DT News - India - Severe form of COVID 19: Mainly a vascular disease? Can 'Anaerobic Bacteria Hypothesis' explain it?

Rajeev Chitguppi, Dental Tribune South Asia

Tue. 5 May 2020

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Sandeep Chakraborty (B-Tech, Electrical Engineering IIT Kharagpur, 1997), (Masters. Computer science, IIT Kharagpur, 2008) is a researcher focused on computational protein modelling, genome projects, and designing anti-microbial peptides. Dental Tribune South Asia had earlier published his interview where he had highlighted his observations, saying that we should focus on the role of anaerobic bacteria like Prevotella causing COVID complications - "Metagenomic data of COVID19 patients from across the globe shows a certain distinct pattern- anaerobic bacteria (Prevotella primarily) seem to predominate, i.e. there is a disruption of balance (homeostasis) with aerobic counterparts." Does the emerging evidence, which shows that COVID 19 could be primarily a vascular disease add credence to his bacterial hypothesis? Read the second part of the interview.

Dental Tribune had published Sandeep Chakraborty's first interview a few days back. Click here to read it

Interview -2:

Many people are now classifying COVID19 as primarily a vascular disease?

Yes - disseminated intravascular coagulation (DIC). DIC is a serious disorder characterized by small blood clots developing throughout the bloodstream, blocking small blood vessels, depleting platelets and clotting factors, leading to excessive bleeding. Several studies are reporting that COVID19 is more of a vascular problem than one of the lungs [1–3]. Preliminary studies also suggest that diffuse bilateral pulmonary inflammation is a lung-specific vasculopathy - pulmonary intravascular coagulopathy (PIC) - which is distinct from DIC [4]. International Society on Thrombosis and Haemostasis (ISTH) has issued interim guidance for recognition and management of coagulopathy, specifically to monitor blood clotting markers [5].

What is your hypothesis - and how does it align with the DIC observation?

Based on sequencing data from COVID19 patients from across the globe, I have noticed a distinct pattern - the virus SARS-CoV2 is enabling anaerobic bacteria (Prevotella mostly) to disrupt the homeostasis in its favour [6]. These bacteria are known to cause many of the symptoms associated with COVID19 - but the correlation was not conclusive. Until, serendipitously I found another disease - Lemierre’s syndrome - where an anaerobic bacteria was the cause of DIC in many patients [7–12].

What is Lemierre’s Syndrome?

Lemierre (1875-1956) was a French bacteriologist. In a seminal paper in 1936 [13] title ‘On certain septicaemias due to anaerobic organisms’, he described for the first time what was an infection driven by anaerobic bacteria (usually Fusobacterium), mostly in children and young adults. The bacteria first infect the peritonsillar blood vessels and then the internal jugular vein, wherein a bacteria-containing thrombus (blood clot) is formed. This clot can disseminate to other parts of the body (lungs, liver, spleen, kidneys and nervous system) where they can form abscesses and blood blockages. I hypothesize something very similar is happening in COVID19.

So is COVID19 the same as Lemierre’s Syndrome?

No, there is a very fundamental difference - the anaerobic colonization in COVID19 begins in the lungs, whereas in Lemierre’s Syndrome its in the jugular vein. For this reason, I believe, COVID19 would be much more benign and easier to treat, it does not have direct access to a blood vessel (as the jugular vein would). This is also, again a hypothesis, why ventilators are proving to be worse - they are making the lungs (alveoli) come in contact with the surrounding blood capillaries.

Are there any other similarities between the two diseases?

Actually yes - a very interesting similarily. Lemierre’s Syndrome is preceded (enabled) by Epstein Barr virus, while COVID19 is enabled by the SARS-Cov2 [11, 14–16]

What about theories that the SARS-CoV2 itself is attacking the haemoglobin?

Well, the paper that made waves with this theory was a computational modelling study, which is often inaccurate [17]. There is another reason. For SARS-Cov2 to break the haemoglobin using its proteins, it has to enter red blood cells (let's assume it can do that) and then make proteins from its DNA using the cell machinery. But, RBCs have no nucleus - and thus can't make proteins. Some studies have shown some weak protein synthesis within RBC’s - but the chances are low. Also most importantly, deep sequencing of 3 blood samples did not yield any virus in a study from China [18]. If the virus was indeed breaking haemoglobin, this would be a much deadlier pandemic.

So what, in your opinion, is responsible for haemoglobin degradation leading to DIC?

One possibility is the cytokine storm (though some papers are refuting there is a storm [19]) can lead to such vascular damage. However, these bacteria express haemoglobin degrading proteins [20], heme-binding proteins sequestering heme after haemoglobin degradation [21], ‘plundering‘ iron, and thereby sequestering oxygen [22]. And a very important enzyme - hemagglutinin, which causes thrombus formation, initially in venules and then in arterioles. SARS-CoV2 does not have hemagglutinin - but you know which virus has? Influenza! The virus was responsible for the ’Spanish” influenza’ pandemic in 1918. And that seems a more plausible hypothesis. And this is not just theoretical - these proteins are being expressed in patients, as observed from the sequencing data.

What are COVID toes - are they related to DIC?

COVID toes are cutaneous manifestations of COVID-19 - these are skin rashes, lesions around the hands and feet, which could be painful or itchy Early reports are linking this to asymptomatic children. A recent study shows a similar manifestation (ischemia in the legs and the arms) in an adult diagnosed with Lemierre’s syndrome [10].

Do you think COVID toes is the Kawasaki disease, as is being reported?

