CAM in India had Contribution of Unknown Factors

CME INDIA Presentation by Dr. Ravindra Shukla (Endo) Department of Endocrinology and Metabolism, All India Institute of Medical Sciences Jodhpur, Jodhpur, Rajasthan, India. Inputs: Aakash Kasatwar (Chandrapur, Maharasthra), Nivrutti Rathod (Chandrapur), Jayshri Nandanwar (Chandrapur), Divyangi Mishra (Jodhpur) and Akshay Dhobley (Durg).

Corona Assisted Mucormycosis (CAM)

Quick Take Aways

SPAROS Study

• Recently published Surgically treated Post Covid Acute Invasive Fungal Rhino-Orbital sinusitis in Chandrapur Study (SPAROS) gives scientific world a very important appraisal of facts.
• Surgically treated Post COVID Acute invasive fungal Rhino-Orbital Sinusitis in Chandrapur (SPAROS) study was a prospective observational study of all those who developed mucormycosis and had a positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) result after 1 March 2021.

This study has found much lower prevalence and mortality

• SPAROS study reports CAM data from a district registry in Chandrapur, Maharashtra, which is incidentally the region where the Delta variant of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was first reported (Jain et al., 2021).
• The present study involved prospective follow-up of cases from the mucormycosis registry of Chandrapur District between 11 and 24 May 2021.
• The present study has found that the prevalence of mucormycosis was 710 per million patients hospitalized with COVID-19.
• This means that factors related to the management of COVID-19, and the disease itself being causative.
• The prevalence of CAM in this study was 2300/million COVID-19 infections.It is at least 10-fold higher compared with the prevalence of mucormycosis in transplant recipients.
• As such, The incidence of CAM in patients with COVID19 is higher than that of mucormycosis in the general population. It is also several fold higher than that of mucormycosis in organ transplant recipients and patients with diabetes mellitus.
• This study has found much lower prevalence (0.07% vs 0.27%) and mortality (2% vs 45%) rates compared with rates reported by Patel et al. (2021) from India.

Higher male preponderance

• Higher male preponderance has been described previously for non-COVID mucormycosis and CAM and is likely due to the fact that testosterone increases expression of glucose regulated protein (GRP78), a stress protein crucial for hyphal invasion by Mucorales spp.

Clinical presentation

• Headache and orbital complaints were common.
• Fever was rare in this study. Previous case series on mucormycosis have described fever as a common presentation.
• SARS-CoV-2-induced transient T-cell suppression in the presence of broad-spectrum antibiotics, and the use of steroids may also explain the lack of fever.
• All of the patients in the present study had maxillary involvement.
• A peculiar interaction between COVID19, steroids and hyperglycaemia inducing fungal invasion has been seen in the present study.
• Maxillary sinus is the most common site of non-invasive fungal infection, and is a likely conduit of fungal spores in otherwise healthy states.

Role of steroids

• While inappropriate use of glucocorticoids has been implicated previously in CAM, this study found that a sizable percentage (29.5%) of cases of CAM had not received steroids.
• Cases without steroid exposure were likely to present late.
• Glucocorticoids predispose to fungal angioinvasion by impaired neutrophil margination and repression of adhesion factors.
• The methylprednisolone was found to be associated with earlier CAM presentation. Methylprednisolone impairs conidial phagocytosis by neutrophils, and predisposes to invasive fungal infection.
• Due to perceived higher clinical efficacy against COVID-19, methylprednisolone has been widely used, in comparison with dexamethasone in India (Ranjbar et al., 2021).
• Whether the use of methylprednisolone per se could have contributed to increased prevalence of CAM in India remains speculative.

Role of hyperglycaemia

• The present study found strong correlation between CT severity score and blood glucose level at presentation. Mean blood glucose level at presentation (236 mg/dL) was higher than that described after severe COVID-19 (170 mg/dL) However, it was much lower than levels at which mucormycosis occurred in pre-COVID times.
• In fact, the blood glucose levels of patients hospitalized with COVID-19 who did not develop mucormycosis did not differ from those in the COVID-19- associated diabetes and mucormycosis (CADM) cluster.
• In the other CAM clusters [COVID-19-associated classical mucormycosis (CACM) and COVID-19-induced mucormycosis (CIM)], antecedent hyperglycaemia seemed to play a clear role in the cause of mucormycosis. Elevated blood glucose can increase viral replication exponentially by increasing glucose in the pulmonary airway surface liquid.
• Non-CAM cases in this study had higher blood glucose levels that those described in other countries.

Need to recognize factors above and beyond hyperglycaemia in the pathogenesis of CAM

• The present findings for the CADM subtype call for the need to recognize factors above and beyond hyperglycaemia in the pathogenesis of CAM.
• None of the patients in this study had DKA, in contrast to the pre-COVID era.

Prognosis

• Mucormycosis associated with diabetes, especially DKA, has a far better prognosis compared with mucormycosis associated with neutropenic states such as haematological malignancy. This is likely because underlying conditions such as DKA and hyperglycaemia can be optimized rapidly.
• The better-than-expected prognosios of patients with CAM in the present study can be explained similarly.
• The severity of COVID-19 is likely to decrease within 2 weeks in most survivors. This, along with cessation of steroids, may lead to the excellent overall prognosis in these patients.

Exploratory analysis for CAM classification

• It was based on factors implicated as necessary for fungal mucosal invasion:
• Diabetes.
• Hyperglycaemia at mucormycosis presentation.
• Use of glucocorticoid receptor agonists.
• Covid-19. Type of diabetes (pre-existing, occurred during covid-10/no diabetes) and hyperglycaemia at presentation were considered separately.

