A randomized clinical trial conducted by researchers from the Faculty of Medicine, Mansoura University – Egypt has found that inhalable sodium bicarbonate could be used as adjuvant in COVID-19 prophylactic and treatment protocols.
The study findings were published on a preprint server and are currently being peer reviewed.
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. 
In agreement with our hypothesis, Jimenez et al.  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.  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 . 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 .
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  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 .
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 , 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 . 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) .
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 .
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.  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 . 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 .
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%  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 .
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) . 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 . 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. , 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.
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.