a hyper-activation process that regulates the nuclear factor kappa B (NF-κB) [12, 13, 14]. Ultimately, this cascade of events can be fatal in 75% of cases due to the development of ARDS and other acute organ failures including thrombotic complications [15].

4. Nebulized ethanol: potential benefits and risks

Potential benefits: Direct delivery of a drug with viricidal activity against SARS-CoV-2 (or other susceptible respiratory viruses, i.e., influenza) to the epithelial cells of the upper and lower respiratory tracts in an effort to destroy the virus before severe disease can ensue seem advantageous—and is logical. Ethanol/ethyl alcohol/EtOH suits this purpose. Ethanol is volatile and has long been used as an antiseptic/disinfectant, and constitutes the basis for many hand rubs and disinfectants used in healthcare settings [16, 17] as well as by the general public. Ethanol and other alcohols are known to inactivate many enveloped viruses like SARS-CoV-2 by dissolving the virus’ lipid membrane causing its destruction [18, 19, 20]. Notably, alcohol-based hand rub solutions have been shown to inactivate SARS-CoV-2 in as little as 30 s [21]. In addition to coronavirus, the effective viricidal activity of ethanol against many other common viruses (i.e., influenza, adenovirus, etc.) as well as Zika and Ebola has been demonstrated [22].

Ethanol is presently used worldwide as a generally nontoxic antiseptic and disinfectant and has been effectively and safely used in medicine for methanol poisoning [23], and as late as the 1950s as an inhalational treatment of pulmonary edema [24, 25] and alcohol withdrawal [26, 27].

Published reports suggest promise for the use of inhaled ethanol in the treatment of ARDS [28]. Ethanol is a well-known efficient surfactant (wetting agent), as it is an amphiphilic chemical compound possessing both hydrophilic and lipophilic properties. Surfactant proteins are critical components of alveolar function, and laboratory studies on animal lungs indicate ethanol has the potential to restore surfactant activity in experimentally-induced non-compliant lungs (produced with nebulized saline) [29]. Notably, analysis of SARS-CoV-2-infected lung tissues has revealed that surfactant proteins are indeed severely downregulated in infected lungs, causing respiratory distress [30].

Ethanol has mediator effects on inflammation [31] and thus could potentially have a beneficial effect on the prevention of cytokine storms [13]. In addition, there may be a possible benefit with ethanol in the prevention of thrombus formation shown by autopsy findings to frequently occur in COVID-19 [15, 32, 33]. Ordinarily, cutting of the fibrin mesh by plasmin enzyme leads to the production of circulating fragments that are cleared by other proteases or by the kidney and liver. Tissue plasminogen activator (t-PA) and urokinase then convert plasminogen to the active plasmin, allowing normal fibrinolysis to occur. Ethanol has been shown to “upregulate” the urokinase receptor in human endothelial cells and thus may be helpful in the elimination of thrombi [34].

Potential risks: Ethanol is flammable and combustible, and if ignited, can cause severe injury or even death. Appropriate cautionary measures are absolutely mandatory with its usage.

The risks and negative health effects on the immune, cardiovascular, pulmonary, gastrointestinal-hepatic, and neurologic systems of chronic oral consumption of ethanol are well-known [35]. Even acute oral consumption of large amounts is known to have the potential for serious health consequences, including even fatal toxicity. Vaporized ethanol used recreationally (AWOL = “alcohol without liquid”) appears to some extent becoming more prevalent, and serious concerns have appropriately been raised about its acute and unknown long-term health consequences, especially in young adults. However, a review of the literature fails to show any significant acutely negative effects of the short-term intake of small amounts of ethanol on the immune system or other organ systems [36, 37, 38, 39, 40].

Inhaled ethanol can irritate the eyes, as well as the nose, throat, and plausibly the lungs [41, 42]. In one small study, a decrease in ventilator flow rates on partial expiratory flow volumes [43] was found up to ninety minutes after inhalation, but no significant change in FEV₁ (forced expiratory volume) occurred compared to placebo (inhaled saline solution). Interestingly, pretreatment with disodium cromoglycate considerably diminished the acute reductions of flow rates caused by ethanol inhalation, suggesting that ethanol in some persons may act, at least partly, through the release of mediators with bronchoconstrictive action.

