A randomized controlled trial of adjuvant inhalable sodium bicarbonate role in treatment of COVID-19

doi:10.21203/rs.3.rs-2214180/v1

Entry of coronavirus (SARS-CoV-2) into a host cell is pH dependent. Intracellular alkalinization by sodium bicarbonate (SB) could elevate endosomal pH and block viral entry into the host cells. So, we assessed the role of inhalable SB as an adjuvant treatment for COVID-19 in the study groups of this randomized, controlled trial. Here we show a significantly shorter duration to clinical improvement and hospital stay in the study group, while the number of deaths is significantly less only in severe grade of the study group. But the time to death is not significantly different in both groups. CRP and d-dimer levels are significantly lower in the severe cases of the study group. The overall median CT score is significantly better in the study group at one & 2 months. Our data thus suggest that inhaled SB (8.4%) could be a possible adjuvant therapy for patients with moderate and severe COVID‑19 pneumonia.

Health sciences/Diseases/Infectious diseases

Health sciences/Diseases/Respiratory tract diseases

Biological sciences/Microbiology

Health sciences/Diseases

Covid-19

sodium bicarbonate

human

RCT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) pandemic resulted in 505,817,953 confirmed cases and 6,213,876 deaths around the world ^[1].

Several vaccines for COVID-19 have been approved to be highly effective in reducing the frequency of hospitalization and mortality. However inadequate, immunization coverage remains ^{[2, 3]}. In Egypt, a total of 80,130,948 vaccination doses have been delivered, but those who have received all of their vaccinations account for 32.7% of the population ^[4]. Even among t vaccinated population, the duration of protection and efficiency of the existing vaccines against developing SARS-CoV-2 variants remain questioned. Overall, we still in need of more effective COVID-19 therapy ^[5].

After the virus is recognized by the cell ACE2 receptor, a clathrin-mediated endocytosis pathway allows entry of the virus into the host cell. While inside the endosome, vacuolar acidification due to fusion with cell lysosomes promotes cleavage of the ACE2-S protein complex via cathepsin L, resulting in the fusion of the viral and endosomal membranes, releasing the viral nucleocapsid inside the cell ^{[6, 7]}. Drugs that interfere with membrane fusion or interact with clathrin, to raise the endosomal pH, may disrupt this process and prevent the viral genome release, hence blocking the viral replication ^{[8, 9]}.

Antiviral agents that target the host have the benefit of not being influenced by viral mutations ^[10]. In a prospective controlled study, published recently concluded that SB 8.4% inhalation with its nasal instillation could be a possible adjuvant therapy for patients with non-severe COVID-19 pneumonia ^[11]. Nevertheless, that study had several shortcomings, being nonrandomized, with limited number of patients and short duration of follow-up. Moreover, that study excluded mild and severe cases of COVID-19 and included moderate cases only identified according to CT findings

The current study was designed to avoid the disadvantages of the previous nonrandomized small study and to provide consolidated information regarding the role of inhalable SB as an adjuvant treatment of COVID-19.

Between -September 1st, 2021, and April 30, 2022, we recruited 956 patients presented with symptoms suggestive of COVID-19, a total of 546 fulfilled the inclusion criteria, completed the study, followed and analyzed as shown in the CONSORT flow chart (Fig. 1). The patients were randomly assigned into study group (n = 272) and control group (n = 274). Both groups were comparable in term of demographics, vaccination, co-morbidities, clinical presentation, COVID disease grades, severity of clinical presentation, laboratory parameters, and CT score. The place of treatment was also comparable among patients of both groups (Table1).

All cases of both groups completed one week of follow-up. A total of 238 patients of the study and 229 of the control groups completed one month of follow-up. At 2 months, 234 of the study and 220 of the control groups were available for analysis. Figure 1 shows the causes of dropouts.

Primary Outcomes

Primary outcomes are shown in table (2). The overall duration to clinical improvement was significantly shorter in the study group. This observation is maintained in all grades of the disease. For patients requiring hospital admission, the overall duration of hospital stay was significantly shorter in the study group. This significant difference was evident in moderate and severe grades but not in critical cases. The overall frequency of death was not significantly different between both groups. No mortality was reported in mild cases. The number of deaths was significantly less in severe grade of the study group, but this difference was not shown in moderate and critical cases of both groups. The time to death was not significantly different neither in the overall results nor in any of the grades of the disease.

Secondary Outcomes

At one week:

Clinical outcomes after one week are shown in table (3). A total of 32 cases from the study and 42 from the control groups can't be assessed because they were on mechanical ventilation. Overall clinical results showed that only expectoration score was significantly better in the study group. This significant difference was evident in moderate grade only. Other secondary clinical parameters in terms of SpO₂, respiratory rate, dyspnea score, and cough score were comparable in both groups. Laboratory and radiological parameters at one week are shown in table (4). Overall results showed that none of the laboratory parameters was significantly different between both groups. Nevertheless, the level of CRP was significantly lower in the severe cases of the study group. Moreover, the level of the D-dimer was significantly lower in mild and severe cases of the study group. The total WBC count was significantly lower in critical cases of the study group than in control group. The overall median CT score was not significantly different among both groups but was significantly better in moderate and severe cases of the study group.

At one month:

Clinical, laboratory, and radiologic secondary outcomes after one month are shown in table (5). The overall clinical results showed that SpO₂ was marginally significantly better in the study group. This significant difference was evident only in moderate cases. Overall results showed that none of the laboratory parameters was significantly different between both groups. The overall radiological results showed significantly better improvement of the CT score in the study group. This significant difference was observed in all grades of the disease except the mild and critical grades.

