The coronavirus COVID-19 potentially activates preexisting mycobacteria in a coinfection scenario.
By John D. Peabody III, PhD., Esq.
April 26, 2020*
At least some of the coronavirus pandemic morbidity may be attributable to an indirect second order effect that is based on coinfection with a mycobacteria. The mycobacterial infection is a preexisting condition that may be active or a latent-persistent untreated infection and includes both tuberculosis and non-tuberculosis mycobacterial infections.
The ongoing coronavirus pandemic appears to be caused by a coronavirus infection (now dubbed COVID-19) that in some patients causes rapid extreme lung damage and results in terminal pulmonary system failure. There is growing compelling evidence that experimental off-label use of two old drugs in combination (hydroxychloroquine an old antimalarial drug and azithromycin a macrocyclic antibiotic) can be useful for treatment and/or prophylaxis of acute severe COVID-19 coronavirus infections. [1]
The question is why would an antiparasitic (hydroxychloroquine) and an antibiotic (azithromycin) alone or in combination have antiviral activity against this specific coronavirus? It would be extremely unlikely that two old antimicrobial drugs with historically different (typically non-antiviral activities) would by serendipity have a direct antiviral effect (i.e. have direct antiviral biological activity) against the COVID-19 virus. This question naturally leads us to considering the potential mechanism of action of hydroxychloroquine/azithromycin in severe presentations of the COVID-19 infection.
The current thinking (not the only one) is that a side-effect of hydroxychloroquine is responsible for an indirect COVID-19 antiviral effect and azithromycin (a broad spectrum antibiotic) is along for the ride simply as a precaution to prevent potential bacterial infection of the lungs [2]. This is a good start at unpacking the situation, but I am not so sure this really gets at what is happening or explains why in certain patients there can be a sudden progressive unstoppable catastrophic degradation in pulmonary function and other organ failure.
My sense is that simple idiopathic coronavirus viremia is entirely inadequate at this point to explain the ongoing instances of extreme morbidity of COVID-19 infection in certain patients. A possible theory for COVID-19 pathology can be inferred and correlates nicely with the appropriate understanding of a cooperative mechanism of action of the combination of hydroxychloroquine and azithromycin that is consistent with the well-known biological activities of these drugs, in the context of a potential pre-existing coinfection (e.g. mycobacterial infection).
The mounting circumstantial evidence points to coinfection by COVID-19 with a preexisting mycobacterial infection that can supercharge the latter so as to cause rapid conjoined bacterial and viral based pulmonary damage and other organ failure. Connecting the circumstantial evidence goes as follows:
(a) Mycobacterial infections (including tuberculosis) exist either as active or persistent latent infections in a certain segment of the population.
(b) Mycobacteria need a source of free-ionic iron to support microbial processes in order for the infection to proliferate in the host system. [3]
(c) Normal human blood plasma concentrations of free-ionic iron is low and therefore is bacteriostatic to mycobacteria (i.e. normally low iron concentration in healthy human blood plasma does not support (rapid) propagation and growth of mycobacteria).[3]
(d) COVID-19 infection labilizes iron that is bound in hemoglobin in red blood cells, thereby destroying the ability of human blood to carry oxygen [4][5], and at the same time drastically and rapidly increasing the plasma concentration of free ionic iron.
(e) Increased free ionic iron plasma concentrations caused by COVID-19 infections is essentially rocket fuel for a pre-existing mycobacterial coinfection. The iron released from destructive action of COVID-19 essentially supercharges existing mycobacterial pathology that then results in lung damage and pulmonary failure (as well as potentially other organ failure).
(f) Azithromycin is active against mycobacterial infections. [6] [N.B. 7]. Also, it is known that the antimicrobial activity of azithromycin is pH related and is enhanced by increasing pH [8][9].
(g) The combination of hydroxychloroquine with azithromycin enhances the antimicrobial activity of the later by increasing the pH in the intracellular microenvironment.
(h) Computed Tomography (CT) scans of COVID-19 patients show “ground glass opacity” in the lungs. Ground glass opacity radiology findings are known to correlate with many infectious processes, including potentially miliary tuberculosis and nontuberculosis mycobacterial infection. [10][11]
HIV patients logically are the prototype group of individuals that have a higher incidence of active or latent persistent mycobacterial infections because of obvious host immune system suppression. The link is clear between immune suppression and incidence of mycobacterial infection. However, a much larger population group of patients at risk of having active, untreated, subclinical and/or latent/persistent mycobacterial infections are aging baby-boomers with degraded immune systems due to aging and other factors. Another risk group that have potential immune suppression are indigent or underserved demographic population groups that are known to have higher incidence of untreated mycobacterial infections. All of these groups are potentially at risk of having acute lethal coronavirus infection that induces the pre-existing mycobacterial infection break-out so as to create rapid extreme and terminal morbidity that is not limited simply to pulmonary system failure.
All the main risk factors listed for acute severe COVID-19 — that is age, diabetes, cardiovascular disease (CVD) and hypertension can be (potentially) linked to an underlying immunocompromised condition involving the existence of either active mycobacterial disease or latent/persistent mycobacterial infection. In addition to age being a risk factor for active or latent mycobacterial infection [12], diabetes patients are also known to be immunocompromised and susceptible to serious non-tuberculosis mycobacterial infection. [13][14] Similarly, CVD has been linked to both tuberculosis disease and latent persistent tuberculosis mycobacterial infection. [15][16] Hypertension and diabetes co-morbidity have been linked to TB infection. [17]
Risk factors for serious acute COVID-19 outcomes all seem to point to and suggest coinfection with a mycobacterium. The surprising therapeutic utility of the combination of hydroxychloroquine and azithromycin provides a compelling inferential mechanism for COVID-19 acute disease pathology whereby virus infection of red blood cells liberates ionic iron that supercharges and activates a mycobacterial coinfection.
In the past it was found that “induction of Tregs [regulatory T-cells] in coronaviral infections protects against the more severe forms of the disease attributable to the host response.”[18] However, recently it has been discovered that COVID-19 appears to be somewhat different in that it is able to infect (and destroy) T-cells by possibly one or more entry mechanisms [19][20]. It can be hypothesized that the concomitant COVID-19 infection of host red blood cells and host T-cells potentially disrupts and degrades the delicate (pre-existing) immune response balance that otherwise keeps the mycobacterial coinfection substantially in check in some patients. [see also 21]
It is possible that acute severe COVID-19 infection results in unrecognized, undiagnosed activated and untreated mycobacterial coinfection in patients that results then in devastating disseminated intravascular coagulation (DIC). DIC in tuberculosis patients is known to have an extremely poor prognosis [22] which is consistent with what has been seen in the clinic with certain COVID-19 patients [23].
Understanding that the coronavirus pandemic morbidity may be attributable at least in part to a second order effect that is based on coinfection with a mycobacteria may be critical to identifying and deploying in the short-term off-the-shelf counter measures (chemotherapeutic and/or vaccine) that will immediately save lives and potentially arrest the panic associated with extreme manifestations of the COVID-19 pandemic.
*This article was written on April 17, 2020 and submitted as an Op-Ed commentary to a news outlet but was considered too advanced and challenging for a general newspaper reader. Even though it is a bit technical and perhaps a dry read, I believe it is a time sensitive piece that discloses a critical theory and mechanism regarding COVID-19 acute morbidity that needs to be put in the public domain. My hope is that it will motivate others to think outside the box and advance ideas that will support a useful unified understanding of what COVID-19 is/ is doing.