Ethanol Inhalation in Treatment and Prevention of Coronavirus Disease (COVID-19)

Abstract

The goal of this study was to determine if nebulized ethanol (EtOH) is safe and effective in treating COVID-19. A randomized controlled trial was carried out on 99 symptomatic and RT-PCR-positive patients admitted to a hospital that were given Remdesivir and Dexamethasone. They were randomly given either a 35% EtOH spray (intervention group, IG) or distilled water spray (control group, CG). For a week, each group underwent three nebulizer puffs every 6 hours. Global Symptomatic Score (GSS) comparisons between the two groups at the initial visit and on days 3, 7, and 14. Secondary outcomes include the readmission rate and the Clinical Status Scale (CSS), a seven-point ordinal scale that ranges from death to full recovery. The intervention and control groups, respectively included 44 and 55 patients. The GSS and CSS considerably improved in the IG, despite the fact that there was no difference at admission (p = 0.016 and p = 0.001, respectively) (Zero vs. 10.9%; P = 0.02). The IG readmission rate was much reduced. Inhaled-nebulized EtOH responds well in quickly improving the clinical status and limiting the need for further therapy. Further investigation into the therapeutic and preventative properties of EtOH is advised due to its affordability, availability, and lack of/tolerable side effects.

1. Introduction

Deaths from cytokine storms are frequently caused by COVID-19. Alcohol has been shown to have in vitro antiviral effects on coronavirus glycoprotein destruction [1] and the breakdown of the fat layer [2]. Ethyl alcohol (EtOH) has been shown to have antiviral effects on extracellular surfaces in the past [3]. Inflammatory factors such TLR, interleukin-6, and TL9, as well as TNF-mRNA protein and mitogen-activated protein kinase, have been proven in immunological investigations to have immunomodulatory effects on the innate immune system and to attenuate cytokine storm [4, 5]. Additionally, it promotes bronchoalveolar macrophages’ chemotaxis [6]. Other effects of ethanol include the prevention of viral multiplication through RNA-dependent polymerase inhibition [7], bronchial dilatation by relaxing involuntary smooth muscles [8], patient sedation and relaxation [9], and analgesic effects on muscles [10]. Methanol poisoning [11], fat embolism [12], premature labor prevention [13], preeclampsia [14], and pulmonary edema [15] have all been treated with ethanol-specific treatments in the past. Castro-Balado et al. [16] have shown the histological safety of inhalation ethanol treatment on rats’ lungs and respiratory systems. Ethanol was authorized by the Food and Drug Administration. Can ethanol inhalation treatment be beneficial in treating COVID-19? Given the effects of ethanol on virus wall breakdown, proliferation inhibition, and immunological hyperactivity inhibition, the use of inhaled ethanol as a COVID-19 treatment is still unknown. One month following the COVID-19 epidemic in Iran, this concept was initially put forth and published [17, 18]. Later, a paper explaining the justification for ethanol usage in this area was presented [19]. Recent research on the combined administration of dimethyl sulfoxide and ethanol in healthcare professionals, demonstrated positive effects on COVID-19 prevention [20]. We conducted a randomized clinical study to assess the impact of ethanol treatment on the clinical condition and prognosis of a predetermined group of patients in an effort to discover the solution. The Medical University of Isfahan Research and Ethics Committee accepted the study, which was then registered at https://irct.ir/trial/58201.

2. Materials and methods

Study Design and Oversight (Figure 1). The Isabn-e-Maryam Hospital (Christian hospital) at the Medical University of Isfahan in Iran, where this study was carried out in September 2021, was the site of a randomized double-blind clinical trial with a control group and parallel design. The patients were matched one to one at random. The study was initially intended to be conducted on hospitalized patients, but because the country’s policy had been changed to allow for the establishment of respiratory clinics in hospitals and the prescription of Remdesivir and Dexamethasone to patients with moderate COVID-19, the study was instead carried out in this clinic. The referral of the patient to the respiratory clinic and this report were shared with the doctors of patients who were being treated in hospitals.

Figure 1.

Flowchart of the study.

