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.

REFERENCES:

[1] 2020–03–20_Gautret et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial; “Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.” LINK: https://www.sciencedirect.com/science/article/pii/S0924857920300996

[2] 2020–03–25_(ATP Science) Hydroxychloroquine: How does it kill the COVID-19 virus; “Endosomes are where viruses enter cells. For viruses to successfully enter the cells to infect them, they need a low pH (slightly acidic) environment. As hydroxychloroquine increases the pH, the medicine inhibits the virus infecting the cell.[3]”; “Hydroxychloroquine also reduces the replication of the virus. It achieves this feat by increasing the pH in another part of the cell, called the Lysosome. Increasing the pH in the Lysosome reduces the replication of COVID-19. This means the virus is unable to replicate in the cells, which is another mechanism by which hydroxychloroquine benefits the COVID-19 sufferer.[4]” LINK: https://atpscience.com/hydroxychloroquine-how-does-it-kill-the-covid-19-virus/

[3] 1999_De Voss et al., Iron Acquisition and Metabolism by Mycobacteria; “Iron is a prerequisite for in vitro growth of mycobacteria. Iron is an obligate cofactor for at least 40 different enzymes encoded in the Mycobacterium tuberculosis genome (8). Iron sequestration represents a formidable challenge to in vivo growth of pathogenic mycobacteria.”; “An important component of the mammalian host defense against bacterial pathogens involves restricting access of such organisms to iron (35).”; and “The serum of many mammals, including humans, is tuberculostatic because of its ability to sequester iron from the bacilli (32, 34). The addition of iron to such sera relieves the bacteriostatic effect completely. In a tragic attempt to rectify what was perceived as a debilitating iron deficiency in infected patients in Somalia, iron supplementation was found to actually promote the development of active tuberculosis (54). Other clinical studies in Africa have also established a strong correlation between dietary iron overload and an enhanced risk of death from tuberculosis (20, 52).” Link: https://jb.asm.org/content/181/15/4443

[4] 2020–04–10_Hana Levi Julian_Scientists Study Coronavirus Attack on Hemoglobin, Iron, & Test New Treatments with Old Standbys; “Chinese researchers Dr. Liu Wenzhong, PhD from Sichuan University of Science & Engineering and associate professor Hualan Li from Yibin University found the RNA of the virus codes for a number of non-structural proteins which then hijack the red blood cells and attack the hemoglobin, removing the iron ions from the “heme groups” (HBB) within the hemoglobin and replacing themselves in their stead.” LINK: https://www.jewishpress.com/news/us-news/ny/scientists-study-coronavirus-attack-on-hemoglobin-test-new-treatments-with-old-standbys/2020/04/10/

[5] 2020–04–13_(revised) Wenzhong et al., COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism; “The results showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide.” LINK: https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173

[6] 1999_Koletar et al., Azithromycin as Treatment for Disseminated Mycobacterium avium Complex in AIDS Patients; “Azithromycin is a useful alternative treatment for disseminated MAC [Mycobacterium Avium Complex] infection in AIDS patients. Symptomatic improvement correlates with measurable decreases in mycobacterial load.” LINK: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC89578/

[7] 2011_Renna et al., Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection; “We found that in primary human macrophages, concentrations of azithromycin achieved during therapeutic dosing blocked autophagosome clearance by preventing lysosomal acidification, thereby impairing autophagic and phagosomal degradation. As a consequence, azithromycin treatment inhibited intracellular killing of mycobacteria within macrophages and resulted in chronic infection with NTM [nontuberculous mycobacteria] in mice. Our findings emphasize the essential role for autophagy in the host response to infection with NTM, reveal why chronic use of azithromycin may predispose to mycobacterial disease, and highlight the dangers of inadvertent pharmacological blockade of autophagy in patients at risk of infection with drug-resistant pathogens.” [JDP comment — Long term use of azithromycin can result in a drug resistant mycobacterial infection, which then is free to propagate because the host immune system regarding cellular process of autophagy is impaired by the ongoing treatment with ineffectual azithromycin. Nevertheless, shorter term use of azithromycin would still be expected to be very effective for treating an active mycobacterial infection — even it the therapy is unable to clear the virus.] LINK: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163956/