At 2 months:

Clinical, laboratory, and radiologic secondary outcomes after two months are shown in table (6). The overall clinical results showed that SpO₂ was significantly better in the study group. This significant difference was evident in moderate cases only. Laboratory variables were not significantly different among both groups in all grades of the disease. Overall radiological results showed significant improvement of the CT score of the study group. This significant difference was reported in moderate and severe cases. Examples of radiological profiles of the control and study groups are shown in figures (2–3).

The main idea of our research depends on the fact that the entry of SARS-CoV-2 into a host cell is pH dependent, since when the virus fuses with a human cell via the S glycoprotein, it is subsequently endocytosed into clathrin-coated pits and fuses with the endosomal membrane when the pH is lowered. ^[6]

In agreement with our hypothesis, Jimenez et al. ^[12] demonstrated that human primary monocytes cultivated in low pH showed increased ACE2 expression and a higher viral load for SARS-CoV-2 infection, indicating that pH has a significant impact on the severity of SARS-CoV-2 infection.

The plasma membrane in general, including alveolar epithelial cells, is permeable to CO2, whereas its conjugate base, HCO3, can only enter or exit through specialized membrane transport mechanisms such as Cl⁻/HCO3⁻ exchangers. Therefore, there is a relative demand for HC03 - for intracellular alkalinization that depends on an outwards-driven gradient for Cl. ^{[13– 15]} For HCO3 induced endosomal alkalinization, we depend on a study done by Xu et al. ^[16] who concluded that the Cl/HCO3 − exchanger is also present in endosomes and has a role in enhanced bicarbonate absorption, but their research involved medullary collecting duct cells.

Based on the theory that combination therapies using two or more direct-acting antivirals from different classes (e.g., a nucleotide analog as favipiravir or remdesivir plus a monoclonal antibody) will likely reduce the probability of mutant variants to emerge and may enhance the clinical benefit of treatment ^[17]. So, SB inhalation has been regarded as a safe add-on therapy to the standard treatment of COVID-19.

The present study is the continuation of what we published before on the role of SB inhalation as an adjuvant nontoxic tool for enhancing both clinical and radiological recoveries of non-severe COVID-19 pneumonia as a controlled randomized study including 182 patients ^[11]. But the present study, SB inhalation was added to conventional treatment in a randomized order to reduce bias, and a larger sample size of 546 patients, including all COVID-19 severity grades, was used. The study group received conventional treatment according to the protocol of the Egyptian Ministry of Health ^[18] as well as inhalation of SB 8.4% via jet nebulizer and nasal instillation, while the control group received only conventional treatment.

In our study, 22.2% of the cases were classified as having a mild illness, 46.7% as moderate, 22.3% as severe, and 8.8% as critical. COVID-19 has a wide variety of presentations, from asymptomatic to severe pneumonia with respiratory failure that can result in invasive mechanical ventilation and even death ^[19]. According to a report by the Chinese Center for Disease Control and Prevention during the first several months of the pandemic, which comprised roughly 44,500 confirmed illnesses, the following was discovered ^[20], 81% of cases were reported to have mild disease (no or mild pneumonia), 14% to have severe disease, and 5% to have critical disease. When the Omicron (B.1.1.529) variant of SARS-CoV-2 emerged, it marked a turning point in the COVID-19 pandemic. When compared to the previous version Delta (B.1.617.2), it has been observed to result in increased infection prevalence and lower disease severity in adults ^[21]. According to a study by Abdullah et al., ICU hospitalizations for the Omicron variant were 1% vs. 4.3% for prior waves (p < 0.00001) ^[22].

The average age of the 546 patients in this trial was 50.7 ± 16.8, with 215 men and 331 women participating. The following clinical symptoms were most frequently reported: bone ache (96.5%), headache (94.7%), fever (91.6%), cough (87.0%), sore throat (82.4%), dyspnea (81%), sputum production (57%), anosmia (58.4%), loss of taste (58.2%), dizziness (48.5%), and diarrhea (26.7%). In an observational study that assessed the reported clinical symptoms of 63,000 confirmed COVID-19 cases from two time periods (June to November 2021, when the Delta variant was most prevalent, and December 2021 to January 2022, when the Omicron was most prevalent), nasal congestion (77 to 82%), headache (75 to 78%), sneezing (63 to 71%), and sore throat (61 to 71%) were the most prevalent presenting symptoms ^[23]. COVID-19 can be presented by a variety of neurological manifestations, such as anxiety, depression, sleep problems, headache, dizziness, impaired sense of smell or taste. ^{[24, 25]}. In the present study, dizziness was a relevant symptom of COVID-19. Also, Aldè et al. ^[26] evaluated 1512 mild-to-moderate COVID-19 (765 females, 747 males), with a median age of 51 ± 18.4 years. They reported new-onset dizziness in 16.6% of patients, in the form of light headedness, disequilibrium, presyncope, and vertigo, in decreasing order.

The findings of this study showed that the addition of inhaled SB considerably shortened the duration to clinical improvement, with 3 days (2–18) in the study group and 5 (2–22) in the control group, respectively (p < 0.001). This improvement was maintained in all the grades. These findings are similar to a prior controlled non-randomized study by El-Badrawy et al., ⁽¹¹⁾.

