Conditions Favoring Increased COVID-19 Morbidity and Mortality: Their Common Denominator and its Early Treatment

Abstract

The factors contributing to increased morbidity and mortality in SARS-CoV-2 infection are diverse, and include diabetes, obesity, Chronic Obstructive Pulmonary Disease (COPD), advanced age, and male sex. Although there is no obvious connection between these, they do have one common denominator—they all have a tendency towards lower urine pH, which may indicate a lower-than-normal tissue pH. Furthermore, it has been shown that lower pH has two important negative influences: 1) it enhances viral fusion via the endosomal route, thereby facilitating viral multiplication; and 2) it facilitates increased production of inflammatory cytokines, thereby exacerbating the cytokine storm. This paper discusses published literature on lower tissue/interstitial pH in those diseases/co-morbidities that are known risk factors of severe COVID-19, and hypothesize that small doses of baking soda could be a simple, cost-effective, and rapid method of reducing both morbidity and mortality in COVID-19 patients.

Introduction

Morbidity and mortality with COVID-19 are increased with diabetes, obesity, chronic obstructive airways disease, advancing age, and in males. The common denominator is a tendency toward a lower urine or tissue pH, as listed here:

1. Diabetes. Patients with type 2 diabetes exhibited a significantly lower 24-hour urine pH (5.45 ± 0.27 versus 5.90 ± 0.42; P < 0.01),^{1, 2} and low urine pH is in itself an independent predictor of diabetes.³

2. Obesity in males. Obesity is significantly correlated with lower urinary pH (≤5.5) in men,^{4, 5} and urine pH shows a stepwise decrease with increasing Body Mass Index.⁶

3. Chronic Obstructive Pulmonary Disease (COPD). A consequence of hypercapnia due to alteration of gas exchange in COPD patients is an increase of H⁺ concentration.⁷

4. Advanced age. With increasing age, there is a significant increase in the steady-state blood H+ (p < .001), and reduction in steady-state plasma HCO3 (p < .001), indicative of a progressively worsening low-level metabolic acidosis.⁸ The decline of urine pH with age was highly significant. The fall in urine pH with age was monotonic, and, except for the final hexile in women, every hexile was significantly lower than the previous,⁹ and males.^{10, 11}

5. Urine pH reflects acid–base balance and is readily measurable.¹² Average urine pH is usually 6.0 - slightly acidic, but the normal range is 4.5 to 8.0. The pH of the blood is tightly regulated between 7.35 and 7.45. Plasma and interstitial fluid contain similar amounts of bicarbonate buffer, blood additionally has powerful pH buffering protein molecules such as haemoglobin and albumin. Because of this difference, interstitial fluid pH is more variable than that of plasma.¹ Consequently, in conditions with mild but not severe acidosis the normal pH range of interstitial fluids can vary much more than that of the blood.

This article highlights the possible role of low interstitial fluid pH in SARS-CoV-2 infections and explains the mechanisms by which the increased acidity that occurs in the five groups of people listed above may increase both morbidity and mortality in COVID-19.

There are two ways that increased interstitial fluid acidity may adversely affect COVID-19 prognosis: low pH enhances viral fusion and entry into cells via the endosomal route,^{13, 14} thereby facilitating viral multiplication, and low pH increases the production of inflammatory cytokines,¹⁵ exacerbating the cytokine storm and the dire consequences thereof.

Viral Fusion

For all enveloped viruses such as SARS-CoV-2, a critical event during the entry of the virus into cells is the fusion of the viral envelope with the membrane of the host cells,¹⁶ enabling viral multiplication.¹⁷ The process ends with transfer of viral genomes inside host cells, where viral replication takes place.¹⁴ Disruption of the SARS-CoV-2 fusion mechanism offers a potential therapeutic target.¹⁸

It has been shown that fusion of Corona viruses does not occur at neutral pH and that fusion activation is a direct low-pH-dependent process occurring within acidic endosomes. Little or no fusion occurred above a pH of 6.0. The pH optimum for fusion was 5.0 at 37°C, where fusion occurred rapidly.¹⁷ Viral fusion proteins undergo dramatic transitions during membrane fusion. For viruses such as SARS-CoV-2 that enter through the endosome, these conformational rearrangements are typically pH sensitive. A low pH enhances virus entry into the cell, facilitating viral replication and proliferation.¹⁹ Conversely, virus entry into cells is inhibited by inhibitors of pH-dependent endocytosis.¹⁷ It has previously been suggested that future antiviral approaches targeting coronavirus fusion may need to take into account a rapid virus-cell fusion reaction with a low-pH-dependent trigger.¹⁷