As with any nebulized treatment, nebulized ethanol poses a risk for aerosolization of respiratory viruses like SARS-CoV-2 and transmission of the disease. Appropriate infection control precautions must be strictly followed when such conditions exist.

In the swarm of patients requiring inpatient care for acute hypoxemic respiratory failure due to SARS-CoV-2 in March 2020, those patients who deteriorated necessitating intubation for adult respiratory distress syndrome (ARDS) were having mortality exceeding 75% [3]. While governments were scrambling to issue emergency-use authorization for experimental treatments as well as civil protections for healthcare providers trying to best care for these patients, patients continued to literally smother ultimately requiring intubation and mechanical ventilation. The situation was not only grim, but it seemed hopeless. The urgency to find an effective treatment for this novel virus had never before been witnessed in the lives of most medical professionals. While some treatments were showing promise (i.e., remdesivir, dexamethasone, etc.), there remained an existential need for an effective readily available treatment. Given its proven viricidal efficacy, history of harmless use in the treatment of other medical conditions, as well as a lack of evidence for acute detrimental health effects when used in mild, non-chronic, non-excessive intake, the reasoning that nebulized ethanol may prove beneficial in the treatment of COVID-19 is rational.

5. Nebulized ethanol for treatment of COVID-19: results of a clinical study

In March 2020, at Forrest General Hospital (a non-profit community hospital in Hattiesburg, Mississippi) due to the emergent onslaught of this lethal and “untreatable” disease, and out of necessity and companionate care, a novel treatment regimen of nebulized ethanol was developed to offer patients with COVID-19 who required inpatient treatment for acute hypoxemia as a sole or supplemental treatment option, at the discretion of their attending physicians. While Shintake [44] had proposed the potential use of inhaled ethanol to eradicate the virus in the respiratory tract, extensive research of the medical literature otherwise revealed no reports of inhaled ethanol for treatment of COVID-19 infection¹ (or any other viral respiratory infection for that matter).

As a sole or additional option, a protocolized order set for the administration of nebulized ethanol was made available to hospital physicians in the electronic medical record beginning in April 2020. Education of all involved healthcare personnel was conducted prior to making the order set available. Administration of all nebulized treatments was performed by respiratory therapists, who in addition to nurses, monitored the patients. Access to and dispensing of the ethanol was meticulously controlled by the hospital pharmacy, which also confirmed that all of the following criteria were met prior to dispensing:

1. Admission for COVID-19 with dyspnea and/or hypoxemia;

2. Non-intensive care unit admission (general medical floor);

3. Positive PCR (polymerase chain reaction test) via nasopharyngeal swab;

4. Pulmonary infiltrates typical of COVID-19 on chest radiographs or chest tomography (CT);

5. No contraindication to the intake of ethanol;

6. Informed consent.

5.1 Dose and administration

Ninety-five percent pure grain ethanol was used for a three-day regimen (3 total doses). Each daily dose was weight-based (actual body weight): female patients = 0.31 g/kg, and males = 0.33 g/kg. An equal volume of sterile water was mixed with the ethanol for a final concentration of 47.5%, and 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 pre-treatment supplemental oxygen requirement) at a flow rate of 10 l/min. An anti-viral filter was connected to the exhalation port of the face mask. Respiratory therapists closely observed the patients and monitored SpO2 (oxygen saturation via pulse oximetry) during treatments, and nurses recorded pre-treatment blood pressure, pulse and respiratory rates, and temperature, as well as every 15 min during and for one-hour post-treatment. No other persons were allowed in the room during or post-nebulization except per hospital policy, which included strict adherence to isolation precautions and protection measures such as personal protection equipment.

5.2 Data collection, statistical analysis, and outcomes

Demographic, clinical, and outcomes data were collected by retrospective review of the medical records of three hundred-six patients admitted for COVID-19 with respiratory disease from April through December 2020. Patients who completed the three-day regimen (Ethanol Group) were compared to randomly selected patients (Control Group) who had been admitted to the general medical floor during the same time-period but had received only “standard” therapy for COVID-19 (i.e., no ethanol treatment). Statistical analysis was performed using the T-Test and Fisher’s Exact Test, with a statistical significance of p-value < 0.05.

