Thermal Helium-Oxygen Mixture as Part of a Treatment Protocol for Patients with COVID-19

Full Text

At the end of 2019 the world faced an unprecedented threat of the respiratory infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2). The novel acute respiratory viral infection was first reported in December 2019 in Wuhan, the capital city of Hubei province of China, and has spread since then worldwide, which has resulted in an ongoing coronavirus pandemic in 2019 and 2020 [1, 2].

 About 28,506,254 cases of COVID-19 and 915,920 deaths were registered globally at the beginning of September (as of September 11, 2020) [3]. Ten to fifteen percent of patients develop severe or critically severe disease. Acute respiratory failure is one of the most common complications of COVID-19. Even with enhanced supply of oxygen delivered via a face mask with a reservoir bag (flow rates of 10-15 L/min), high-flow oxygenation with FiO₂ of 0.60-0,95, or non-invasive ventilation (NIV), respiratory support may be ineffective. In Russia, the mortality rate of COVID-19 patients who received mechanical ventilation is 76.5% [4]. The fight against complications of the coronavirus infection is an extremely urgent issue that requires the development of new methods to expand currently available therapeutic and preventative options. Inhalation therapy with thermal helium-oxygen mixture (t-Не/О₂) is one of modern methods of respiratory support.

Helium is an inert gas which was discovered by P. Janssen and N. Lockyer, who reported the discovery independently to the French Academy of Sciences (1868). Academician P.L. Kapitsa played an important role in the study of the physicochemical properties of helium. He began his research during his internship in Rutherford's laboratory in London (1938), and continued it later in Moscow together with Academician D.L. Landau [5, 6]. Both scientists were awarded the Nobel Prize for their research on the physical properties of helium.

 Helium has high diffusion capacity, high heat capacity, and high thermal conductivity. The diffusion capacity of helium through the solids is three times higher than that of air and about 65% higher than that of hydrogen. This property should be kept in mind when using helium in patients with diffuse damage to the alveolar-capillary membrane, which develops in the acute phase of COVID-19. The diffusing capacity of red blood cells decreases significantly, resulting in hypoxemia. Inhalation of helium-oxygen mixture improves oxygen transport across the lung.

 Of note, helium has unique heat capacity and thermal conductivity. It has an extremely high specific heat capacity (5.23 kJ/kg ·K) and a thermal conductivity of 0.1437 W/(m · K), which is higher than that of other gases. These properties of helium provided the basis for the concept of using helium-oxygen mixture. Due to such heat capacity and thermal conductivity of helium, inhalation of t-Не/О₂ does not cause tissue damage or thermal injury to the airways, which was demonstrated in a joint study with S.D. Varfolomeev [7].

Currently, helium is widely used in such industries as airship construction, which has now a new lease of life, nuclear energetics, diving medicine, chemistry, food industry, metallurgy, and machinery manufacturing. In medicine, helium is used to prevent and treat decompression sickness and to treat asthma exacerbations and wheezing attacks in asthma patients.

Such limited medical use of helium is explained by side effects that develop during helium inhalation. Inhalation of helium may be complicated by the appearance of mucus plugs in distal airways, which, in some cases, causes sudden death due to acute asphyxia.