Cluster 1 (CADM)

• It included the majority of cases.
• These subjects received steroids during COVID-19, followed by hyperglycaemia and diabetes precipitation, and had uncontrolled hyperglycaemia for some days.
• There was no predilection for orbit or lower jaw involvement.
• These patients had mild-to-moderate COVID-19, and aggressive glucocorticoid therapy precipitated diabetes and invasive fungal sinusitis.
• Most cases of active COVID-19 with mucormycosis were seen in this subgroup.
• These cases require single debridement and have an excellent prognosis.
• Control of hyperglycemia in this group – even for a few hours – can yield favourable results. Notably, this is the only subgroup in which mild cases were seen.
• This may point to inappropriate use of steroids.

Cluster 2 (CIM)

• It consisted of patients in whom a high SARS-CoV-2 load appeared to precipitate mucormycosis. These patients had not received steroids, did not have a history of diabetes, and had no risk factors for mucormycosis.
• Blood glucose levels were not significantly different from patients without mucormycosis.
• However, all subjects had severe COVID-19 and there was a predilection for jaw involvement including osteonecrosis of the jaw. The thrombotic response to SARSCoV-2 may play a central role in causing fungal invasion in this subgroup his classification has practical implications for the management of patients with CAM.

Cluster 3 (CACM)

• It consisted of the majority of cases with pre-existing diabetes.
• These subjects had longstanding uncontrolled diabetes, and severe COVID-19 followed by mucormycosis which required extensive surgery.
• These subjects were likely to have systemic involvement, orbital involvement and had a higher mortality rate.
• Blood glucose during mucormycosis admission for this cluster was the highest of the three subgroups (approximately 300 mg/dL), which is suggestive of uncontrolled diabetes.
• Clinically, this resembles mucormycosis described previously in patients with and without COVID-19.
• CACM is likely to be over-represented in studies from tertiary care hospitals. The only deaths that occurred in this study were patients in this subgroup.
• Aggressive surgery and antifungal therapy should mainly be directed at this group.

Current guidelines on CAM management bundle it into one entity.

• Appropriate triaging is needed given the highly heterogeneous nature of CAM.
• CADM and CIM may not require aggressive management, apart from hyperglycaemic control and simple debridement, whereas CACM should be managed aggressively.
• Antiplatelets/anticoagulants are likely to be the optimal preventative strategies for CIM.

Postulated CAM hypothesis

• Identification of a phenotype without steroid exposure and associated with increased severity of COVID-19 points to a role played by the disease itself in the causation of mucormycosis.
• Combined with steroid-induced neutrophil dysfunction, this may lead to fungal angioinvasion.
• This hypothesis also explains the excellent prognosis of CAM.
• Once COVID-19 resolves, GRP78 levels come down, blood supply and immunosuppression recover fast, and there is rapid clinical improvement.
• A certain level of hyperglycaemia seems to be essential for mucormycosis, but this plays a minimal role in recovery and final outcome.
• Steroid exposure is facilitatory in earlier precipitation and causation in susceptible patients, but it is not essential in the pathogenesis of CAM.
• The use of methylprednisolone may accelerate and possibly precipitate CAM.
• It is tempting to speculate that methylprednisolone may lead to increased GPR78 expression as glucocorticoid receptor agonists differ in transactivation profiles.

Final Points

References:

1. Kasatwar A, Shukla R, Rathod N, Nandanwar J, Mishra D, Dhobley A. Insights from Surgically treated Post Covid Acute Invasive Fungal Rhino-Orbital sinusitis in Chandrapur Study (SPAROS): A Population Based study of Coronavirus Associated Mucormycosis (CAM) characteristics in India. IJID Reg. 2022 Dec;5:21-29. doi: 10.1016/j.ijregi.2022.08.005. Epub 2022 Aug 24. PMID: 36035237; PMCID: PMC9398937.
2. Lu X, Cui Z, Pan F, Li L, Li L, Liang B, et al. Glycemic status affects the severity of coronavirus disease 2019 in patients with diabetes mellitus: an observational study of CT radiological manifestations using an artificial intelligence algorithm. Acta Diabetol. 2021;58:575–586.
3. Bode B, Garrett V, Messler J, McFarland R, Crowe J, Booth R, et al. Glycemic characteristics and clinical outcomes of COVID-19 patients hospitalized in the United States [published correction appears in J Diabetes Sci Technol 2020 Jun 10:1932296820932678] J Diabetes Sci Technol. 2020;14:813–821
4. Deutsch PG, Whittaker J, Prasad S. Invasive and non-invasive fungal rhinosinusitis – a review and update of the evidence. Medicina. 2019;55:319
5. Patel A, Agarwal R, Rudramurthy SM, Shevkani M, Xess I, Sharma R, et al. MucoCovi Network3. Multicenter epidemiologic study of coronavirus disease-associated mucormycosis. India. Emerg Infect Dis. 2021;27:2349–2359
6. Jain VK, Iyengar KP, Vaishya R. Differences between first wave and second wave of COVID-19 in India. Diabetes Metab Syndr. 2021;15:1047–1048. 
7. Ranjbar K, Moghadami M, Mirahmadizadeh A, Fallahi MJ, Khaloo V, Shahriarirad R, et al. Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial. BMC Infect Dis. 2021;21:337



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