5.3 Demographics

Ninety-one patients received one or more doses of nebulized ethanol, while two hundred twenty-five randomly selected “control” patients were identified. Of the ninety-one patients who received any ethanol treatment, eighty-one (89%) completed the three-day regimen. (Note: The total number of patients who were offered but refused treatment with alcohol is not known.)

5.4 Severity of hypoxemia

The severity of hypoxemia was assessed in all patients before receiving any COVID-19 treatment, at 96 h after the first treatment, and again at the time of discharge from the hospital, using the SFR (SpO₂/FiO₂ ratio; “normal” ≥ 4.57) [45, 46, 47].

5.5 Outcome metrics

The following data and clinical outcomes of the two groups were collected and compared:

1. Change in level of SFR from admission to discharge;

2. Need for transfer to ICU for progression of disease severity;

3. Need for intubation for invasive mechanical ventilation;

4. Inpatient mortality and survival;

5. The average length of stay (ALOS);

6. Discharge disposition: home, need for supplemental home oxygen, home health services, hospice, or post-hospitalization admission/transfer to another healthcare facility, i.e., nursing home, skilled-nursing facility, rehabilitation center, or long-term acute care center.

5.6 Results

Eighty-one patients completed the three-day regimen (Ethanol Group), and were compared to the Control Group (225). Ten patients (11%) who initially gave informed consent to try inhaled ethanol treatment did not complete the three-dose regimen and were not included in the final data analysis. One was in the respiratory extremis prior to starting the first treatment and received an unknown quantity before requiring emergent intubation and immediate transfer to the ICU, and received no further ethanol treatments. This patient subsequently expired after a prolonged hospital stay on mechanical ventilation. The other nine (9.9%) did not complete the first treatment dose or refused the second dose due to a universally reported side effect of immediate mild coughing and / or burning sensation in the naso-oropharynx. Two of these nine patients (22.2%) later required transfer to ICU and intubation for disease progression, and both subsequently expired. Seven of the nine patients (77.8%) improved after prolonged hospital stays and were subsequently discharged from the hospital with home health or to a skilled nursing facility.

As shown in Table 1, average age of both groups was similar: 63.6 years (median 64; range 41–96) in the Ethanol Group, compared to 65.5 years (median 62; range 28–99) in the Control Group (p = 0.50). Gender distribution was also comparable between the two groups: 42% (34) females and 58% (47) males, 51.6% (116) females and 48.4% (109) males in the Control Group (p = 0.15). Average BMI (body mass index = kg/m²) was similar: 35.3 (median 34), compared to 33.4 (median 34) in the Control Group (p = 0.06).

Demographic	Ethanol group; (n = 81)	Control group; (n = 225)	p-value*
Average age (years); Median; range	63.6; 64; 41–96	65.5; 62; 28–99	0.50
Gender; M = male; F = female	M = 58% (47); F = 42% (34)	M = 48.4% (109); F = 51.6% (116)	0.15
Average BMI**; Median	35.3; 34.5	33.4; 34	0.06
Comorbidities ≥ 1***	92.6% (75)	87.1% (196)	0.22
Average Pre-treatment SFR****; Range	2.86; 2.65–3.07	3.83; 3.33–3.93	<0.001

Table 1.

Demographic data.

*

Statistical significance: p < 0.05.

**

BMI = body mass index, kg/m².

***

Comorbidities include diabetes mellitus, chronic obstructive pulmonary disease, drug-induced. immunosuppression (i.e. chemotherapy for cancer), obesity, hypertension, end-stage renal disease, and autoimmune disease (i.e. rheumatoid arthritis).

****

SFR = SpO₂/FiO₂ Ratio (Example: “normal” SFR: SpO₂ 0.98/0.21 = 4.67).

Likewise, the presence of one or more significant co-morbidities was similar in both groups, including diabetes mellitus, chronic obstructive pulmonary disease, drug-induced immunosuppression (i.e., chemotherapy for cancer), obesity, hypertension, end-stage renal disease, and autoimmune disease (i.e., rheumatoid arthritis): 92.5% (75) in the Ethanol Group, and 87.1% (196) in the Control Group, (p = 0.22). The average pre-treatment SFR was statistically worse (p < 0.001) in the Ethanol Group (2.86) compared to the Control Group (3.83).