[8] 2020_(Drugs.com) Azithromycin Dihydrate; “The antibacterial activity of azithromycin is pH related and appears to be reduced with decreasing pH.” LINK: https://www.drugs.com/pro/azithromycin-dihydrate.html

[9] 2009_Mestorino et al., Effect of pH on the Antibacterial Activity of Azithromycin and Penicillin against Staphylococcus Aureus; “The AZT [azithromycin] MIC [Minimum Inhibitory Concentration] was approximately 16 times higher at pH 5.0 than at pH 7.4.” LINK: https://www.researchgate.net/publication/263315124_EFFECT_OF_pH_ON_THE_ANTIBACTERIAL_ACTIVITY_OF_AZITHROMYCIN_AND_PENICILLIN_AGAINST_Staphylococcus_aureus

[10] 2014_Lee et al., Clinical relevance of ground glass opacity in 105 patients with miliary tuberculosis ; “MT patients with an extent of GGO >50% had more rapidly progressive manifestations and a greater potential for delayed diagnosis and poorer prognosis. Nevertheless, mortality was not higher in confirmed MT patients with an extent of GGO >50% than in those with an extent of GGO ≤50%.” LINK: https://www.sciencedirect.com/science/article/pii/S0954611114001255

[11] 1999_Erasumus et al., Pulmonary Nontuberculous Mycobacterial Infection: Radiologic Manifestations; “Nonclassic infection is the second most common form of pulmonary NTMB [Nontuberculous Mycobacteria] infection. Affected patients are typically elderly white women without underlying lung disease (,2,,18). . . Cavitation, ground-glass areas of increased attenuation, volume loss, and adenopathy are uncommon findings of nonclassic infection (,2).” LINK: https://pubs.rsna.org/doi/full/10.1148/radiographics.19.6.g99no101487

[12] 2014–03–29_Mirsaeidi et al., Management of Nontuberculous Mycobacterial Infection in The Elderly; “The incidence of nontuberculous mycobacteria (NTM) has increased over the last decades. Elderly people are more susceptible to NTM and experience increased morbidities.” LINK: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067452/

[13] 2020–02–25_Fernando J Bula-Rudas, Infections in the Immunocompromised Host; “An immunocompromised host is a patient who does not have the ability to respond normally to an infection because of an impaired or weakened immune system. This inability to fight infection can be caused by a number of conditions, including diseases (eg, diabetes, human immunodeficiency virus [HIV] infection), malnutrition, and drugs.” LINK: https://emedicine.medscape.com/article/973120-overview

[14] 2020_(Center for Disease Control) TB and Diabetes; “People with latent TB infection are not sick because the body is able to fight the bacteria to stop them from growing. People with TB disease are sick and have active TB because the body cannot stop the bacteria from growing. People living with diabetes who are also infected with TB are more likely to develop TB disease and become sick with TB. Someone with untreated latent TB infection and diabetes is more likely to develop TB disease than someone without diabetes.” LINK: https://www.cdc.gov/tb/topic/basics/tb-and-diabetes.html

[15] 2018_Huaman et al., The Relationship Between Latent Tuberculosis Infection and Acute Myocardial Infarction; “LTBI was independently associated with AMI. Our results suggest a potentially important role of LTBI in CVD.” LINK: https://www.ncbi.nlm.nih.gov/pubmed/29069328

[16] 2015_Hauman et al., Tuberculosis and cardiovascular disease: linking the epidemics; “Monocyte/macrophages, lymphocytes and cytokines involved in cellular mediated immune responses against Mycobacterium tuberculosis are also main drivers of atherogenesis, suggesting a potential pathogenic role of tuberculosis in CVD via mechanisms that have been described for other pathogens that establish chronic infection and latency. Studies have shown a pro-atherogenic effect of antibody-mediated responses against mycobacterial heat shock protein-65 through cross reaction with self-antigens in human vessels. Furthermore, subsets of mycobacteria actively replicate during latent tuberculosis infection (LTBI), and recent studies suggest that LTBI is associated with persistent chronic inflammation that may lead to CVD. Recent epidemiologic work has shown that the risk of CVD in persons who develop tuberculosis is higher than in persons without a history of tuberculosis, even several years after recovery from tuberculosis. Together, these data suggest that tuberculosis may play a role in the pathogenesis of CVD.” LINK: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729377/