As regards clinical assessment of the studied cases; the current study showed a limited role of SB inhalation in the mild grade. The virus travels from the nasal epithelium to the upper respiratory tract during this mild stage. The majority of patients do not progress past this stage because, at this time, the virus-infected cells release interferons (IFN-ß and IFN-λ), which trigger a sufficient immune response and halt the spread of infection ^{[19, 27]}.

The subjective clinical improvement was noticed only in the moderate grade of the study group starting from the first week, in the score of each of dyspnea, cough, and expectoration (p = 0.021, p = 0.009, and p = 0.002, respectively) as compared to the control group. For these direct-acting antivirals to be effective, they must be administered early during infection before the virus reaches its replication peak and are therefore used to prevent progression to severe disease. Direct-acting antivirals, in addition to corticosteroid and/or immunomodulatory medications, have a role in promoting viral clearance and, thus, reducing hyperinflammatory responses in the severe grade based on COVID-19 pathogenesis ^[28]. On the other hand, antivirals have been shown to be ineffective when administered late in critically ill patients who develop ARDS and diffuse alveolar injury. In these cases, anti-inflammatory medications may be more effective in managing the condition ^[29]. There was a statistically significant difference in SpO2 between the study and control groups at one and two months of follow-up, however this was only noticeable in moderate cases. It has little clinical significance because resting oxygen saturation is only regarded abnormal if it is less than 95% ^[30] and both groups' means were within normal range and practically comparable (97.8 ± 0.54 in the study group and 97.4 ± 0. 84 in the control group).

In this study, the COVID-19 related mortality rate was 13.5%. Although, SB inhalation didn’t significantly lower the overall frequency of COVID-19–related deaths (32 cases in the study group versus 42 cases in the control group, p = 0.224). The sub-analysis done according to the disease severity showed that the number of deaths was significantly lower in the severe grade of the study group (11 cases in the study group versus 22 cases in the control group, p = 0.014) and also in the moderate grade (one case in the study group versus 5 in the control group but without statistical significance). Notably, there was no impact of SB inhalation in the mortality detected in the critical cases (20 cases in the study group versus 15 cases in the control group, p = 0.335). this could be explained in part by the small number of critical cases.

A meta-analysis of 42 studies including 423,117 patients was conducted to study mortality-related risk factors for COVID-19. The analysis results showed that the pooled prevalence of mortality among hospitalized patients with COVID-19 was 17.6%. They came to the conclusion that a fatal outcome linked to COVID-19 is clinically predisposed by demographic factors such as male gender and older age; chronic comorbidities such as COPD, diabetes, hypertension, cardiovascular diseases, cancer, current smokers, and obesity; and complications such as respiratory failure, acute respiratory distress syndrome (ARDS), sepsis and septic shock, thromboembolism, and/or multi-organ failure ^[31]. In our analysis, the associated comorbidities were hypertension (28.4%), diabetes mellitus (20.1%), obesity (19.8%), ischemic heart disease (13.2%), smoking (12.8%), COPD (7.7%), hypothyroidism (7.7%), and bronchial asthma (6.2%). Despite the fact that all of the aforementioned mortality-related risk factors, such as age, gender, co-morbidities, disease severity, and basic inflammatory markers, were comparable between the study and the control group, they were not correlated to the mortality rate.

The level of D-dimer and CRP in our study showed variable results and were not useful to differentiate between the results of treatment of both groups but sub-analysis done according to the grade severity showed that CRP and D-dimer levels measured at one week were significantly improved with SB inhalation in the severe grade. In cases with severe pneumonia, lung injury is resulting from the cytokine storm and the subsequent inflammation where the virus-laden pneumocytes release many different cytokines and inflammatory markers such as interleukins (IL-1, IL-6, and IL-8), tumor necrosis factor-α (TNF-α), IFN-λ and IFN-β, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) and this was associated with elevated concentrations of inflammatory markers, including D-dimer, ferritin and C-reactive protein (CRP) ^[27]. However, as the COVID-19 infection subsides, one would anticipate a steady decline in both D-dimer and CRP blood levels. ^{[32, 33]}

CRP levels have been reported to be higher in severe cases than in non-severe patients, suggesting that the role of CRP levels as a biomarker of disease severity and progression in patients with COVID-19 ^{[34, 35, 36, 37]}. This is consistent with our findings, which showed the importance of inflammatory markers in monitoring the treatment response in severe cases as opposed to mild and moderate cases.

Several studies found a significant increasing trend in the counts of WBC, total lymphocytes, total T cells, CD4 + T cells, and CD8 + T cells, and the improvement of COVID-19 ^{[38, 39, 40]}. This study couldn't find the same significance of WBC and lymphocyte count in assessing the efficacy of treatment. Although the critically ill patients in the control group had a higher incidence of leukocytosis, which could be related to the sepsis that developed as a side consequence of severe COVID-19, this didn't affect the mortality rate between both groups, but this may help to explain why the clinical improvement in the study group's survivors was more rapid.