2.1 Patients

Patients who tested positive for SARS-CoV-2-RT-PCR are the foundation of the study population. They were admitted to the hospital’s respiratory clinic because they had moderate COVID-19 (based on the national guideline for managing COVID-19, O2Sat 90–94% or lung involvement [21]). The following criteria were required for inclusion: informed consent, age of at least 12 years old, no pregnancy, no history of epilepsy, alcoholism, or asthma, no contraindications to ethanol usage, and no use of ethanol-interacting medications. Intolerance to inhaled ethanol and incomplete or partial therapy were the exclusion criteria. To investigate possible allergies to alcohol, a skin test with ethanol was performed. In this study, the patient’s arm was linked to a gauze pad with an ethanol drop on it. Symptoms including skin redness, swelling, or itching were seen after around 7 minutes. These signs may be indicative of an alcohol allergy or intolerance.

2.2 Intervention

According to Iran’s national clinical norms, both the control and intervention groups were enrolled in the standard medical treatment [21]. The national standard treatment included intramuscular Dexamethasone, 8 mg/day (5 days), and 200 mg of Remdesivir intravenously on day 1, followed by 100 mg of Remdesivir once daily for 4 days, infused over\s30–60 minutes. Patients received normal care as per routine and were then randomly allocated to either the control group (distilled water spray) or the intervention group (35% ethanol spray). The delivery of two 100 ml sets of spray was done in accordance with randomization. Each patient was told to spray the mask three times per day (every 6 to 8 hours) and inhale deeply. We stressed that, depending on the duration of symptoms, this procedure had to be repeated for 7 days. Patients were guided through the process by nurses until they were able to do it on their own. At each appointment for referrals and follow-up care, patient compliance was evaluated. Failure to follow the protocol (spray not used or used incorrectly) resulted in removal from the trial.

3. Clinical and laboratory monitoring

The demographic and clinical information were separated into different sections on the data collecting sheet. A qualified nurse performed the data-collecting checklist based on clinical symptoms, clinical outcomes, and clinical examination after obtaining demographic data from the patient’s records. Up to discharge, information on study variables, such as blood oxygen saturation measured by pulse oximetry, the requirement for supplementary care or hospital readmission, and clinical complaints in both groups, was gathered.

3.1 Study outcomes

Primary outcomes: The global symptomatic score (GSS), which is calculated by adding up the cumulative scores of clinical signs and symptoms like anorexia, fever, headache, body aches, sore throat, runny nose, chills, coughing, and loss of taste and smell, is regarded as a gauge of a patient’s clinical condition. This index was created to provide a concise list of clinical symptoms. Using a pulse oximeter, oxygenation status was tracked and documented each day. The patient was not receiving any additional oxygen at the time of the measurement and was breathing room air with a fixed pulse oximeter. Changes in blood C-reactive protein (CRP) levels were used to characterize the presence of inflammation.

Secondary outcomes: On day 14 of the treatment period for the investigation, clinical conditions were evaluated using a modified 7-point ordinal scale [22].

There are seven indicators in this scale:

1. Death.

2. A patient in a hospital receiving invasive mechanical ventilation.

3. High-flow oxygen or non-invasive ventilation systems used in hospitals.

4. Hospitalized and in need of low-flow oxygen.

5. Hospitalized for any cause, requiring continuous medical care (whether linked to COVID-19 or not), and requiring home oxygen supplementation.

6. Continued signs or symptoms of COVID-19 without requiring supplemental oxygen, no longer require ongoing medical care.

7. Both groups reported and dealt with full recovery as well as any potential side effects.

The necessity for critical care unit admission, adverse medication reactions, clinical symptoms, and death in the research samples were noted and tracked in both groups. The last follow-up was scheduled on the day fourteenth of the illness. Physical examinations, history-taking, phone calls, reviews of patient records, and documents from the hospital information system were all used during follow-up. After receiving informed consent, side effects were documented. The main endpoints have undergone some alterations. This was due to the study’s implementation restrictions, which coincided with the disease’s peak in Iran, and the fact that patients who required hospitalization were followed up on an outpatient basis in the respiratory clinic. We informed the sponsor and institutional review board in great detail of the protocol revisions. The length of stay was the key anticipated result. This index was replaced with a more detailed clinical status since all moderate patients were treated on a 5-day regimen during the surge.

3.2 Sampling

An easy random sample technique was used to do the sampling. Random assignment was performed using a computerized random number table. The order of the random distributions was decided by one nurse. Each participant who was qualified and gave their agreement to participate in the experiment was randomly assigned from a list that she kept confidential. One by one, a different nurse added 100 ml of diluted distilled water or ethanol-35% to the sprays (nebulizers) and labeled them with the numbers from the list. Each spray was given to a participant, who was then instructed on how to use it by their family or companion. Blinding was carried out by analysts, nurses, and clinicians.