Table 2 shows the use of “standard” (non-ethanol) treatments in both groups were similar, with all patients having received one or more of the following drugs: remdesivir, tocilizumab, azithromycin, intravenous steroids (dexamethasone or methylprednisolone), and convalescent plasma. The most frequent in both groups were remdesivir and intravenous steroids, but no statistical difference was found between both groups for anyone “standard” treatment (p = 0.07–0.86).

Medication*	Ethanol group; (n = 81)	Control group; (n = 225)	p-value**
Remdesivir	45.7% (37)	56.4% (127)	0.22
Tocilizumab	4.9% (4)	8.9% (20)	0.34
Convalescent Plasma	17.3% (14)	16.4% (37)	0.86
Intravenous Steroids***	55.6% (45)	70.2% (158)	0.26
Hydroxychloroquine****	6.2% (5)	53.3% (12)	0.78
Azithromycin	28.4% (23)	14.7% (33)	0.07

Table 2.

“Standard” COVID-19 medications received.

*

All patients in both groups received vitamins C, D3, and zinc.

**

Statistical significance: p < 0.05; no statistical difference was found between the two groups.

***

Dexamethasone or methylprednisolone.

****

Removed from hospital “COVID-19 Formulary” in July 2020.

Table 3 shows pre-treatment SFR, and average post-treatment SFRs for both groups. In the ethanol group, the average SFR at 96 h (2.89) compared to pre-treatment (2.86) was unremarkable. Notable, the average SFR at 96 h in the Control Group had decreased from 3.83 to 3.69, but not statistically significant from the Ethanol Group (p = 0.21). Although not quite statistically significant (p = 0.06), the Ethanol Group had considerable improvement (21.7%) from the average pre-treatment SFR (2.86) to discharge (3.48), compared to the Control Group which had a minor increase (1.3%) from the average pre-treatment SFR (3.83) to discharge (3.88).

Time of SFR*	EtOH group; Average SFR; (Range)	Control group; Average SFR; (Range)	p-value
Pre-treatment	2.86; (2.65–3.07)	3.83; (3.33–3.93)	<0.001
96 h post-treatment	2.89	3.69	0.21
Discharge from hospital	3.48; (3.28–3.68)	3.88; (3.87–3.89)	0.13
Δ pre-treatment versus 96 h	+1%	−3.7	0.23
Δ pre-treatment versus discharge	+21.7%	+1.3	0.06

Table 3.

Pre- and post-treatment SPO₂/FIO₂ ratios.

^*

SFR = SpO₂/FiO₂ ratio; “normal” SFR: SpO² 0.98/0.21 = 4.67.

Comparison of clinical outcomes is shown in Table 4. Progression (e.g., worsening) of COVID-19 disease requiring transfer to the intensive care unit (ICU) occurred less in the Ethanol Group compared to the Control Group: 8.6% (7), and 14.7% (33), respectively (p = 0.18), equating to a 41% less chance of requiring transfer to ICU for disease progression in the Ethanol Group. Intubation was necessary for all seven patients in the Ethanol Group who required transfer to ICU, compared to 82% (27) in the Control Group but was not statistically significant (p = 0.57). Notably, one of the seven patients in the Ethanol Group who required transfer to ICU had developed progressive respiratory failure and sepsis due to hospital-acquired pneumonia (Serratia marcescens) on day five of admission (two days post-third ethanol treatment), requiring intubation and vasopressor support for shock, and subsequently expired in ICU. Another patient expired having required transfer to ICU after emergent intubation for sudden cardiac arrest the day following the third EtOH treatment, although having been stable pre-arrest with no worsening hypoxemia or hemodynamic instability.

Clinical metric	EtOH group; (n = 81)	Control group; (n = 225)	p-value
Transfer to ICU	8.6% (7)*	14.7% (33)	0.18
Intubation	8.6% (7)	82% (27)	0.57
ALOS (days)	6.88	9.98	0.03
Median	5.5	8
Range	4–27	6–33
Inpatient overall mortality	7.4% (6)	17.8% (40)	0.03
Overall survival	92.6% (75)	82.2% (185)	0.03
ICU mortality	71..4% (5)	48.5% (16)	0.41
Home	81.4% (66)	40.9% (92)	<0.001
Home oxygen	45.7% (37)	64.4% (82)	0.15
Home health	34.6% (28)	28.9% (65)	0.40
DC to another facility**	6.2% (5)	38.2% (86)	<0.001
Hospice	4.9% (4)	3.1% (7)	0.49

Table 4.