Higher CT scores are associated with worse outcomes, including a higher mortality risk, showing the importance of imaging when managing patients and evaluating their prognosis ^[41]. Both moderate and severe grades in the study group showed radiological improvement in the severity of lung involvement at all points of follow up; one week, one month and 2 months. However, there was no noticed radiological improvement in the critically ill cases of the study group when compared to the control group. In the context of that, the results of this study showed that SB inhalation significantly reduced the overall length of hospital stay for patients who needed to be admitted, but only in moderate and severe grades—not in critical cases. No hospitalization was required in mild-grade COVID cases. Although some of the mild cases in our study had radiological infiltrates during the follow up, all cases in both groups were minimal. According to Liu et al. ^[42], lung opacities in 53.0% of patients with mild COVID-19 disappeared without causing any negative side effects. Since fibrosis is the primary side effect of persistent infection and associated inflammation, it is crucial to reduce the viral load and, subsequently, the duration of viral pneumonia ^{[43, 44]}. At the 6-month follow-up, a chest CT revealed that almost half of patients who were recovering from severe COVID-2019 pneumonia had lung fibrosis. Age over 50, ARDS, noninvasive mechanical ventilation, a total chest CT score of 18 or higher on first CT scans, and a hospital stay of at least 17 days are all suggestive independent predictors ^{[45, 46]}. The significance of SB inhalation in this context should, therefore, be assessed following the correlation of the other risk factors mentioned above in future studies.

This study is the first RCT with adequately calculated sample size that sheds the light on the role of SB in the treatment of different grades of COVID-19.

Our study has some limitations. Stratification of the cases into 4 grades significantly reduced the sample size particularly in critical cases. The small sample size has resulted in type II statistical error that can explain failure to show significant statistical differences in variable parameters among patients of both treatment groups. We did not examine the relationship between co-morbidities and mortality rate to draw a firm conclusion on the absolute value of SB inhalation in lowering death in severe cases. We relied on laboratory and radiological results rather than measuring the viral load to determine the direct impact of SB inhalation. Multicenter studies with bigger number of patients with different grades of COVID-19 are invited to consolidate results of our current study as no previous similar randomized controlled trial.

In conclusion, Inhaled SB (8.4%) together with nasal drops is an effective adjuvant therapy for patients with COVID‑19 pneumonia, as it shortens the overall duration to clinical improvement, hospital stay for the admitted cases, improving their CT score, and lowering the mortality only in the severe grade of COVID‑19 pneumonia patients.

Setting and design:

The study was approved by the IRB (Institutional Research Board) of Mansoura Faculty of Medicine (code number: R.21.07.1376) and first registered 05/09/2021 in the clinicaltrial.gov, (ID: NCT05035524). A fully informed consent was obtained from all patients. All patients were treated according to the principles of Declaration of Helsinki.

The study is a randomized controlled trial that was carried out in our center between -September 1st, 2021, and April 30, 2022.

Patients were randomized by closed envelope technique in a 1:1 ratio and simply randomized without restrictions to either study group that received standard treatment plus SB or control group that received standard treatment only. We followed the principles of consolidated standards of reporting trials (CONSORT) reporting guidelines.

- Inclusion / exclusion criteria:

Inclusion criteria

adult patients with definite diagnosis of COVID-19 by reverse transcription- polymerase chain reaction assay (RT-PCR) with or without comorbidities. The study included all grades of COVID-19 according to the Egyptian Ministry of Health and Population ^[18] mild, moderate, severe, and critically ill.

Exclusion criteria

patients with negative RT-PCR, those under the age of 18 years, pregnant patients and those who refused to be included in the study or lost follow up.

- Initial assessment:

It included detailed history including history of contact with COVID − 19 cases and vaccination against COVID with routine clinical examination. Laboratory investigations included nasal or oral swab for COVID-19 RT-PCR, complete blood count, C- reactive protein (CRP) and D- dimer. Chest CT and image analysis was done according to Bernheim et al., ^[47].

- Treatment:

Standard treatment protocol was carried out according to the protocol of Egyptian Ministry of Health ^[18] for mild, moderate, severe and critically ill patients. Adjuvant treatment with SB was given for the study group according to El-Badrawy et al., ⁽¹¹⁾. Inhalation of SB 8.4% via an electric nebulizer (5 ml every 4 h) starting at 7:00 to 23:00 hours every day for 30 days together with instillation of SB 8.4% nasal drops 4-times daily (three drops for each nostril) were offered to all patients in the study group ^{[48, 49]}.

All patients were treated at home and were admitted to the hospital if they showed deterioration or no clinical improvement. Home isolation was done according to the European Center for Disease Prevention and Control ^[50]. For patients isolated in the hospital, clinicians adopted the appropriate personal protective measures as defined by our local infection control

- Follow up:

Follow up was carried out after one week, one month and 2 months. Duration of treatment varied according to the severity of the disease and tailored according to the response of the patients. COVID- 19 RT-PCR was repeated after one week. Other laboratory investigations were repeated at one week, one month and 2 months. Chest CT was repeated at the 3 time points of follow up except in mild cases, it was repeated if there was clinical deterioration.

- Outcome measures:

Primary outcomes of both groups included duration to clinical improvement that was defined as number of days from diagnosis until reporting a better feeling by the patients, duration of hospital stay for admitted patients, frequency of mortality and time to death.

Secondary outcomes were classified as clinical, laboratory and radiological measures. Clinical parameters were SpO₂, respiratory rate, cough score ^[51] dyspnea score ^[52] and expectoration score ^[53]. Clinical parameters were assessed only after one week except SpO₂ which was assessed at the 3 time points of follow-up as most of the admitted patients were discharged home before the end of the first month and SpO₂ was the only clinical parameter that was assessed and followed-up at home. Laboratory measures were total leukocytic count, percentage of lymphocytes, CRP and D- dimer.

Radiological Measures

included CT chest. The severity of lung involvement was evaluated according to Bernheim et al., ^[47].