Inflammatory Cytokines and Low pH

There is strong evidence favouring the existence of links between acid-base balance and cytokine concentrations with acidosis as potential factor for the trigger threshold of the inflammatory response.¹⁵ The pH of the extracellular milieu affects a wide range of immunological functions,^{20, 21} with a lower pH enhancing cytokine production.^{22, 23}

There is also a body of evidence showing that low interstitial fluid pH is a common feature associated with the course of inflammatory reactions against pathogenic microorganisms in peripheral tissues.^24–26 These studies strongly suggest links between acid-base balance and cytokine concentrations, with low pH as a potential trigger of the inflammatory response.¹⁵

Low pH is among the most common abnormalities seen in patients suffering from severe pulmonary and systemic illness. In these patients, the mainstay of therapy is treatment of the underlying condition, and not correction of the pH. Although studies suggest that low pH itself has profound effects on the host, particularly in the area of immune function,²⁷ some consider the acidosis to be protective, especially in the presence of lung inflammation.²⁸

Increased mortality in COVID-19 patients is a consequence of the increased inflammatory response and the excessive cytokine production—the so-called “cytokine storm.” The loss of local control of the release of these cytokines leads to systemic inflammation and potentially deleterious consequences.²⁹ Studies analyzing cytokine profiles from COVID-19 patients have suggested that the cytokine storm correlates directly with lung injury, multi-organ failure, and the poor prognosis of severe COVID-19.³⁰ Reducing cytokine production during the management of COVID-19 patients would doubtless improve survival rates and reduce mortality.³⁰

Discussion

Abnormalities in systemic acid-base balance represent attractive targets for COVID-19 therapy. Interstitial fluid pH is easily altered and rendering its pH more alkaline may indeed alter both viral load¹⁹ and the immune response.²⁷ Interstitial fluid pH is easily rendered more alkaline by the oral administration of small doses of bicarbonate of soda. Normalizing the pH of the interstitial fluid in susceptible individuals may reduce both virus multiplication and cytokine production. One of the major factors affecting acidity is diet. Foods that make the urine more acidic include grains, fish, high protein foods, and sugary foods. Alkaline foods that reduce the acidity are nuts, vegetables, and most fruits. Changing to a more alkaline diet can reduce the acidity of the urine. Unfortunately, this takes time, and is of little help with COVID-19, as in COVID-19 the tissues must be made less acidic as quickly as possible after a positive COVID-19 test. It is easier and quicker to reduce the body’s acidity levels by taking bicarbonate of soda It is interesting to note that the use of bicarbonate of soda to treat viruses has a precedent—as long ago as the 1920s, bicarbonate of soda was widely used to treat flu. Now the flu virus is not a Corona virus, but what is important is that the flu virus also enters the cell by endocytosis in order to multiply—that is, it enters the cells by the same mechanism as the COVID-19 virus. Bicarbonate of soda is widely used as an antacid and millions of people use it regularly for dyspepsia without problems or adverse side effects. It is cheap, readily available at any grocery store without a prescription, and is safe in the recommended dose of a level teaspoon in warm water four times a day.

Viral replication occurs in most cases during the first week or so of being infected. Consequently, the use of bicarbonate of soda to reduce viral multiplication would only be beneficial during this period. The indications for its use in susceptible groups would be either a positive COVID-19 test or in patients with mild disease, preferably as soon as possible after on first onset of symptoms. It must be emphasized that there is no evidence that reducing the tissue acidity in susceptible individuals will prevent COVID-19 infection, and neither does the evidence suggest that it would be of any value once severe manifestations have developed. On the contrary, the presence of acidosis once lung inflammation is present may reduce mortality.²⁸

Conclusion

This manuscript presents evidence suggesting in patients with early COVID-19 infection, treating the mild acid/base imbalance as early as possible in the progression of the disease may impede virus fusion and replication, as well as slow down or reduce the inflammatory changes in general. This might be done safely and inexpensively with bicarbonate of soda. In COVID-19 patients with mild disease and risk factors, would alkalinization be a useful therapeutic strategy to prevent severe illness? Only time and more extensive research will tell. I’m saying it’s time for more extensive research to tell.