Clinical outcomes.

*

One patient developed hospital-acquired pneumonia and progressive shock due to S. marcescens on day 5.

**

Facility = long-term acute care, nursing home, other skilled nursing, or rehabilitation.

hospitalization; another required intubation for sudden cardiac arrest the day after 3rd EtOH treatment.

Abbreviations: ALOS = average length of inpatient stay; DC = discharge from hospital.

ALOS was less in the Ethanol Group (6.88 days, median 5.5, range 4–27) versus the Control Group, (9.98, median 8, range 6–33) and was statistically significant (p = 0.03).

Inpatient mortality was also statistically less in the Ethanol Group (6) compared to the Control Group (40): 7.4% and 17.8%, respectively (p = 0.03), translating to a significantly improved survival in the Ethanol Group of 92.6% (75) compared to 82.2% (185) in the Control Group (p = 0.03). The mortality rates of patients who required transfer to ICU because of disease progression were not statistically different between the two groups (p = 0.41), although a larger percentage of patients in the Ethanol Group (71%; n = 5) died compared to the Control Group (48.5%; n = 16). Note: Post-discharge mortality rate is not known at this time.

Interestingly, and statistically significant, 81.4% (66) in the Ethanol Group were able to be discharged to their homes compared to 40.9% (92) in the Control Group (p < 0.001), and only five (6.2%) in the Ethanol Group required discharge/transfer and admission to another healthcare facility for ongoing care (i.e. long-term acute care, nursing home, skilled nursing, or rehabilitation) compared to 38.2% (86) in the Control Group (p < 0.001). Four survivors (4.9%) in the Ethanol Group were discharged to hospice care, comparable to 7 (3.1%) in the Control Group (p = 0.49). The need for home health services post-discharge was similar: 34.6% (28) in the Ethanol Group, and 28.9% (65) in the Control Group (p = 0.40). Considerably fewer patients required supplemental home oxygen in the Ethanol Group (45.7%; n = 37) versus the Control Group (64.4%; n = 82), though not statistically significant (p = 0.15).

5.7 Discussion

The results of this study suggest a number of positive benefits of inhaled ethanol in the treatment of COVID-19 in non-ICU patients with acute hypoxemia. Statistically significant benefits included decreased ALOS, improved survival, and increased chance of discharge to home as opposed to requiring post-hospital treatment in long-term acute care, extended care facility (i.e., nursing home), or other skilled nursing facility (i.e. rehabilitation center, etc.). Other benefits included the decreased need for transfer to ICU due to disease progression, decreased need for intubation and decreased need for home oxygen. If such outcomes are confirmed in larger studies, the benefits to patients and healthcare systems worldwide would be incredible.

The science is sound as noted by other researchers [48, 49] regarding the potential use of inhaled ethanol as a treatment for COVID-19. Ethanol is rapidly absorbed in the respiratory tract and then transported via the circulatory system to other tissues. Nebulization into the nares (and mouth) has the benefit of direct deposition and contact with the virus in the upper and lower respiratory tissues, from which it can then circulate to other tissues where the virus has been shown to be present in autopsy findings [12], allowing ethanol to circumvent the “first pass” metabolism by alcohol dehydrogenase in the liver. The hypothesis is logical: direct deposition of ethanol on respiratory tissues may inactivate the virus in the respiratory epithelium thereby inhibiting viral replication and thus decreasing the viral load—and the risk of the inflammatory response (i.e., cytokine storm) which is responsible for organ failure (i.e., ARDS, acute kidney injury, etc.). The clinical results in this study support the hypothesis.