- Chest CT protocol

Non-enhanced multi-detector CT (MDCT) chest examination done for all patients during end of inspiration in supine position, using MDCT scanners: SOMATOM go. Now (Siemens Heathinears Henkestraβe. 127, 91052 Erlangen Germany) on days 0,7, 30, and 60 days of randomization. The images were viewed on both mediastinal (window width, 350 HU; level, 40HU) and lung (window width, 1600 HU; level, − 600 HU) windows by an expert radiologist who was blinded to the treatment protocol. The imaging parameters used were as follows: 120 kVp, 100– 200 mAs, 3mm slice thickness, 1 mm section reconstruction, collimation, 0.625 mm, and pitch, 0.75–1.5.

- Image analysis

CT images for each patient were assessed for the following abnormalities: ground-glass opacity (GGO), nodules, consolidation, number of lung lobes affection, interlobular septal thickening, and pleural effusion. In cases of GGO and consolidation, the severity of the lung involvement was evaluated according to Bernheim et al. ^[47], with each of the five lung lobes assessed and scored for the degree of involvement and classified as: score 0, no involvement (0% affected); 1, minimal (1–25%); 2, mild (26–50%); 3, moderate (51–75%); and 4, severe (76–100%). A total severity score was obtained by summing the five lobe scores, with a range between 0 and 20. A score of 1–5 was graded as ‘minimal’, 6–10 as ‘mild’, 11–15 as ‘moderate’ and 16–20 as ‘severe’

- Sample size calculation:

The power of the study was calculated by using the G*Power program (University of Dusseldorf, Dusseldorf, Germany) to determine an adequate sample size based on previous trial ⁽¹¹⁾ that demonstrated a 15.7% clinical improvement with SB inhalation use. Using the prior test with accuracy mode calculation and an effect size convention of 0.15 for the chi-square test, with an error probability of 0.5, provided 93% power with expected 15% dropout rate for a total sample size of 551 patients.

- Statistical analysis:

We used two-tailed test. Continuous variables were presented as mean ± standard deviation (SD) when normally distributed and as median and range (min-max) when non-normally distributed. Nominal variables were presented as frequency and percentage. Comparison between variables of both groups was carried out by independent and paired sample Student^, s t-test, Mann-Whitney, Wilcoxon, Chi square and Fisher^, s exact tests as appropriate. A p value < 0.05 was considered statistically significant, where t = t value, and f = f value.

Data availability

The data associated with this study are available within the article, its supplementary information, and Source Data file. This trial is registered on ClinicalTrials.gov under the identifier NCT05035524. Source data are provided with this paper.

Author contributions

Mohammad Khairy El-Badrawy, Mohammed Shehta, Tamer Ali El-Hadidy, and Rehab Ahmad Elmorsey Contributed to the treatment of the cases. Mohammad Khairy El-Badrawy, Ahmed A. Shokeir, Tamer Ali El-Hadidy, and Rehab Ahmad Elmorsey prepared the scientific rational of the study. Adel El-Badrawy, performed and interpreted the CT. Ahmed A. Shokeir, Mohammad Khairy El-Badrawy, Rehab Ahmad Elmorsey, Mohammed Shehta, and Ibrahim El-Said Abdelwahab wrote the first draft of the manuscript. Ahmed A. Shokeir, and Rehab Ahmad Elmorsey performed the statistical analysis of the study. All authors read and approved the manuscript.

Competing interests

The authors declare that they have no conflicts of interest with the contents of this article.

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Table 1

Demographics and baseline characteristics
Variable	All patients (n = 546)	Study group (n = 272)	Control group (n = 274)	P value
Age, years, mean ± SD	50.7 ± 16.8	50.3 ± 16	51.1 ± 17.45	0.563
Sex (male/female) n	215/331	105/167	110/164	0.712
Days before examination, median (range)	7 (2–27)	8 (2–27)	7 (2–27)	0.353
Vaccination n (%)
No of received doses:
2 doses vaccination	34 (6.2%)	15 (5.5%)	19 (6.9%)	0.492
1 dose vaccination	76 (13.9%)	31 (11.4%)	45 (16.4%)	0.090
Types:
Sinovac	17 (3.1%)	5 (1.8%)	12 (4.4%)	0.087
Sinopharm	43 (7.9%)	21 (7.7%)	22 (8.0%)	0.894
Astra	50 (9.2%)	20 (7.4%)	30 (10.9%)	0.145
Co-morbidities n (%)
Lung cancer	2 (0.4%)	2 (0.7%)	0 (0.0%)	0.155
Rheumatoid disease	7 (1.3%)	4 (1.5%)	3 (1.1%)	0.696
Renal transplantation	3 (0.5%)	2 (0.7%)	1 (0.4%)	0.558
Liver transplantation	4 (0.7%)	3 (1.1%)	1 (0.4%)	0.312
Immune suppression	60 (11%)	26 (9.6%)	34 (12.4%)	0.287
Smoking	70 (12.8)	34 (12.5%)	36 (13.1%)	0.823
Hypothyroid	42 (7.7%)	19 (7%)	23 (8.4%)	0.537
Malignancy	4 (0.7%)	2 (0.7%)	2 (0.7%)	0.994
Hypertension	155 (28.4%)	70 (25.7%)	85 (31.0%)	0.171
Ischemic heart disease	72 (13.2%)	35 (12.9%)	37 (13.5%)	0.826
Bronchial asthma	34 (6.2%)	17 (6.2%)	17 (6.3%)	0.982
Chronic obstructive pulmonary disease	42 (7.7%)	18 (6.6%)	24 (8.8%)	0.348
Obesity	108 (19.8%)	48 (17.6%)	60 (21.9%)	0.212
Diabetes mellitus	110 (20.1%)	49 (18%)	61 (22.3%)	0.216
Clinical presentation n (%)
Sore throat	450 (82.4%)	224 (82.4%)	226 (82.5%)	0.968
Bone ache	527 (96.5%)	261 (96%)	266 (97.1%)	0.473
Headache	517 (94.7%)	257 (94.5%)	260 (94.9%)	0.833
Dizziness	265 (48.5%)	123 (45.2%)	142 (51.8%)	0.123
Anosmia	319 (58.4%)	155 (57%)	164 (59.9%)	0.496
Loss of taste	318 (58.2%)	153 (56.3%)	165 (60.2%)	0.347
Diarrhea	146 (26.7%)	73 (26.8%)	73 (26.6%)	0.959
Cyanosis	111 (20.3%)	55 (20.2%)	56 (20.4%)	0.732
Cough	475 (87.0%)	240 (88.2%)	235 (85.8%)	0.391
Expectoration	311 (57%)	158 (58.1%)	153 (55.8%)	0.596
Shortness of breath	442 (81%)	226 (83.1%)	216 (78.8%)	0.205
Crepitations	251 (46%)	129 (47.4%)	122 (44.5%)	0.496
Fever	500 (91.6%)	250 (91.9%)	250 (91.9%)	0.778
Wheezes	57 (10.4%)	25 (9.2%)	32 (11.7%)	0.342