 At a joint workshop with B.N. Pavlov (1984), who was a Russian leading expert in diving medicine, the target was first set to develop an inhaler device that would make it possible to mix helium and oxygen, heat the inhalation mixture, and adjust the dose of heated helium-oxygen mixture. This task was successfully completed by A.A. Panin and his group of engineers. This development made it possible to use t-Не/О₂ in patients with respiratory failure of various etiology and severity. The authors of this paper have more than twenty years of clinical experience with helium. A total number of their patients who received helium treatment exceeds 3,000 people.Initially, we used a thermal helium-oxygen mixture in patients with hypoxemic respiratory failure, and then in patients with hypercapnic respiratory failure. Most patients who received respiratory support with inhalation of a thermal helium-oxygen mixture had chronic obstructive pulmonary disease. Both short-term and long-term results demonstrated a high effectiveness of inhalation of a thermal helium-oxygen mixture. This treatment is well tolerated and has no clinically significant side effects [8]. Clinical experience obtained during this period made it possible to develop a treatment algorithm and establish the criteria for the therapeutic window for t-He/О₂ inhalation [9]. In the recent years, this experience has been translated into a neurological clinic and used for the treatment of patients with ischemic stroke accompanied by signs of hypoxemic respiratory failure [10, 11] and in obstetrics to correct the oxygen status of pregnant women in the third trimester [12]. Our clinical studies of the efficacy of t-He/O₂ inhalation in the treatment of acute respiratory failure in COVID-19 patients receiving standard therapy was preceded by a theoretical analysis of the development of acute viral infection with an assessment of the potential therapeutic effects of t-He/O₂ inhalation. The kinetic model included a description of changes in the concentrations of viral particles, amounts of damaged host cells and pathogenic agents, concentrations of hydrogen ions, and catalytic activity of the key enzymes. The concept of heating a gas mixture was assessed based on its physicochemical properties, and t-He/О₂ was predicted to have great therapeutic benefits [13]. In April 2020, some authors reported the efficacy of high temperatures in the treatment of coronavirus infection. Scientists from the University of Provence, Division of Emerging Viruses (Université de Provence, Unité des Virus Émergents), France, reported that a heating protocol consisting of 92°C-15min was able to inactivate totally the virus. The heating protocols of 60°C-60min and 56°C-30min helped reduce the viral activity, but did not stop replication of some viral isolates [14]. The authors from the Xi'an Jiaotong University reported that at +70°С the virus is destroyed within 5 minutes and that coronavirus remains active for less than 30 minutes at +56°С, not longer than two days at +37°С, and about a week at + 22°С [15].

Therefore, the use of the new technique (inhalation of thermal helium-oxygen mixture), a 20-year clinical experience with t-He/О₂, and data in the literature about the efficacy of high temperatures against coronavirus were the key factors to support the use of helium in COVID-19 patients who develop life-threatening acute respiratory failure.

 

 

 

 

Materials and Methods

Seventy patients with COVID-19 and respiratory failure were included in a single-center, randomized, prospective study. Patients were divided into two groups. Group 1 (n = 38) consisted of patients who were given thermal helium-oxygen mixture (t-He/О₂) in addition to the standard COVID-19 treatment; and Group 2 (n = 32) was made up of patients who the received standard treatment in accordance with the Clinical Treatment Guidelines for patients with confirmed coronavirus infection, developed by the Ministry of Health of the Russian Federation. The male/female ratio was 18/20 in Group 1 and 18/4 in Group 2. The study groups were matched by sex. The mean age of the patients in the study was 53.5 years (45; 61): 56 years (45; 59.5) in Group 1 (t-He/О₂) and 52 years (46; 66) in Group 2. The groups were also matched by age. All patients who were enrolled in the study conducted under protocol No. 10-20, approved by the Ethics Committee on Biomedical Ethics, received treatment for pneumonia caused by SARS-CoV-2 from April 21 to June 2020, both inclusive. All patients provided voluntary informed consent to participate in the study and signed a consent form. All patients had CT signs of lung injury (ground-glass opacities and areas of consolidation) and signs of acute respiratory failure and met the following study inclusion criteria: 1) age >18 years; 2) Sepsis-related Organ Failure Assessment (SOFA) score <6; 3) CT signs of viral pneumonia (grade CT2 or CT3); and 4) PaO₂/FiO₂ >100, according to the Berlin classification.

Patients who met the following criteria excluded from the study: an oxygenation index ≤100, mechanical ventilation, severe impairment of consciousness (score on the Glasgow scale less than 10), unstable hemodynamics (systolic blood pressure <90 mm Hg, heart rate [HR] <50 beats per min or >160 beats per min), hemoglobin <115, profuse sputum secretion, vomiting that interfered with mask wearing, acute cerebrovascular accident (ACV), acute myocardial infarction (AMI) within the last 6 months, or pregnancy.