Obviously, while ethanol is known to inactivate SARS-CoV-2 on skin surfaces, the amount needed to inactivate SARS-CoV-2 in the respiratory tract (and other human tissues) is not known. The dose in this regimen was weight-based (0.31 g/kg for females, and 0.33 g/kg for males), estimated to produce a blood alcohol concentration of less than 0.08 mg %. Five ounces or 148 ml of wine is 12% EtOH by volume and contains about 14 g of EtOH, or 0.095 g/ml, whereas 95% EtOH contains 0.75 g/ml. Thus, in this regimen, for example, a 70 kg male would receive a nebulized dose of EtOH of about 23 cc of EtOH or about 17 g of EtOH—3 g more than that in one glass of wine [50]. (Of note, serum EtOH levels were not detectable 1-h post nebulization treatments.) While the dosing of EtOH in this study showed benefits, the optimal dosing and method of administration need further study. Plausibly, different dosing, frequency, and duration of therapy may prove even more beneficial, and it may prove more beneficial if initiated earlier, or within a specified time period of the initial onset of COVID-19 symptoms. (Note: In this study, the duration of symptoms before seeking treatment is not available.)

This regimen proved safe and was well tolerated in the great majority (89%) of patients who were known to have been offered the treatment. 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 personnel. 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 three-day regimen was found to have physical evidence of naso-oropharyngeal mucosal inflammation. Likely, dilution of the nebulized weight-based dose with sterile water by one-half is beneficial in reducing the mild cough and/or burning sensation.

6. Where we currently stand

The ability of COVID-19 to cause widespread morbidity, mortality, and profound stress on healthcare systems worldwide has been harrowing. Not only increased costs of healthcare due to COVID-19 on the world economy, but this pandemic has had major negative effects on the entire well-being of society—previously unseen for many decades. No other disease has affected the current generation of medical professionals (or the world) like COVID-19. While other diseases exist for which there is no effective treatment, the mere volume of cases of COVID-19 has made its indelible mark.

From its beginning, the entire world felt the urgent need to find an effective treatment for this novel virus, and the discovery and development of new treatments for SARS-CoV-2 have been remarkable. Published data suggest definite benefits with a variety of medications including antivirals, monoclonal antibodies [51, 52], and high-titer convalescent plasma [51]. Based on COVID-19 pathogenesis, therapies that attack the virus itself are more likely to work early in the course of infection, whereas treatments that restrain the immune response (cytokine storm) may have more influence later in the disease [13, 14, 53]. Unfortunately, these medications are costly, and the prescriber of such treatments as the antiviral nirmatrelvir-ritonavir must also consider the potential for significant adverse reactions and interactions with a wide variety of other common medications that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and or life-threatening reactions [54].

Obviously, as new COVID-19 variants arise, current therapy guidelines will need to be amended. For example, bebtelovimab has activity against Omicron BA.2, but there is a paucity of good clinical data showing an associated reduction in COVID-19 mortality [55, 56]. Monoclonal antibody therapies like sotrovimab, casirivimab-imdevimab, and bamlanivimab-etesevimab have shown a reduction in death and the need for hospitalization in outpatients who have a non-severe disease but at risk for progression [57, 58]. However, these formulations are not appropriate for use in areas where COVID-19 infection is most probably due to SARS-CoV-2 variants that are not susceptible (i.e., Omicron, subvariants, etc.) [59].

Beyond question, prevention of this devastating disease is of utmost importance, and vaccines are very promising. Several COVID-19 vaccines are available globally, but unfortunately, there are areas and populations of people who do not have access to vaccinations [60, 61]. In addition, as with current therapeutic treatments (e.g., anti-virals, monoclonal antibodies, etc.), the existing and future effectiveness of vaccines is a genuine concern given the recurrent mutations already witnessed in the SARS-CoV-2 genome. However, while vaccinations are a mainstay of prevention, there will always remain a need for efficacious treatment for those who become acutely infected.

6.1 Final comments

The results of this novel study should not be ignored. Not to downplay the importance of new treatments and vaccines which have been developed since the start of the COVID-19 Pandemic, unfortunately for the foreseeable future as new variants arise, the proclivity of SARS-CoV-2 to mutate and cause widespread infection and wreckage to the health of individuals and society alike remains a global health concern. The world needs an effective, safe, widely-available, and inexpensive treatment for COVID-19—and inhaled ethanol may well be that needed treatment. Extensive studies are needed to confirm and better define the use of inhaled ethanol in combatting this disease—and other susceptible respiratory viruses (i.e. influenza, etc.). If confirmed, inhaled ethanol has the potential to prevent morbidity, and save lives, healthcare resources, and economies the world over. Extensive research is needed to confirm the findings herein, but the results must not be unheeded.²