Table 1

(continued) Demographics and baseline characteristics
Variable	All patients n = 546	Study group n = 272	Control group n = 274	P value
COVID severity grades, n (%)
Mild	121 (22.2%)	59 (21.7%)	62 (22.6%)	0. 944
Moderate	255 (46.7%)	125 (45.9%)	130 (47.4%)
Severe	122 (22.3%)	63 (23.2%)	59 (21.5%)
Critical	48 (8.8%)	25 (9.2%)	23 (8.4%)
Severity of clinical presentation
Cough score, median (min-max)	2 (0–3)	2 (0–3)	2 (0–3)	0.713
Expectoration score, median (min-max)	1 (0–2)	1 (0–2)	1 (0–2)	0.769
Dyspnea score, median (min-max)	2 (0–4)	2 (0–4)	2 (0–4)	0.541
Respiratory rate, (breaths/min), mean ± SD	23.193 ± 4.7464	23.210 ± 4.3876	23.182 ± 5.1051	0.947
SpO₂% on room air, mean ± SD	91.985 ± 5.3209	91.621 ± 5.6816	92.347 ± 4.9206	0.111
Temperature, ºC, mean ± SD	38.192 ± 0.6118	38.236 ± 0.6387	38.155 ± 0.5733	0.123
Laboratory results
Total leucocytic count/µl, mean ± SD	6487.85 ± 3727.885	6701.91 ± 3887.322	6257.41 ± 3555.839	0.164
Lymphocytes %, mean ± SD	23 ± 12.3	22.71 ± 11.9	23.13 ± 12.5	0.687
CRP (mg/L), median (min-max)	44.5 (1.27–240)	44 (1.65–240)	45 (1.27–200)	0.906
D-dimer (mg/L), median (min-max)	0.5 (0.10-3)	0.6 (0.1-3)	0.500 (0.1-3)	0.505
Platelets count/µl, mean ± SD	217.3 ± 74.44	216.4 ± 76.1	218.5 ± 73.1	0.742
HB gm/dl, mean ± SD	12.47 ± 1.7	12.47 ± 1.6	12.48 ± 1.75	0.917
Neutrophils %, mean ± SD	70.1 ± 14.6	70.77 ± 15.7	69.65 ± 13.33	0.369
CT score, median (min-max)	10 (0–20)	10 (0–20)	10 (0–20)	0.419
• Minimal, n (%)	121 (22.2%)	59 (21.7%)	62 (22.6%)	0.978
• Mild, n (%)	179 (32.8%)	88 (32.4%)	91 (33.2%)
• Moderate, n (%)	123 (22.5%)	63 (23.2%)	60 (21.9%)
• Severe, n (%)	123 (22.5%)	62 (22.8%)	61 (22.3%)
Place of treatment
Hospital treatment n (%)	181 (33.2%)	92 (33.8%)	89 (32.5%)	0.785
Home treatment n (%)	365 (66.8%)	180 (66.2%)	185 (67.5%)	0.785