Detailed patient characteristics are shown in Table 1. During the study all patients received standard treatment in accordance with the Provisional Guidelines “Prevention, diagnostics, and treatment of the novel coronavirus infection (COVID-19)” [version 5 (approved by the Ministry of Health of the Russian Federation on March 8, 2020), version 6 (approved by the Ministry of Health of the Russian Federation on April 28, 2020), version 7 (approved by the Ministry of Health of the Russian Federation on June 3, 2020)].

Table 1. General characteristics of patients at the enrollment, Me (25%; 75%)

Parameter	Group 1 (n= 38)	Group 2 (n= 32)
Age (years)	56 [42; 64]	52 [43; 66]
Sex: (m/f)	18/20	18/14
BMI, kg/m2	29.61 [26.8; 34.1]	29.11 [25.8; 33.7]
Duration of the disease (days)	8 [7; 10]	7 [5; 9]
HR (min-1)	120.6 [95.2; 130.3]	118.9 [93.4; 128.2]
RR (min-1)	26.3 [21; 28]	25.7 [21.4; 27]
SpO2 (%)	88 [82; 92]	86 [ 84; 90]
mMRC dyspnea score	1.6 [0; 3]	1.75 [0; 3]
Positive PCR for SARS-CoV-2 (n)	32	27
CT signs of pneumonia (lesion volume, %)	44.1 [25; 75]	35.4 [25; 50]
NIV / high-flow oxygen therapy (%)	100	100

Note: RR = respiratory rate, HR = heart rate, BMI = body mass index, SpO₂= hemoglobin saturation with oxygen, CT = lung computed tomography, NIV = non-invasive ventilation, mMRC = modified Medical Research Council Dyspnea Scale.

Study design

At baseline all patients underwent a clinical assessment, including measurement of respiratory rate (RR) and heart rate (HR), dyspnea assessment using the Medical Research Council (MRC) Scale, assessment of organ failure, risk of death and sepsis in intensive care unit (ICU) patients, using the Sequential Organ Failure Assessment (SOFA), and questionnaire completion (Table 2). The study investigations and examinations included a PCR test for COVID-19, lung computed tomography, blood gases (pH and partial pressure of oxygen in arterial blood [PaO₂]), partial pressure of carbon dioxide in arterial blood (PaCO₂), bicarbonate (HCO₃) and lactate levels; complete blood count (hemoglobin, white blood cells, neutrophils, lymphocytes, ant platelets); blood chemistry (alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, direct bilirubin, ferritin, C-reactive protein, and procalcitonin); blood coagulation profile (D‐dimer, a fibrin degradation product); international normalized ratio (INR), echocardiography (cardiac output [CO]), and mean pulmonary artery pressure (mPAP). Monitoring intervals (days) used in the study are shown in Table 3. The design of the study is shown in Figure 1.

Figure 1. The design of the study in parallel groups.

 

Table 2. Patient-reported symptom questionnaire

Symptoms	n = 38		n = 32
	Yes	No	Yes	No
Loss of smell and taste	27 (71%)	11 (29%)	25 (78.1%)	7 (21.9%)
Runny nose	7 (18.4%)	31 (81.5%)	6 (18.7%)	26 (81.3%)
Shortness of breath	37 (97.3%)	1 (2.7%)	32 (100%)	0
Dyspnea	30 (78.9%)	8 (21.1%)	28 (87.5%)	4 (12.5%)
Weakness	34 (89.4%)	4 (10.6%)	27 (84.3%)	5 (15.7%)
Fever >38 ℃	32 (84.2%)	6 (15.3%)	29 (90.6%)	3 (9.4%)
Fever >37 ℃	34 (89.5%)	4 (10.5%)	30 (93.7%)	2 (6.3%)
Headache	29 (76.4%)	9 (32.6%)	25 (78.1%)	7 (21.9%)
Muscle pain	28 (73.6%)	10 (26.4%)	26 (81.2%)	6 (18.8%)
Sore throat	20 (52.6%)	18 (47.4%)	15 (46.8%)	17 (53.2%)
Dry cough	37 (97.3%)	1 (2.7%)	32 (100%)	0
Productive cough	-	-	-	-
Hemoptysis	-	-	-	-

