The surge in Covid related mucormycosis

Mucormycosis(MM), a sequelae of clinical event post COVID-19 infection, is an uncommon opportunistic infection caused by a filamentous fungus (class: Zygomycetes and order: Mucorales) with a high degree of morbidity & mortality.^{1 , 2} The point to ponder therefore is, whether SARSCoV2 is the major culprit which compromises the immune system of the host and thereby make the host more vulnerable to this secondary opportunistic infection, thus accounting for higher incidence of MM during second wave in India? Earlier published literature including several retrospective case series analyses have reported vulnerability of immune-compromised patients with pre-existing comorbidities e.g. diabetic ketoacidosis(DKA) treated with systemic glucocorticoids, Zn supplement, and longer ICU stay with O2 support towards mucormycosis.3, 4, 5, 6, 7 However, These observations are not backed by sufficient scientific evidence to account for the proportionately higher Covid-associated MM in the second wave.

There are several clinical forms of MM infection reported till date including pulmonary, gastrointestinal, cutaneous, and rhinocerebral.⁸ MM has a typical clinical presentation characterized by rapid progression of tissue necrosis due to sequential invasion and thrombosis of blood vessels. Rhino-cerebro-orbital mucormycosis, the major form in this pandemic is diagnosed through CT paranasal sinus and MRI brain.^{9 , 10}

It is now known that the surge in second wave is related, at least in part, to the new variants of concern in the SARSCOV-2 virus making it more transmissible and difficult to treat.^{11 , 12} It was well established that the virus gains entry into cells using the ACE-2 receptors.¹³ A greater rate of endocytosis will be facilitated if the virus has additional “routes” of entry. Ibrahim et al. and others have reported that the GRP 78 could act as an alternative and additional route for the virus to gain entry into the host cell.^{14 , 15} The genome of the prevalent SARSCoV2 variant (B.1.1.7 & B.6.117) in India is believed to be the cause of the increased infection.^{16 , 17} In-silico studies have shown stable interaction between RBD domain of spike protein (C480-488,) with that of GRP 78 predicting its role in endocytosis.^{18 , 19} It is to be noted that MM also have the same port of entry i.e GRP78 into the nasal and paranasal sinus mucosa through its coat protein CotH3.²⁰ Two hypotheses can be formulated for over expression of GRP78 one due to High glucose and iron content found during DKA and second dexamethasone induced GRP78 expression and thus may facilitate the invasion of MM into target cells for further proliferation.21, 22, 23 There is still a less explored reason for GRP78 over expression namely endoplasmic reticulum(ER) stress. In perfectly healthy condition, the protein folding ability of endoplasmic reticulum matches with the body's protein synthesis ability. However, in stress condition e.g. virus infection cells accumulates excessively high number of unfolded viral structural proteins in ER leading to over expression of GRP78 at cell surface making the cells vulnerable to fungal pathogens e.g. MM.24, 25 The GRP 78 binding being common to both the new variants as well as MM, could explain both the higher transmissibility of SARSCoV2 and surge in COVID-19 associated MM in the second wave.

We propose, therefore, that this is the right time to conduct a stringent medical audit of MM cases with a detailed questionnaire and medical records to identify risk predictors for future plans of action. Assessment of GRP78 expression in target cells or in circulation during hospital discharge, If not in all cases, at least in high-risk individuals like diabetics supplemented with steroid and had a history of long ICU admission, can be recommended. Additionally, such individuals could be considered for low-dose anti-fungal prophylaxis to decrease the morbidity and mortality due to MM.

CRediT authorship contribution statement

Somesh Chandra: Writing – original draft. Rakesh Rawal: Writing – original draft.

Declaration of Competing Interest

None.