Table 2

Primary outcomes in both groups
	All grades of COVID (n = 546)			Mild grade (n = 121)			Moderate grade (n = 255)			Severe grade (n = 122)			Critical grade (n = 48)
	Study	Control	P value	Study	Control	P value	Study	Control	P value	Study	Control	P value	Study	Control	P value
	(n = 272)	(n = 274)	P value	(n = 59)	(n = 62)	P value	(n = 125)	(n = 130)	P value	(n = 63)	(n = 59)	P value	(n = 25)	(n = 23)	P value
Days to clinical improvement
Mean ± SD	4.2 ± 2.5	5.8 ± 3.1	< 0.001	3.2 ± 0.9	4.5 ± 1.2	< 0.001	3.2 ± 0.9	4.8 ± 1.4	< 0.001	7.3 ± 3.3	9.5 ± 4.3	0.007	8.4 ± 2.5	13.8 ± 2.6	0.004
Median (min-max)	3 (2–18)	5 (2–22)		3 (2–6)	4.5 (2–7)		3 (2–7)	5 (2–12)		6 (3–18)	8 (5–22)		7 (6–12)	14.5 (8–16)
Hospital treatment:
No (%)	92 (33.8%)	89 (32.5%)	0.785				7 (5.6%)	9 (6.9%)	0.663	60 (95.2%)	57 (96.6%)	0.702	25 (100%)	23 (100%)
Hospital stay:
Mean ± SD	9.57 ± 4.6	12.2 ± 4.6	< 0.001				6.9 ± 3.6	13.9 ± 5.4	0.011	8.6 ± 4.2	11.5 ± 4.8	0.001	12.7 ± 4.5	13.4 ± 3.5	0.591
Median (min-max)	8 (5–25)	12 (5–25)					6 (5–15)	12 (8–23)		6 (5–22)	12 (5–25)		12 (6–25)	13 (8–21)
Days to death:
Mean ± SD	13.7 ± 4.01	14.3 ± 4.2	0.575				15	17.2 ± 5.1	0.715	13.5 ± 4.1	14.4 ± 3.9	0.543	13.8 ± 4.2	13.1 ± 3.9	0.636
Median (min-max)	14 (8–25)	14 (8–25)						17 (10–23)		12 (8–22)	14 (8–25)		14 (8–25)	12 (8–21)
Died cases: No (%)	32 (11.8%)	42 (15.3%)	0.224				1 (0.8%)	5 (3.8%)	0.109	11 (17.5%)	22 (37.3%)	0.014	20 (80%)	15 (65.2%)	0.335

Table 3

Secondary clinical outcomes in both groups after one week of treatment:
	All grades (n = 472)			Mild grade (n = 121)			Moderate grade (n = 249)			Severe grade (n = 89)			Critical grade (n = 13)
Results after one week	Study	Control	P value	Study	Control	P value	Study	Control	P value	Study	Control	P value	Study	Control	P value
Results after one week	n = 240	n = 232	P value	n = 59	n = 62	P value	n = 124	n = 125	P value	n = 52	n = 37	P value	n = 5	n = 8	P value
SpO₂%, mean ± SD	95.4 ± 2.4	95.2 ± 2.9	0.423	97.02 ± 1.5	97.2 ± 1.1	0.380	95.8 ± 1.7	95.5 ± 2.1	0.160	93.4 ± 1.9	92.9 ± 1.8	0.317	87.6 ± 2.5	86 ± 2.8	0.318
Respiratory rate, mean ± SD	20.1 ± 2.9	20.2 ± 4.1	0.668	18.2 ± 2.02	18.3 ± 1.9	0.845	19.6 ± 2.3	19.9 ± 3.9	0.514	22.9 ± 3.1	23.1 ± 4.01	0.755	24.4 ± 1.5	27 ± 4.8	0.269
Dyspnea score, median (min-max)	1 (0–4)	1 (0–4)	0.683	0 (0–2)	0 (0–2)	0.686	1 (0–2)	1 (0–3)	0.028	2 (2–4)	2 (2–4)	0.906	3 (3–4)	3 (3–4)	0.206
Cough score, median (min-max)	1 (0–3)	1 (0–3)	0.364	1 (0–2)	1 (0–2)	0.548	1 (0–2)	1 (0–3)	0.016	1 (1–2)	1 (1–2)	0.553	2 (1–3)	2 (1–2)	0.474
Expectoration score, median (min-max)	0 (0–2)	0 (0–2)	0.013	0 (0–1)	0 (0–1)	0.863	0 (0–1)	0 (0–2)	0.003	0 (0–1)	1 (0–2)	0.234	0 (0–2)	1 (0–1)	0.510.

Table 4

Secondary laboratory and radiological outcomes in both groups after one week of treatment:
	All grades (n = 546)			Mild grade (n = 121)			Moderate grade (n = 255)			Severe grade (n = 122)			Critical grade (n = 48)
Results after one week	Study	Control	P value	Study	Control	P value	Study	Control	P value	Study	Control	P value	Study	Control	P value
Results after one week	n = 272	n = 274	P value	n = 59	n = 62	P value	n = 125	n = 130	P value	n = 63	n = 59	P value	n = 25	n = 23	P value
Total WBC count/µl, mean ± SD	7638.9 ± 3173.1	8050.2 ± 3929.8	0.179	7070.9 ± 2190.1	6521.8 ± 2190.1	0.127	6999.8 ± 2715	7310.2 ± 3111.3	0.397	8772.7 ± 3805.3	9328.7 ± 4373.4	0.455	9318 ± 4167.2	13073 ± 5969	0.014
% Of lymphocytes, mean ± SD	27.4 ± 9.7	27.1 ± 10.2	0.669	31.9 ± 5.8	31.3 ± 6.3	0.584	30.6 ± 5.9	30.2 ± 7.8	0.591	23.8 ± 9.8	21.2 ± 11.8	0.201	10.2 ± 9.3	13.8 ± 8.2	0.242
CRP, median (min-max)	12 (1.17–192)	12 (1.2–220)	0.685	5 (1.17-48)	4.5 (1.2–50)	0.384	6 (1.2–112)	6 (1.2–150)	0.841	25 (10–120)	40 (12–220)	0.001	90 (12–192)	100 (22–200)	0.179
D-dimer, median (min-max)	0.3 (0.1–1.6)	0.3 (0.1-2)	0.247	0.3 (0.1–0.5)	0.3 (0.1–0.7)	0.041	0.3 (0.1–1.09)	0.3 (0.1–1.8)	0.278	0.3 (0.1–1.32)	0.5 (0.1-2)	0.001	1.1 (0.3–1.6)	1.2 (0.2–1.6)	0.643
CT score, median (min-max)	8 (0–20)	8 (0–20)	0.258	0 (0–5)	0 (0–8)	0.525	7 (0–17)	8 (0–20)	0.022	13 (9–20)	15 (9–20)	0.047	17 (15–20)	19 (14–20)	0.202

