Thread by @ashwinrajenesh

(1/n) Thread: Epi-immuno-pathogenesis of #BlackFungus, misnormer for #Mucormycosis.
As of 26th of May 2021, India had noted close to 12,000 cases of Mucor along with the #COVIDSecondWave.
The centre has advised it a notifiable disease under Epidemic act.
pib.gov.in/PressReleseDet…

(2/n) Pre #COVID19India, Mucor in India was almost exclusive to patients with uncontrolled diabetes, and usually presented along with DKA.
The other subset was among profoundly immuno-compromised hosts and iron overload states.

(3/n) Interestingly, different etiological risk factors cause various clinical presentations of mucor.
- Diabetes with Rhino-orbital disease
- Solid organ transplant recipients with pulmonary disease
- Disseminated disease in hematological malignancies
doi.org/10.1016/j.cmi.…

(4/n) - The point to note is that our immune system is complex and involves multiple interconnected pathways.
The above three risk factors suppress different aspects of our immunity. Hence the varied clinical disease caused by the similar organisms.

(5/n - For non medics) The human immune system compromises of both an innate system as well as a acquired (AKA adaptive) system.
The innate is non-specific first line defense.
The adaptive system is specific and compromises of B-cell (Humoral) and T-cell (Cellular) systems.

(6/n) Mucorales are an ubiquitous fungi order. Among the mucorales, Rhizopus, Mucor, and Rhizomucor are the main genera causing infections in humans.
They are opportunistic fungi causing infection in immuno-supressed individuals, especially when innate immunity is affected.

(7/n) In an immuno competent individual, the spores reaching the upper respiratory mucosa is cleared by cilia to the nasopharynx and ingested and are cleared via the GI tract.
Spores breaching mucosa are cleared by phagocytois.

mdpi.com/2309-608X/3/3/…
mdpi.com/2309-608X/6/3/…

(8/n) The ability of Mucorales to establish disease within the human host begins at the failure of the innate immune system to kill fungal spores and halt fungal germination, thus ceasing to limit the expansion of disease.
academic.oup.com/cid/article/54…

(9/n) Mucorales adheres to and invades endothelial cells by specific recognition of the host receptor glucose-regulator protein 78 (GRP78).
This recognition causes host cellular death by induction of the endothelial cell–mediated fungus endocytosis.

(10/n) Now, induced immunosupression for solid organ transplant such as steroids affects primarily T cell subset of adaptive immunity.
Whereas neutropenia (Low PMN among WBC) common in hematological malignancies affect innate immunity and thus cause disseminated disease.

(11/n)
Uncontrolled diabetes doesn't just create a sugary medium for micro-organisms to grow in. It incapacitates the immune system manifold.

So how does uncontrolled diabetes affect the immunological mechanism and cause susceptibility to infections?

(12/n)
1. Suppression of cytokine production
2. Defect in leukocyte recruitment
3. Defect in pathogen recognition
4. Neutrophil dysfunction
5. Macrophage and monocyte dysfunction
6. NK cell dysfunction
7. Inhibition of antibody and complement effector.
ncbi.nlm.nih.gov/pmc/articles/P…

(13/n) Mucor in DKA:
A unholy cocktail of acidosis, hyperglycemia, iron overload in the endothelial cells causing an upregulation of GRP78 protein.
journals.plos.org/plospathogens/…

(14/n) Rhino-orbital +/- cranial mucor.
This is the predominant variety that we are seeing associated with the COVID second wave in India similar to the clinical presentation seen in DKA.
Nasal mucosal angio infiltration, microthrombosis, infarction and necrosis.

(15/n) Causes linking the Mucor outbreak to COVID are postulated.
The first two seem likely in the current setting:
1. Steroid misuse
2. Uncontrolled diabetes and hyperglycemia secondary to steroids, pancreatic dysfunction.

https://twitter.com/VincentRK/status/1398114145371893773?s=20

(16/n)
3. Steam inhalation: Also likely to be contributory considering that it can cause burns to the nasal mucosa, affecting innate immunological barriers and facilitating the epithelial breach for fungal invasion.

https://twitter.com/IndiaToday/status/1396889895616999425?s=20

(17/n)
4. Zinc supplementation:
Indian poly-pharmacy has been exposed during the COVID outbreak. Zinc was almost universally prescribed.
Iron stores and zinc can facilitate growth of saprophytic fungi. Likely contributory at best.

https://twitter.com/RajeevJayadevan/status/1396031337685942273?s=20

(18/n)
5. Oxygen humidifiers, delivery systems, industrial O2.
Very unlikely.
Mucorales are not colonizers in fluid environments. Like bread mold, it needs damp, humid, air exposed devitalized tissue to germinate.

https://twitter.com/JacquesMeis/status/1396744938671513601?s=20

(19/n)
@RajeevJayadevan mentioned the need to identify the "Third factor" causing the Mucor outbreak with the COVID second wave, almost exclusively in India.
The above list fails to explain a crucial linking phenomena.

https://twitter.com/IndiaToday/status/1396712659836231680?s=20

(20/n)
The SARS-2-CoV viral disease activity in itself seems to be directly linked to the increased incidence of Mucor.
This could be macrophage dysfunction, adaptive immune dysregulation caused by the virus.
Mutant strains could be further propagating these effects.

(21/n)
Of particular interest is the GRP78/CotH chaperone heat shock protein complex which as described on tweets 9, 10, 13, 14 is essential for endothelial fungal invasion.
Over expression of GRP78 increases susceptibilty to mucor.
link.springer.com/article/10.100…

(22/n)
And COVID has been shown to increase the GRP78 protein expression.
The paper also showed that GRP78 levels were linked to severity.
Probably also explains why Mucor is not being observed among individuals with completed vaccination status.
sciencedirect.com/science/articl…

(23/n) Hence postulating a hypothesis warranting further investigation:
SARS-2-CoV infection up-regulating the GRP78 protein complex is responsible for the high incidence of Mucor in COVID patients. And that dominant mutant strains in India may be particularly responsible for it.

@PSampathkumarMD @VincentRK @RajeevJayadevan @lancelot_pinto @ajumathew_ @cspramesh @paimadhu @PriyankaPulla

@ArvinderSoin @A_Spallonii @GermHunterMD @IDdocAdi @PaulSaxMD @HarsimranPGI @FungalDoc