4. Statistical analysis

Using a 2-sided significance level of 0.05, we calculated that 88 patients (44 in each group) would offer higher than 90% power to detect an odds ratio of 3 for the ethanol group vs. the placebo group. The analysis was restricted to individuals who, in accordance with the research protocol and inclusion criteria, got full treatments and contributed to the outcomes, as per the “treatment-on” or “per-protocol” method. Means, standard deviations, and percentages (%) were used to report both quantitative and qualitative information. The chi-square test was used to evaluate qualitative characteristics between the two groups, and a mixed model was used to compare SpO2 readings and GSS on days 1, 3, 7, and 14. Repeated-measures analysis was used to calculate the average changes from baseline values. With the use of Mauchly’s statistics and the Geisser-Greenhouse adjustment, the sphericity hypothesis was disproved. The cumulative odds ordinal logistic regression with proportional odds was used to compare clinical status between the two groups on day 14, and the two test was used to determine the proportion of patients in each group who required additional medical care after 14 days. These tests were carried out at 0, 3, and 14 days after the intervention. For the intervention group compared to the usual care group, an odds ratio larger than 1 showed changes in clinical status across all categories toward category 7. For clinical status, if a patient recovered, the ordinal score was recorded as 7 on the day of recovery and all subsequent days unless the patient was hospitalized for COVID-19-related reasons or others; all statistical analyses were performed using SPSS software version 22 (SPSS Inc., Chicago, IL, USA), and p < 0.05 was considered significant. The outcome markers were adjusted for the patient’s gender.

5. Results

Patient Characteristics from September to November 2021, 150 patients from the COVID-19 Respiratory Outpatient Clinic of the Isabn-e-Maryam Hospital of the Isfahan University of Medical Sciences were assessed for participation in the research based on the positive outcome of the RT-CPR test. A total of 24 patients disagreed with the research, and 2 patients did not meet the inclusion requirements. Randomly, 124 more patients were divided into two groups (Intervention and Control). In the next days, 25 participants were removed from the trial due to intolerance to ethanol inhalation (6 patients); their intolerance was mostly caused by hiccups, eye irritation, coughing, shortness of breath, sneezing, and the unpleasant odor of alcohol. On the other hand, 19 patients (9 in the control group and 10 in the intervention group) were disqualified from the trial because of irregularities or failure to adhere to the suggested procedure. Finally, 99 patients entered the analysis: 44 patients in the IG and 55 patients in the CG (Table 1).

Index	Control group N = 55	Intervention group N = 44	P value
Age (years) (Mean ± SD)	46.15 ± 13.15	45.91 ± 12.58	0.928
BMI (Kg/m2) (Mean ± SD); Normal weight; Overweight; Obesity; Excessive obesity	16 (29.1); 25 (45.5); 10 (20); 3 (5.5)	9 (20.5); 22 (50); 10 (22.7); 3 (6.8)	0.804
Gender N (%); Female; Male	37 (67.3); 18 (32.7)	19 (43.2); 25 (56.8)	0.024
Education Level N (%); Illiterate and Elementary; Secondary; Diploma; Bachelor-higher; Unknown	3 (5.4); 8 (14.3); 28 (50); 16 (26.8); 2 (3.6)	8 (16.3); 7 (14.3); 16 (32.7); 16 (30.6); 3 (6.1)	0.251
Risk factors for disease N (%); Not any; 1 risk factor; 2 risk factors; 3 risk factors	23 (52.3); 19 (43.2); 2 (4.5); 0	38 (69.1); 12 (21.8); 4 (7.3); 1 (1.8)	0.614

Table 1.

Demographic characteristics in two research groups.

Table 1 summarizes the baseline characteristics and demographics of the two groups of patients. The male-to-female patient ratio was 43/56 (42.4/56.6%). The patients were 46.4 years old on average. A total of 38 patients had multiple conditions. Diabetes mellitus was the most prevalent underlying condition in both groups, with 6 (14.3%) in the intervention group and 4 (7%) in the control group. Seven individuals had high blood pressure and seven others had additional cardiovascular issues. The two groups’ mean ages, weights, levels of education, and total number of risk variables did not significantly differ from one another.