 

Table 3. Monitoring intervals (days) in the study groups

	Screening Randomization	Day
		1	2	3	4	5	6	7	8	9	10
Symptom questionnaire		+	+	+	+	+	+	+	+	+	+
Body temperature		+	+	+	+	+	+	+	+	+	+
PCR	+		+	+			+				+
CT	+							+			+
Clinical assessment		+	+	+	+	+	+	+	+	+	+
Blood gases	+		+		+		+		+		+
Complete blood count	+		+	+	+	+	+	+	+	+	+
Blood chemistry	+			+						+	+
Procalcitonin	+		+		+		+		+
Blood coagulation profile	+	+	+	+	+	+	+	+	+	+	+
Echocardiography	+		+		+		+		+		+

Treatment with gas mixtures

The t-He/O₂ therapy was performed on the Heliox-Extreme apparatus (LLC Medtekhinnovatsii Russia, medical device code: 944460 [TU 9444-001 0116489960-2915]) through separate oxygen and helium ports. Oxygen was supplied from a centralized hospital oxygen distribution system. Medical helium type "A" was supplied form a 10-liter metal cylinder under pressure of 200 atm through a 15 atm pressure regulator (GCE, China). In this study, we used medical helium type "A" (99.995%; TU 20.11.11-005-45905715-2017, NII KM, RF). The apparatus mixed two gases (helium and oxygen) in the concentrations specified. Through the breathing filter Inter-Guard™ (Intersurgical Ltd, UK) and the Flextube hose (Intersurgical Ltd, UK), the mixture of He and O₂ was then fed into the thermistor of the Heliox-Extreme apparatus, which was connected to the exhalation valve (Intersurgical Ltd, UK) and an anesthetic face mask QuadraLite (Intersurgical Ltd, UK).

Patients received daily 60-minute inhalations for 10 days. Each inhalation session lasted at least 7-10 minutes, depending on the patient’s compliance and the degree of respiratory muscle fatigue.

The concentration of He and O₂ was selected individually for each patient in a range of 79% to 50% (He) and 21% to 50% (O₂) to maintain SpO₂ between 97% and 99%. The mixture temperature was also chosen on an individual basis within a range of 75°C and 100°C, depending on saturation index, tidal volume, and patient comfort.

At SpO₂ ≥ 93%, inhalation of t-He/O₂ was started with 79% He and 21% O² heated to 85-96°C with a gradual increase in O₂ fraction by 2% every minute until the target SpO₂ 97-99% was reached.

At 85% ≤ SpO₂ ≤ 92%, inhalation of t-He/O₂ was started with 70% He and 30% O² heated to 85-96°С with a gradual increase in O₂ fraction by 2% every minute until the target SpO₂ 97-99% was reached.

At SpO₂ <85%, inhalation of t-He/O₂ was started with 65% He and 35% O₂ heated to 75-84°C with a gradual increase in O₂ fraction by 2% every minute. The O₂ fraction did not exceed 50%, i.e. the helium/oxygen ratio was not more than 50% : 50%, and SрO₂ was maintained at 97-99%.

We continued the inhalation therapy as long as tidal volume (TV) did not exceed 1,000 ml. If TV exceeded 1000 ml, we interrupted the breathing cycle from the circuit of the apparatus and allowed one or two breaths of an air mixture to prevent hyperventilation. Then, the face mask was put back on, and breathing with t-He/O₂ was continued with the same concentration of He and O₂ that was used when the inhalation was stopped. SрO₂ was monitored using an OxyShuttle pulse oximeter (Sensor Medics, USA). TV was monitored with a monitor incorporated into the Heliox-Extreme apparatus.

