The French Connection!

François D, et al. High mortality of COVID-19 associated Mucormycosis in France: a nationwide retrospective Study. medRxiv preprint, 2021. doi: https://doi.org/10.1101/2021.07.05.21260041

Dr. Sheelu Srinivas^1,*, Dr. Venkita S. Suresh^2,*, Dr. Ragya Bharadwaj³

¹Department of ENT, Kauvery Hospital, Bengaluru, India

²Group Medical Director, Kauvery Hospitals, India

³Infection Control Officer, Kauvery Hospital, Trichy, India

^*Correspondence: [email protected] (S. Srinivas); [email protected] (VS. Suresh); [email protected] (R. Bharadwaj).

Abstract

We studied COVID-19 associated mucormycosis based on 17 cases reported nationwide and assessed the differences with India. They differed by frequencies of diabetes mellitus (47% in France versus 95% in India), hematological malignancies (35% versus 1%), anatomical sites (53% lung versus >80% rhino-orbito-cerebral) and prognosis (>80% mortality versus <50%)

Commentary from Dr. Venkita S. Suresh

Dear Readers,

Dr. Sheelu Srinivas, Consultant Surgeon OtoRhinoLaryngology and Head and Neck Surgery from Kauvery Hospital, Bengaluru and I thought that we should review this paper from France on Mucormycosis associated with COVID, to bring out in stark relief the dramatic differences in presentation, pathology, pharmaco-therapeutics, progression and the related puzzles and predicaments that divide the developed countries in the west and the developing countries in the south and east.

First, I have summarized the salient features in the French paper.

Dr. Sheelu Srinivas, who has treated a good number of patients through a very stormy period of Mucor in this country, whose comprehensive study is soon being published, has brought in her unique personal perspectives in the second part of this commentary.

Dr.Ragya Bharadwaj, who both editorialized and wrote a ‘ state of the art and science’ review on the KAUVERIAN when we launched the first two of our quadrilogy on Mucormycosis, rounds up this Journal Club discussion.

In fact, we have to thank the authors for their very gallant decision to focus the paper on India and compare the impact of the disease on these two great countries who believe in freedom in thought and action, socialist France and democratic and secular India.

COVID is one disease that has ruthlessly exploited the vulnerabilities of the populations as well as exposed the weaknesses of health systems.

This paper confines itself wisely to the strict confines of scientific medicine.

The highlights of the French paper:

Let us look at the glaring differences.

Nationwide, this study from France only harvested 17 cases!

They differed in the frequencies of Diabetes – 47% in France and 95% in India, Hematological and malignancies – 35% in France and 1% in India, anatomical sites – 53% lung versus 80% Rhino-orbito-cerebral – and prognosis – more than 80% mortality in France compared to less than 50% in India.

Now, some details:

Fifty-nine French laboratories reported COVID-associated Mucor (CA Mucor) from March 2020 to June 2021. Cases occurring within three months of COVID-19 diagnosed by RTâ€“PCR were only included. Diabetes Mellitus and prescription of Dexamethasone were the host factors. Positive Mucorales PCR in serum, blood or plasma were taken as mycological evidence.

The 17 patients came from 11 centers.

We already know from the abstract how the underlying risk factors differed.

As for DM, four developed DM induced by Dexamethasone; over all eight patients had DM, four of them had Ketoacidosis.

What was different in presentation was also that they had three patients with digestive presentation and three had disseminated infection

They did grow Mucorales in samples from 11 patients. Mucorales PCR assay was positive in 15 patients from tissues and body fluids. Histology identified diagnostic hyphae only in four patients

Culture and/or histology were positive in 76%.

Twelve patients received Liposomal Amphotericin B or Isavuconazole. Only three patients had surgery-two of them for Rhino-orbito-cerebral Mucormycosis.

The authors claim this is the largest series from.one country outside India!

The authors felt that the species of Mucorales recovered are influenced by the geographical area, as well as the anatomic site and the underlying risk factors.

They feel their higher mortality was due to higher frequency of pulmonary and disseminated presentations.