5.1 Clinical signs and symptoms at the time of admission

The interval between the onset of symptoms and admission, lung involvement, and early clinical signs and symptoms at baseline did not substantially differ among the patients. The clinical signs and symptoms of the patient’s fundamental characteristics are listed in Table 2.

Characteristic	Control group N = 55	Intervention group N = 44	P value
Distance from onset of symptoms to Start treatment (Mean ± SD)	9.36 ± 5.13	8.50 ± 3.52	0.338
Pulmonary Involvement (CT scan) N (%); Less than 30%; 30–49%; 50% and above; Unknown	22 (40); 25 (45.5); 2 (3.6); 6 (10.9)	19 (43.2); 15 (34.1); 2 (4.5); 8 (18.2)	0.153
Fever N (%)	21 (38.2)	25 (56.8)	0.072
Chills N (%)	35 (63.6)	30 (68.2)	0.675
Cough N (%)	49 (89.1)	41 (95.3)	0.262
Headache N (%)	35 (63.6)	30 (68.2)	0.636
Short Breath N (%)	37 (67.3)	24 (54.5)	0.196
Sore throat N (%)	27 (49)	16 (36.4)	0.204
Rhinorrhea N (%)	18 (32.7)	9 (20.5)	0.173
Body pain N (%)	36 (65.5)	36 (65.5)	0.069
Anorexia N (%)	38 (69.1)	29 (65.9)	0.737
Anosmia N (%)	39 (70.9)	26 (59.1)	0.219
Lack of taste N (%)	32 (58.2)	27 (61.4)	0.749
Global Symptomatic Score (GSS)	6.67 (2.09)	6.72 (2.07)	0.910

Table 2.

Preliminary characteristics of signs and symptoms, risk factors, and laboratory values in baselines.

Cough, body pains, chills, and headaches were the intervention group’s main clinical complaints. The control group had a higher prevalence of anorexia, olfactory disturbance, and cough. There was no discernible change in symptoms. Overall Symptom Score The GSS was evaluated at the start of therapy, 3, 7, and 14 days afterward in two groups. The results are shown in Figure 2.

Figure 2.

Comparison of global symptomatic score (GSS) in the intervention and control groups at the beginning of admission, days 3, 7 and 14 after admission.

The GSS of the two groups was equal at the start of the research, according to statistical analysis, but in the IG group, clinical symptoms reduced more quickly than in the placebo group. The statistical significance of this difference was (p = 0.016).

5.2 Blood oxygen saturation

At the time of the trial, there was no noticeable change in the two groups’ blood oxygen saturation levels (92.07 ± 4.6 in the control group vs. 91.56 ± 3.39 in the intervention group). As seen in Figure 3.

Figure 3.

Comparison of mean blood oxygen saturation (SPO2) in intervention and control groups at the beginning of admission, days 3, 7 and 14 after patient admission.

Both groups had an improvement in blood oxygenation, however, the ethanol group’s slope of oxygenation was greater. The change is not statistically significant, though (p = 0.097) inflammatory factor (CRP) Multiple assessments and statistical comparisons between the two groups revealed a declining trend in CRP (Figure 4).

Figure 4.

Comparison of CRP (C-reactive protein) in the intervention and control groups at the beginning of admission and three days after patient admission.

However, the rate of reduction was much faster and more intense in the IG (p = 0.05). Two sets of CSS based on the modified 7-point ordinal scale were compared. On day 14, the intervention group had 5.7 times the chance of having superior CSS than the control group (95% CI, 2.47–13.19), which is a statistically significant difference (Wald 2 (1) =16.67, p = 0.001). Table 3 provides details.

Characteristic and Score N (%)	Intervention N = 44	Control N = 55
1. Death	0	0
2. Hospitalized, on invasive mechanical ventilation	0	0
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices	0	0
4. Hospitalizations for any reason and need oxygen	0 (0)	2 (3.63)
5. Requiring ongoing medical care or supplemental oxygen at home	2 (4.54)	10 (18.18)
6. Continue signs or symptoms without requiring supplemental oxygen - no longer requires ongoing medical care	13 (29.54)	29 (52.72)
7. Complete recovery	29 (65.90)	14 (25.45)

Table 3.

Comparison of clinical status scale (CSS) of intervention and control groups on the 14th day of admission.

Six patients (10.9%) from the control group were readmitted after the therapy period had ended in order to obtain further care or hospitalization. None of the patients were readmitted to the ethanol group (p = 0.02).