Statistical analysis

Statistical processing of the data was carried out using the SPSS 17.0 software package (SPSS Inc., USA). The quantitative parameters are presented as median (Me) and quartiles (lower and upper quartiles). Nonparametric statistical methods, including the Mann-Whitney U-test, were used to analyze data. Friedman's analysis of variance (ANOVA) followed by paired comparison using the Wilcoxon test was used to compare variables in the study groups. The differences were considered statistically significant at p <0.05.

Results

Inhalation of thermal helium-oxygen mixture combined with standard therapy did not cause any procedure-related side effects in any of the patients. On days 2 and 3 two patients refused to continue inhalation therapy because they did not tolerate high temperatures well. From than moment on, 36 patients continued participation in study Group 1. In all Group 1 patients SpO₂ increased by 8-10% and TV increased two to three times within five to seven minutes after initiation of inhalation. None of the patients in either Group 1 or Group 2 was placed on mechanical ventilation. No deaths were reported in either group. All patients were discharged.

 

Changes in pО₂/FiO₂ over time in the study groups: In Group 1 there was a statistically significant increase in oxygenation index within 10 days. A significant difference in the magnitude of increase in pО₂/FiO₂ between Groups 1 and 2 was seen as early as on day 3, with this trend being maintained on days 7 and 10 (Figure 2).

 

 

 

 

Figure 2. Dynamics of pO₂/FiO₂ in comparison groups (*p<0.05)

Changes in SpO₂ over time in the study groups: At baseline, all patients in Groups 1 and 2 had signs of low levels of blood gases. In all Group 1 patients the SрO₂ achieved during t-He/O₂ inhalation decreased after the inhalation sessions to levels exceeding baseline values. On each following day, pre-inhalation SрO₂ levels were higher than on the previous day and increased every day. In Group 1 a statistically significant increase in SрO₂ was observed on day 3 followed by a further significant rise on days 7 and 10. In Group 2 a statistically significant increase in SрO₂ was observed only on days 7 and 10 (Figure 3).

 

 

 

 

Figure 3. Dynamics of pO₂/FiO₂ in comparison groups (*p<0.05)

 

Changes in the need for respiratory support over time in the study groups: In Group 1 a statistically significant decrease in the need for respiratory support was observed between days 3 and 7. In Group 2 the need for NIV remained significantly higher over 10 days (Figure 4).

 

 

Figure 4. Dynamics of the need for respiratory support in comparison groups (*p <0.05)

 

 Changes in PCR results over time in the study groups: We used PCR to confirm coronavirus infection and subsequently to monitor patients’ status to report the day of virus elimination. Group 1 showed a statistically significant decrease in the number of positive RNA tests for SARS-CoV-2. According to our observations, most COVID-19 patients from Group 1 (inhalation treatment with t-He/O₂) had a negative PCR on day 3 and some patients had a negative result as early as on day 1 after initiation of therapy. In Group 2 (standard treatment), patients tested positive for the viral antigen over the period ranging from seven days to 4 weeks after the onset of the disease and in some cases even longer (Figure 5).

 

 

 

 

 

 

 

 

 

 

а

 

 

 

Figure 5. Dynamics of the number of positive PCR tests in the comparison groups (*p <0.05)

 

Changes in D-dimer levels over time in the study groups: All patients in Groups 1 and 2 had elevated D-dimer levels. In Group 1 patients t-Не/О₂ inhalation resulted in a statistically significant decrease in D-dimer levels as early as on day 3, while in Group 2 this parameter decreased on day 7. In Group 1 the magnitude in reduction in D-dimer levels observed over 10 days was significantly greater in Group 1 (Figure 6).