Table 5

Secondary outcomes in both groups one month after treatment
	All grades (n = 467)			Mild grade (n = 120)			Moderate grade (n = 245)			Severe grade (n = 89)			Critical grade (n = 13)
Results after one month	Study N = 238	Control N = 229	P value	Study N = 59	Control N = 61	P value	Study N = 122	Control N = 123	P value	Study N = 52	Control N = 37	P value	Study N = 5	Control N = 8	P value
SpO₂, Mean ± SD	97 ± 1.3	96.8 ± 1.4	0.050	97.7 ± 0.6	97.7 ± 0.6	0.827	97.3 ± 0.9	96.9 ± 1.12	0.002	95.9 ± 1.6	95.5 ± 1.4	0.220	95 ± 1.9	94.8 ± 2.2	0.837
Total WBC count/µl, mean ± SD	6374 ± 1426	6383± 1513	0.964	6076± 1342	6402 ± 1303	0.180	6546 ± 1391	6332 ± 1502	0.248	6215 ± 1510	6470 ± 1909	0.483	7364 ± 1722	6196± 1356	0.199
Lymphocytes%, mean ± SD	38.6 ± 6.5	39.6 ± 5.8	0.088	39.4 ± 6.5	38.8 ± 5.2	0.598	38.5 ± 6.9	39.4 ± 5.9	0.243	38.1 ± 5.9	40.7 ± 6.3	0.056	38 ± 4.5	43 ± 6.1	0.136
CRP median (min-max)	3 (0.25-26)	3 (0.2–50)	0.189	2 (0.25-12)	2 (0.2–15)	0.476	3 (0.25-24)	3 (0.2–21)	0.547	4.5 (0.25-12)	5 (0.25-50)	0.119	4 (2–26)	6 (4–30)	0.372
D-dimer, median (min-max)	0.2 (0.1–0.8)	0.2 (0.1–0.9)	0.763	0.2 (0.1–0.4)	0.2 (0.1–0.5)	0.921	0.2 (0.1–0.8)	0. 2 (0.1–0.9)	0.399	0.2 (0.1–0.5)	0.2 (0.14–0.4)	0.901	0.2 (0.12–0.5)	0.2 (0.12–0.3)	0.354
CT score, median (min-max)	2 (0–15)	3 (0–16)	0.001	0 (0–5)	0 (0–6)	0.935	2 (0–10)	4 (0–14)	< 0.001	5 (0–13)	8 (2–14)	< 0.001	12 (10–15)	13 (12–16)	0.650

Table 6

Secondary outcomes in both groups at 2 months of treatment:
	All grades (n = 454)			Mild grade (n = 116)			Moderate grade (n = 237)			Severe grade (n = 88)			Critical grade (n = 13)
Results at two months	Study	Control	P value	Study	Control	P value	Study	Control	P value	Study	Control	P value	Study	Control	P value
Results at two months	N = 234	N = 220	P value	N = 58	N = 58	P value	N = 118	N = 119	P value	N = 52	N = 36	P value	N = 5	N = 8	P value
SpO_2, mean ± SD	97.6± 0. 9	97.4± 0.9	0.004	97.9 ± 0.18	97.9 ± 0.28	0.246	97.8 ± 0. 54	97.4± 0. 84	< 0.001	96.9 ± 1.4	96.6 ± 0. 9	0.304	96.6 ± 1.1	96.3 ± 0.6	0.448
CRP, median (range)	2	2	0.213	2	2	0.556	2	2	0.339	3	4	0.101	3	4	0.349
CRP, median (range)	(0.25-12)	(0.2–12)	0.213	(0.25-6)	(0.2-6)	0.556	(0.3-6)	(0.2–10)	0.339	(0.5–6.6)	(0.25-12)	0.101	(3–12)	(3–12)	0.349
D-dimer, median (range)	0.2	0.2	0.534	0.2	0.2	0.691	0.2	0.2	0.277	0.2	0.2	0.556	0.2	0.2	0.318
D-dimer, median (range)	(0.1–0.4)	(0.1–0.5)	0.534	(0.1–0.3)	(0.1–0.5)	0.691	(0.1–0.4)	(0.1–0.4)	0.277	(0.1–0.4)	(0.14–0.4)	0.556	(0.2–0.4)	(0.15–0.3)	0.318
CT score, median (range)	0 (0–12)	1 (0–13)	< 0.001	0 (0–2)	0 (0–6)	0.554	0 (0–9)	2 (0–11)	< 0.001	3 (0–12)	6 (2–12)	< 0.001	10 (10–12)	11 (8–13)	0.706

No competing interests reported.

rawdatalfornature.xlsx

A randomized controlled trial of adjuvant inhalable sodium bicarbonate role in treatment of COVID-19

Status:

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Abstract

Figures

Introduction

Results

Primary Outcomes

Secondary Outcomes

Discussion

Patients And Methods