Well, many diseases have overlapping symptoms - so finding an exact name may be difficult. And quite unnecessary too. But the exact cause for Kawasaki disease has not been found - linked to genes, viruses, bacteria, chemicals, are all possibilities. Whereas Lemierre’s Syndrome is known to be caused by anaerobic bacteria - even Prevotella [23] - the bacteria that started it all for me in COVID-19 [6].

Competing interests: No competing interests were disclosed.

References

1. Tang N, Li D, Wang X, Sun Z (2020) Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. Journal of Thrombosis and Haemostasis.

2. Cui S, Chen S, Li X, Liu S, Wang F (2020) Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. Journal of Thrombosis and Haemostasis.

3. Kollias A, Kyriakoulis KG, Dimakakos E, Poulakou G, Stergiou GS, et al. (2020) Thromboembolic risk and anticoagulant therapy in COVID-19 patients: Emerging evidence and call for action. British Journal of Haematology.

4. Fogarty H, Townsend L, Ni Cheallaigh C, Bergin C, Martin-Loeches I, et al. (2020) Covid-19 coagulopathy in caucasian patients. British Journal of Haematology.

5. Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, et al. (2020) Isth interim guidance on recognition and management of coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis.

6. Chakraborty S (2020). Sars-cov2 enables anaerobic bacteria (Prevotella, et al) to colonize the lungs disrupting homeostasis - symptoms (ARDS, septic shock, blood clots, arterial stroke) finds resonance with key differences, in the ‘forgotten disease’ Lemierre syndrome, caused by anaerobic bacteria enabled by Epstein Barr virus. doi:10.31219/osf.io/usztn. URL osf.io/usztn.

7. Potter M, Drysdale H, Price P, Buck A (1988) Disseminated intravascular coagulation with fusobacterium necrophorum septicaemia. Postgraduate medical journal 64: 155–156.

8. Hagelskjaer L, Prag J, Malczynski J, Kristensen J (1998) Incidence and clinical epidemiology of necrobacillosis, including Lemierre’s syndrome, in Denmark 1990–1995. European journal of clinical microbiology and infectious diseases 17: 561–565.

9. Khan A, Ganesan S, Arora M, Hussain N (2013) Life-threatening complication of sore throat: Lemierre’s syndrome. The Indian Journal of Pediatrics 80: 1059–1061.

10. Surapaneni BK, Omar H, Iguina MM, Suarez M (2020) Fusobacterium necrophorum septicemia leading to Lemierre’s syndrome in an immunocompetent individual: A case report. Cureus 12.

11. Rae J, Misselbrook K (2017) Lemierre’s syndrome–a rare cause of disseminated sepsis requiring multiorgan support. Journal of the Intensive Care Society 18: 329–333.

12. Page Y, Comtet C, Tardy B, Zeni F, Thevenet D, et al. (1990) Disseminated intravascular coagulation in fusobacterium necrophorum septicemia. Scandinavian journal of infectious diseases 22: 743–747.

13. Lemierre A (1936) On certain septicaemias due to anaerobic organisms. The Lancet 227: 701–703.

14. Boz G, Iskender S, Caylan R, Aydin K, Koksal I (2005) A case of Lemierre’s syndrome following Epstein–Barr virus infection. Anaerobe 11: 185–187.

15. Chacko E, Krilov L, Patten W, Lee P (2010) Lemierre’s and Lemierre’s-like syndromes in association with infectious mononucleosis. The Journal of Laryngology & Otology 124: 1257–1262.

16. Allen BW, Bentley TP (2019) Lemierre syndrome.

17. Wenzhong L, Hualan L Covid-19: Attacks the 1-beta chain of haemoglobin and captures the porphyrin to inhibit human heme metabolism. chemrxiv. 2020. Preprint https://doi org/1026434/chemrxiv 11938173: v6.

18. Xiong Y, Liu Y, Cao L, Wang D, Guo M, et al. (2020) Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Available at SSRN 3549993
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19. Leisman DE, Deutschman CS, Legrand M Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Medicine: 1.

20. Guan SM, Nagata H, Shizukuishi S, Wu JZ (2006) Degradation of human haemoglobin by Prevotella intermedia. Anaerobe 12: 279–282.

21. Tong Y, Guo M (2009) Bacterial heme-transport proteins and their heme-coordination modes. Archives of biochemistry and biophysics 481: 1–15.

22. Ndongo S, Khelaifia S, Lagier JC, Raoult D (2019) From anaerobes to aerointolerant prokaryotes. Human Microbiome Journal: 100068.

23. Garza-Alatorre A, Hern ́andez-Rosales C, Rodr ́ıguez-Coronado J, Sol ́ıs-Gonz ́alez MC, Balderrama- D ́avila R, et al. (2015) Atypical Lemierre’s syndrome caused by prevotella oris. Medicina universitaria 17: 218–221.

About Sandeep Chakraborty:

Sandeep Chakraborty is a researcher & independent consultant who completed his B-Tech in Electrical Engineering from IIT Kharagpur (1997), and Masters in Computer science again from IIT Kharagpur (2008). He has worked in the semiconductor industry for companies like nVidia (Santa Clara, USA) and Mentor Graphics (Noida, India) for more than a decade. Since 2010, he has changed his career course and focused on research in computational protein modelling working with Dr BJ Rao in TIFR, Mumbai. Subsequently, he has collaborated with Dr Abhaya Dandekar (UC Davis, USA) on several projects (Walnut genome assembly, designing new anti-microbial peptides) working at UC Davis as an associate specialist. Currently, he works as an independent consultant.

Peer-reviewed publications: 30+

https://scholar.google.com/citations?user=6ZmR8DsAAAAJ&hl=en

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