 

 

Figure 6. Dynamics of the D-dimer indicator in comparison groups (*p < 0.05)

 

Changes in CRP levels over time in the study groups: In both Groups 1 and 2, there was a rise in CRP levels on day 3, but in Group 1 it was not statistically significant. The changes in CRP levels on days 7 and 10 suggested that Group 1 patients had a greater reduction in CRP levels (Figure 7).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 7. Dynamics of the CRP indicator in comparison groups (*p < 0.05)

Changes in ferritin levels over time in the study groups: In Group 1 a statistically significant reduction in ferritin levels was observed on day 3 followed by a further decrease on days 7 and 10. In Group 2 a statistically significant reduction in ferritin levels was observed only on days 7 and 10. A comparison of ferritin levels in Groups 1 and 2 throughout the 10-day period showed that this parameter remained high in Group 2 (Figure 8).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 8. Dynamics of the ferritin indicator in comparison groups (*p<0.05)

 

Changes in the lymphocyte count over time in the study groups: At baseline, low lymphocyte counts were reported in Groups 1 and 2. The addition of t-He/O₂ to the combination therapy resulted in a significant increase in the lymphocyte count in Group 1 on day 3 and its full recovery on day 7. Group 2 showed a decrease in the lymphocyte count on day 3 as compared to the baseline value. On days 7 and 10, the lymphocyte count increased significantly, but this rise was significantly lower than in Group 1 (Figure 9).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 9. Dynamics of the lymphocyte index in the comparison groups (*p <0.05)

Discussion

This study had two principal goals: 1) To demonstrate the safety of inhalation of a thermal helium-oxygen mixture and 2) to assess its efficacy by clinical signs, with a specific focus on the changes in viral load, oxygen status of COVID-19 patients, and inflammation markers.

Inhalation of t-He/О₂ was well tolerated. Out of all study participants, only two patients refused to continue inhalation sessions. One patient could not tolerate a face mask. The other patient did not tolerate the high temperature of the helium-oxygen mixture. The gas mixture temperature was chosen individually for each patient within a range of +75-100°С. These temperatures of t-He/О₂ were well tolerated by the patients, who were well cooperative and reported a significant reduction in breathing discomfort during the inhalation sessions. Most patients asked for repeat He/О₂ inhalations. The patients staying in the intensive care unit, where the study was conducted, had a positive mindset, which showed their highly favorable perception of this treatment choice.

To summarize, this study demonstrated that inhalation of a thermal helium-oxygen mixture is rather safe for patients. Another beneficial effect of helium treatment is patients’ highly favorable perception of this method.

The viral load in COVID-19 patients peaks around the end of the second week after infection. The first five to seven days are the incubation period with no clinical signs of a viral disease. During this time viral particles multiply in epithelial and neuroepithelial cells in the upper airways. Over the next five to seven days the disease manifest itself by symptoms of the common cold. The first critical day in the course of the disease and the peak of viral load are seen around the end of the second week of infection. The more severe the course of COVID-19, the more actively the virus replicates. In our study PCR was done to confirm the diagnosis of COVID-19 and subsequently repeated on days 1, 3, and 7 and at discharge. In Group 2 (standard treatment), patients tested positive for the viral antigen over the period ranging from seven days to 4 weeks after the onset of the disease and in some cases even longer. Our observations showed that most COVID-19 patients from Group 1 (inhalation treatment with t-He/O₂) had a negative PCR on day 3 and some patients had a negative result as early as on day 1 after initiation of therapy. At this point an obvious question arises: What mechanism is responsible for such a fast viral elimination, as evidenced by PCR? We can explain such fast viral elimination in patients with coronavirus infection by the thermal effect of helium, which causes degradation of viral structures. The lymphocyte count is another marker that reflects the effect of t-He/O₂ on viral replication. It is one of markers of viral invasion, which is evidenced by lymphopenia. Therapeutic sessions of t-He/O₂ inhalation were accompanied by restoration of the lymphocyte population in COVID-19 patients.

Of note, patients with COVID-19 had tissue resistance to oxygen therapy. The addition of t-He/O₂ inhalation to the standard therapy improved blood oxygenation and reduced the need for NIV/high-flow oxygen therapy.

Conclusion

The addition of inhalation of a thermal gas mixture of helium and oxygen (t-He/О₂) to the standard therapy for patients with SARS-CoV-2 infection, CT signs of pneumonia (grades СT2 or CT3), and acute respiratory failure improves gas exchange, contributes to a more rapid virus elimination, and indirectly reduces inflammation.