The authors also acknowledge the impact in India by the higher frequency of patients with DM, the higher burden of Mucor in India as well as the differences in clinical management between the two countries.

Kauvery has already published our data from our four hospitals and the stark differences in all parameters- number, presentation, challengers encountered in antifungal treatment and surgery, complications and outcomes are well-documented.

Commentary from Dr. Sheelu Srinivas

1. High number of patients in their study group had preexisting risk factors like dialysis and transplantation. This reminds us of the Mucormycosis which existed in the pre-COVID era.

2. In India, we saw the commonest manifestation as the sinuses’ involvement – Rhino Orbito Cerebral form (>80%). The common presentation in the French group was pulmonary (>53%). Literature suggests phagocytosis in the lung prevents angioinvasion while sinuses can be invaded even with the non-viable fungus.

The isolated organisms and their potential to invade vascular endothelium is also a differentiating factor.

Rhizopus microspores were the most frequent species isolated in their series. However, in our case series, we isolated more Rhizopus Arrhizus and Rhizopus Oryzae which can invade vessels and their endothelium even when the fungus is not viable.

3. Diagnostics and criteria for labelling as Mucormycosis: 71% was proven histopathology in this paper, rest probable (we do not have sufficient data on use of PCR tests and their reliability).

4. Another point is that India saw a surge during the second wave, and we sensed the role of the variant virus. The delta variant caused havoc. We also had our share of Mucor in the first wave which was not a surge like the second wave.

5. As always, when we compare different countries – the genetic makeup and socioeconomic condition differ. Use of steroids (in India, there is no uniformity or supervision or national policy; it is left to individual fancy of each center or a cocktail use by some centers), and other immunosuppressive drugs also differed between the two countries.

6. Finally on the outcomes of being higher in French study, the point 1 addresses that.

7. I have the following observations about why we had more of Rhino orbital.

Pulmonary Phagocytosis in an immunocompetent person is robust to clear the fungus.

Pre-COVID mucormycosis happened mostly in cancer or transplant patients.

Post second wave, we had patients who had raised sugar levels and were immunocompromised but the association of cancer or transplant is not strong.

The incidence of surge in Post-COVID-19 mucormycosis in transplant or cancer patients is not commonly reported or discussed in our groups.

Commentary from Dr. Ragya Bharadwaj

1. India is diabetic capital of the world and since one of the major risk factors for developing mucor is raised sugar levels, we are more susceptible to the fungi [1].

2. We also use other modalities of treatment which causes local oro pharygeal mucosa damage, such as salt-water gargles, drinking kadha and other forms of traditional remedies.

3. The estimated prevalence of mucormycosis is around 70 times higher in India than that in global data [2].

4. In a systemic review and meta-analysis of 851 cases reports published in 2018, death was reported in 389/851 (46%) patients. Case fatality was observed to be highest among patients with disseminated mucormycosis (68%) and lowest in those with cutaneous disease (31%). Hence the higher number of deaths in the west as compared to India [3].

5. Major cause = Abundant presence of Mucorales in the community and hospital environment, large number of susceptible hosts especially diabetics, and the neglect for regular health check-ups of the Indian population. A considerable number of patients are ignorant of diabetes status till they acquire mucormycosis.

6. In Europe, haematological malignancy (34-44%) is the most common risk factor associated with pulmonary mucormycosis, followed by diabetes mellitus (13-14%) Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007 [4].

References

Prakash H., Ghosh AK, Rudramurthy SM, et al. A prospective multicenter study on mucormycosis in India: Epidemiology, diagnosis, and treatment. Med. Mycol. 2019;57:395-402.
Prakash H, Chakrabarti A. Epidemiology of Mucormycosis in India. Microorganisms. 2021;9(3):523.
Cornely OA, Alastruey-Izquierdo A. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis 2019; 19: e405-21. Accessed online from https://www.thelancet.com/action/showPdf?pii=S1473-3099%2819%2930312-3 on 26 May 2021.
Skiada A, Pagano L, Groll A, et al. European Confederation of Medical Mycology Working Group on Zygomycosis. Clin Microbiol Infect. 2011;17(12):1859-67.