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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.
      • Pak J.
      • Tucci V.T.
      • Vincent A.L.
      • et al.
      Mucormycosis in immunochallenged patients.
      ,
      • Singh A.K.
      • Singh R.
      • Joshi S.R.
      • Misra A.
      Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India.
      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.
      • Garg D.
      • Muthu V.
      • et al.
      Coronavirus disease (Covid-19) associated mucormycosis (CAM): case report and systematic review of literature.
      • Ravani S.A.
      • Agrawal G.A.
      • et al.
      Rise of the phoenix: mucormycosis in COVID-19 times.
      • Revannavar S.M.
      • Supriya S.P.
      • et al.
      COVID-19 triggering mucormycosis in a susceptible patient: a new phenomenon in the developing world?.
      • Sarkar S.
      • Gokhale T.
      • et al.
      COVID-19 and orbital mucormycosis.
      • Sen M.
      • Lahane S.
      • et al.
      Mucor in a viral land: a tale of two pathogens.
      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.
      • Fekkar A.
      • Lampros A.
      • Mayaux J.
      Occurrence of invasive pulmonary fungal infections in patients with severe COVID-19 admitted to the ICU.
      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.
      • Hernández J.L
      • Buckley C.J.
      Mucormycosis. Treasure Island (FL).
      ,
      • Mehta S.
      • Pandey A.
      Rhino-orbital mucormycosis associated with COVID-19.
      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.
      • Werthman-Ehrenreich A.
      Mucormycosis with orbital compartment syndrome in a patient with COVID-19.
      ,
      • Grint D.J.
      • Wing K.
      • Williamson E.
      • et al.
      Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England, 16 November to 5 February.
      It was well established that the virus gains entry into cells using the ACE-2 receptors.
      • Frampton D.
      • Tommy Rampling T.
      • Cross A.
      • et al.
      Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study.
      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.
      • Ni W.
      • Yang X.
      • Yang D.
      • et al.
      Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19.
      ,
      • Ibrahim I.M.
      • Abdelmalek D.H.
      • Elshahat D.H.
      COVID-19 spike-host cell receptor GRP78 binding site prediction.
      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.
      • Morales-Franco B.
      • Nava-Villalba M.
      • Medina-Guerrero E.O.
      • et al.
      Host-pathogen molecular factors contribute to the pathogenesis of Rhizopus spp. in diabetes mellitus.
      ,
      • Vaidyanathan G.
      Coronavirus variants are spreading in india — what scientists know so far (News in Focus).
      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.
      • Graham M.S.
      • Sudre C.H.
      • May A.
      Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study.
      ,
      • Elfiky A.A.
      • Ibrahim I.M.
      • Elgohary A.E.
      Host-cell recognition through GRP78 is enhanced in the new variants of SARS-CoV-2; in silico perspective.
      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.
      • Elfiky A.A.
      • Ibrahim I.M.
      Host-cell recognition through GRP78 is enhanced in the new UK variant of SARS-CoV-2, in silico.
      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.
      • Banerjee A.K.
      • Begum F.
      • Srivastava A.K.
      Overexpression of GRP78 receptor and its chemical biology in cancer and autoimmune diseases: high risk for COVID 19?.
      • Sabirli R.
      • Koseler A.
      • Goren T.
      • et al.
      High GRP78 levels in Covid-19 infection: a case-control study.
      • Elfiky A.A.
      • Baghdady A.M.
      • Ali S.A.
      • Ahmed M.I.
      GRP78 targeting: hitting two birds with a stone.
      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.
      • Allam L.
      • Ghrifi F.
      • Mohammed H.
      Targeting the GRP78-dependant SARS-CoV-2 cell entry by peptides and small molecules.
      • Ibrahim I.M.
      • Abdelmalek D.H.
      • Elfiky A.A.
      GRP78: A cell's response to stress.
      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.

      Ethics approval and consent to participate

      Not applicable.

      Consent for publication

      Not applicable.

      Availability of data and material

      Not applicable.

      Funding

      None.

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