[17] 2019–07–05_Segafredo et al., Integrating TB and non-communicable diseases services: Pilot experience of screening for diabetes and hypertension in patients with Tuberculosis in Luanda, Angola. ; “TB patients have a considerable hypertension and diabetes co-morbidity.” LINK: https://www.ncbi.nlm.nih.gov/pubmed/31276500

[18] 2012_Cecere et al., Regulatory T Cells in Arterivirus and Coronavirus Infections: Do They Protect Against Disease or Enhance it?; “Regulatory T cells (Tregs) are a subset of T cells that are responsible for maintaining peripheral immune tolerance and homeostasis . . . The function of inducible Tregs is presumably to maintain immune homeostasis, especially in the context of chronic inflammation or infection. Induction of Tregs in coronaviral infections protects against the more severe forms of the disease attributable to the host response.” LINK: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386620/

[19] 2020–03–14_ Wang et al., SARS-CoV-2 invades host cells via a novel route: CD147-spike protein; “Here, we reported a research finding that SARS-CoV-2 invaded host cells via a novel route of CD147-spike protein (SP). SP bound to CD147, a receptor on the host cells, thereby mediating the viral invasion.” LINK: https://www.biorxiv.org/content/10.1101/2020.03.14.988345v1

[20] 2020–04–07_Wang et al., SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion; “These results suggest that SARS-CoV-2 can also enter T lymphocytes through the receptor-mediated endocytosis pathway . . . it can be concluded that SARS-CoV-2 might infect T cells through S protein-mediated membrane fusion.” LINK: https://www.nature.com/articles/s41423-020-0424-9

[21] 2019–09–11_Cardona et al., Regulatory T Cells in Mycobacterium tuberculosis Infection; “In chronic infectious diseases there is a delicate balance between pro- and anti-inflammatory responses. While Th1 and Th17 are needed in order to control infection by Mycobacterium tuberculosis, the inflammatory onset can ultimately become detrimental for the host.”; “According to the World Health Organization, in 2017, 10 million people developed the disease and 1.6 million people died because of it (1). Compounding the situation, approximately a quarter of the world population is currently infected with Mtb (latent TB infection: LTBI) (2)”; “While progression from Mtb infection to active TB is associated with some known risk factors, including HIV infection and malnutrition, it is still unclear why some apparently healthy people develop the disease.”; “Regulatory T cells (Tregs), which suppress, and thus counterbalance the inflammatory response, are one such mechanism.” LINK: https://www.frontiersin.org/articles/10.3389/fimmu.2019.02139/full

[22] 2005_Wang et al., Mycobacterium tuberculosis inducing disseminated intravascular coagulation.; “. . . tuberculosis can cause DIC [disseminated intravascular coagulation] . . . the prognosis was very poor in patients not treated at an early stage, a high index of suspicion is required, especially in those with clinical findings suggestive of tuberculosis.” LINK: https://www.ncbi.nlm.nih.gov/pubmed/15841321

[23] 2020–04–09 (online publication date)_Giannis et al., Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past; “Preliminary reports on COVID-19 patients’ clinical and laboratory findings include thrombocytopenia, elevated D-dimer, prolonged prothrombin time, and disseminated intravascular coagulation.”; “Emerging data support that patients infected by this novel coronavirus [COVID-19] are at risk of developing disseminated intravascular coagulation (DIC) [4,7,8]. Increased D-dimer and fibrin degradation products levels, and prolonged prothrombin time have been associated with poor prognosis in patients affected by the novel coronavirus [8]. Tang et al. reported that 15 out of 21 non-survivors (8% of the total cohort) developed overt DIC (≥5 points) according to the International Society on Thrombosis and Haemostasis diagnostic criteria [8].” LINK: https://www.sciencedirect.com/science/article/pii/S1386653220301049