Additional Information The paper meets the ethical requirements of the UNESCO Universal Declaration on Bioethics and Human Rights, 2005.

Source of funding: The study was conducted without sponsorship.

Conflict of interest: The authors declare that they do not have any conflict of interest

About the authors

Lyudmila V. Shogenova

The Russian National Research Medical University named after N.I. Pirogov

Author for correspondence.
Email: luda_shog@list.ru
ORCID iD: 0000-0001-9285-9303
SPIN-code: 6210-7482

Candidate of Medical Sciences, Associate Professor of the Department

Russian Federation, 32 bld 4, 11 Parkovaya str., 105077, Moscow, Russia

Sergey S. Petrikov

The Moscow Department of Health N.V. Sklifosovsky Federal Research Institute of Emergency Medicine

Email: petrikovss@sklif.mos.ru
ORCID iD: 0000-0003-3292-8789

MD, PhD, Professor, Сorresponding Member of the RAS

Russian Federation, Bolshaya Sukharevskaya Square 3, Moscow, 129090, Russia

Sergey V. Zhuravel

The Moscow Department of Health N.V. Sklifosovsky Federal Research Institute of Emergency Medicine

Email: zhsergey5@gmail.com
ORCID iD: 0000-0002-9992-9260
SPIN-code: 5338-0571

MD, PhD

Russian Federation, Bolshaya Sukharevskaya Square 3, Moscow, 129090

Pavel V. Gavrilov

The Moscow Department of Health N.V. Sklifosovsky Federal Research Institute of Emergency Medicine

Email: likesport10@mail.ru
ORCID iD: 0000-0001-9640-201X
SPIN-code: 8290-5602

Junior Research Associate

Russian Federation, Bolshaya Sukharevskaya Square 3, Moscow, 129090, Russia

Irina I. Utkina

The Moscow Department of Health N.V. Sklifosovsky Federal Research Institute of Emergency Medicine

Email: irishka_utkina@list.ru
ORCID iD: 0000-0002-5685-4916
SPIN-code: 8105-7338

PhD in Medicine

Russian Federation, Bolshaya Sukharevskaya Square 3, Moscow, 129090, Russia

Sergey D. Varfolomeev

Institute of Physicochemical Foundations of the Functioning of Neural Network and Artificial Intellegence Moscow State University; Emanuel Institute of Biochemical Physics Russian Academy of Sciences;Department of Chemistry Moscow State University.

Email: sdvarf@bk.ru
ORCID iD: 0000-0003-2793-0710
SPIN-code: 7873-3673

PhD in Chemistry, Professor, Corresponding Member of the RAS

Russian Federation, Leninskie Gory, 1–11B, Moscow, 119991; Kosygina str, 4, Moscow, 119334; Leninskie Gory, 1–11B, Moscow, 119991

Anna M. Ryabokon

Emanuel Institute of Biochemical Physics, Russian Academy of Sciences; Department of Chemistry, Moscow State University

Email: amryabokon@gmail.com
ORCID iD: 0000-0001-9043-9129
SPIN-code: 7322-5643

PhD in Chemistry, Senior Research Associate

Russian Federation, Leninskie Gory, 1–11B, Moscow, 119991; Kosygina str, 4, Moscow, 119334

Alexander A. Panin

Society with limited liability "MEDTEHINNOVATSII"

Email: panin.alexander2009@yandex.ru
ORCID iD: 0000-0002-0114-4976

PhD in Economics

Russian Federation, Blagoveshchenskii per, 3-1, Moscow, 123001

Alexander G. Chuchalin

Pirogov Russian National Research Medical University

Email: pulmomoskva@mail.ru
ORCID iD: 0000-0002-6808-5528
SPIN-code: 7742-2054

MD, PhD, Professor, Academician of the RAS

Russian Federation, Ostrovityanova str. 1, Moscow, 117997

References

Supplementary files