5.3 Adverse events and safety

Six out of 50 patients in the ethanol group (12%) quit taking it due to adverse effects that started as soon as inhalation began, and we eliminated them from the research. Only one instance of each negative effect was noted, and it vanished after ethanol consumption was discontinued. Hiccups, eye discomfort, coughing, shortness of breath, sneezing, and a strong alcohol odor were a few of the undesirable side effects.

6. Discussion

The impact of adding nebulized Ethanol inhalation has been researched in this clinical study on patients having positive RT-PCR test results, mild clinical symptoms, and suitability for Remdesivir and Dexamethasone treatment, according to the Iran Ministry of Health protocol. The rationale for the use of EtOH in COVID-19 has been well discussed [19]. There is no question regarding the ability of ethanol in killing or making SARS-CoV-2 inactive, even at concentrations as low as 30% v/v and for only 30 seconds [23]. The virus’s fat layer is broken down by the virucidal effects of EtOH, which then stop the virus from multiplying. EtOH has also been demonstrated to reduce the immune system’s hyperactivity during COVID-19. It seems likely that ethanol is ineffective against intracellular viruses. It is crucial to continue ethanol inhalation for at least 3 days since viral multiplication happens within 48–72 hours, followed by cellular death and shedding. Additionally, ethanol is fundamentally effective against all SARS-CoV-2 variants and other “enveloped” viruses due to its non-specificity. The abnormal presence of Mycoplasma salivarium in the lower tract or the lack of Clostridia in the upper tract was linked to worse outcomes in ICU patients [24]. It is interesting to note that ethanol completely inactivates Mycoplasma and SARS-CoV-2 (Eterpi et al.) [25]. Additionally, certain strains of Clostridia synthesize endogenous ethanol [26]. According to a hypothetical scenario, the lack of nasopharyngeal Clostridia would prevent the local generation of ethanol, which would prevent or drastically limit the inactivation of SARS-Cov-2 at this level, allowing the virus to propagate to the lower respiratory tract. A lot of concern has been expressed regarding the potential mucosal harm that breathed ethanol might cause. Castro-Balado et al. careful research [16] appears to have completely dispelled these concerns. It should be noted that spraying into the mask prolongs the action of the nebulized liquid and maintains its efficiency by reducing the dispersion and evaporation of the liquid. The different smells of the two solutions indicate a potential inherent bias. Patients could only recognize that one spray was different from another since they were unaware of the actual ingredient in the spray. To put it differently, the medication may have been in an odorless spray. Dexamethasone and Remdesivir are administered intramuscularly as part of the COVID-19 standard therapy [21]. According to a recent trial, introducing early antibiotic therapy for COVID-19 pneumonia had no positive effects on 30-day mortality [27]. Despite what was predicted [28, 29], the authors [27] did not discover any appreciable vaccination benefit in reducing illness severity and death among patients with COVID-19 pneumonia. The GSS fell more in the Intervention group than in the control group, according to our findings, and these data reached a statistically significant level (p = 0.016). Nebulized EtOH inhalation had positive effects on lowering CRP levels, which was a significant advantage (p = 0.05). This result supports EtOH’s positive immune- modulation effects [3]. On the other hand, blood oxygenation increased more quickly and had a greater slope in the ethanol than it did in the control group. Regarding blood oxygenation, between the two groups, there was, however, no statistically significant difference (p = 0.097). In terms of CSS, the intervention responded better than the control since no patient had to be readmitted, as opposed to the control where 6 patients (10.8%) had to repeat the normal therapy or be hospitalized. These results provide credibility to EtOH’s virucidal properties.

7. Conclusions

Overall, recovery from moderate COVID-19 is greatly improved by adding EtOH to the conventional therapy (Remdesivir+Dexamethasone). It is advised to do more research and invest more in order to assess ethanol’s therapeutic and preventative effects in the early stages of COVID-19 given its accessibility, low cost, and lack of substantial adverse events. The patients in this experiment were far from our rigorous oversight and switched to other treatments, which was one of its shortcomings. The healthcare system is also concerned about unpleasant alcohol consumption and the potential for non-inhaled alcohol intake. This study is constrained by chance (due to the small sample size), confounding factors (due to the imbalance in gender distribution), and low power, among other things. The randomization sequence is broken by a per-protocol analysis, which also introduces bias into the study.