Mucormycosis Epidemic in India: Out of the Box Menu

CME INDIA Presentation by Admin.

“Only when you start thinking outside-the-box, the box goes away, and the doors of opportunity are opened wider than ever before. Think Outside-the-box!” – Deodatta V. Shenai-Khatkhate, Scientist and Inventor, USA.

Current epidemic of Mucormycosis has created a situation in which no single factor explains this nightmare. CME INDIA tries to understand this scenario.

CME INDIA Discussion

Dr A. K. Singh, DM Endo., Kolkata:

• “Casual Speculation in medicine is a terrible thing and at a time cost very high. Kindly show me a single case report of Mucormycosis due to unfiltered water, reused mask etc. Few doctors coming on TV talks real nonsense and has created extreme panic. Similarly, one Microbiologist from PMCH coined a new term White fungus? What’s going on?”
• “Mucormycosis is not like a common candidal infection. It’s true that Mucor exist in households. Blackening of fruits present in your house is caused by Mucor but human body kills all spores even if you inhale or eat. Only issue is they are opportunistic and harm you when your system can’t kill it. And system only fails at extreme situation.”

The first series on “Black Fungus” Mucormycosis by Prof. VP Pandey, Professor and HOD of department of medicine at MGM Medical College Indore.

• Main findings from series of 210 Mucormycosis patients at Indore:

Comments on Indore Study

Dr Rajeev Jayadevan, Cochin:

Clearly there are factors beyond steroid use & diabetes here.

The obvious question is, what other forms of treatment did these patients receive?

Dr Vikram Sarabhai, Pulmonologist, Delhi:

• There can be overlapping issues in each and the diabetics and steroids can be confounding. Also, not commented on sterility of respiratory equipment / single or multiple users / Delivery of quality of health care with hospital or healthcare hygiene measures used the percentages are all very low on high risks groups.
• One must consider… Multiple users and neglected sterile INTERPHASES Used as Respiratory aids… oxygen cannula / Nebulization Kits / Masks / Bipap or CPAP masks and their unclean filters – because most cases are Rhinosiusitis or Rhinocerebral mucurmycosis- Route of entry is breach of upper respiratory especially nasal passages and through them eyes and brain.
• Why Rheumatologist / Dermatologists haven’t seen Mucurmycosis inspite of very prolonged Steroid therapy in their patients… because their patients don’t use oxygen or Nebulization for prolonged periods in Healthcare facilities and not attended by healthcare workers who may be oblivious of Hand Hygiene / Single and exclusive use of Respiratory Aids and interfaces.
  Majority of Mucurmycosis will be Nosocomial and in episodic outbreaks.
• Why Pulomonologist not seen rampant Mucurmycosis is because their patients are on short courses of steroids and mostly low flow oxygen for shorter ICU and in ward stay in acute exacerbation of Obstructive Airways Disease. In cases of Interstitial Lung diseases use of steroids has drastically come down and most use low flow oxygen and use personal respiratory equipments and personal respiratory interphases such as masks or oxygen cannula.
• Respiratory ICU case who are sicker and need high steroids land on ventilator and either get better fast or deteriorate fast.
• COVID patients – Require very HIGH FLOW OXYGEN (that may breach and dessicate nasal mucosa and infiltrate sinuses) and are given high doses of steroids (not supported by any study but more as the physicians have practiced in other conditions over years) in overflowing healthcare facilities with under optimally vigilant, lesser trained and compliant healthcare worker to strict Respiratory Hygiene measures.
• There is a very strong affinity for Nebulization if bronchodilators / Inhaled Corticosteroids / saline / amongst physicians who would pay very less attention as to how they are delivered by their nurses and ward boys or relatives of patients.
  (I have never known a patient who knows or has been told by their treating physicians how to sterilise their oxygen Nebulization kits and hand hygiene )
• Variance in the bells curve to find some unexplained cases will always be part of any statistics.
• (My explanation is for majority of cases and will refrain from arguments contesting sporadic cases that don’t fit into such cohort).

Dr Keyur Acharya, Intensivist, UK:

• Undoubtedly overuse of steroids, diabetes mellitus, unfiltered water used in oxygen therapy and poorly ventilated rooms are major factors in the surge of cases in a country where maximum Mucor mycosis cases exist.
• There has been an increase in people who were never hospitalized and don’t have diabetes. I believe re use of unsterilized and infected masks could be one of the reasons although opinion is divided on this.
• Sterilization, washing and drying these masks in sunlight before re use must be emphasized.

An article in Diabetes & Metabolic Syndrome: Clinical Research & Reviews dated 21 May 2021

By Awadhesh Kumar Singh, Ritu Singh, Shashank R. Joshi, Anoop Misra, (Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India).

• “Increase in mucormycosis in Indian context appears to be an unholy intersection of trinity of diabetes (high prevalence genetically), rampant use of corticosteroid (increases blood glucose and opportunistic fungal infection) and COVID-19 (cytokine storm, lymphopenia, endothelial damage).”
• Increasing cases of rhino-orbital mucormycosis in people with COVID-19 are being recently reported.
• In an analysis of 101 cases of mucormycosis in patients with COVID-19 have been reported of which 82 cases belong to India, diabetes was present in 80% of cases, while corticosteroid treatment was given for COVID-19 in 76.3% cases.

Union health ministry and ICMR issued an evidence-based advisory outlines risk factors behind black fungus:

• Uncontrolled diabetes
• Immunosuppression by steroids (commonly given to COVID patients)
• Prolonged ICU stay
• Comorbidities

Suspicions by medical professionals

• Industrial oxygen’ (possibly contaminated with the black fungus that is commonly found in the environment and soil) supplied to hospitals amid the pan-India crisis of medical oxygen
• Rheumatologists say that they have used steroids in lakhs of rheumatology patients for weeks but never witnessed such numbers of Mucormycosis.
• Steroid is being used to treat the COVID-19 since the beginning of the pandemic last March but mucor cases have surged recently.
• Dermatologists used high doses of intravenous steroids in conditions like immunobullous disorders but hardly seen mucormycosis.
• ENT specialists used steroids at maximum dose for some indications, but hardly saw Mucormycosis.
• Other factors speculated
• Prolonged use of the same oxygen port
• Contaminated oxygen pipeline
• Not using sterile water in the hospital 
• Contaminated water in Humidifier and steam inhaler

Zinc is also under scanner

By Dr Rajeev Jayadevan, Member Covid Task Force National IMA, Cochin.

• Are Zinc supplements to blame for “Black Fungus”?
• Fact: Fungi feed on Zinc. (They thrive in an environment rich in Zinc)
• And mammalian cells try to escape fungal invasion by “starving” the fungus of zinc, by hiding it.
• In fact, to counter this defence, some fungi dispatch boomerang-like “zinc-fetching molecules” (“Zincophores”) into the vicinity, which search for “any zinc that’s lying around” & bring it back for the fungus cell to use.
• These mammalian self-defence processes against invading fungi, collectively known as “nutritional immunity” help us limit microbial growth, and enhance killing of the invader. Successful pathogens have developed strategies to counteract this and acquire essential micronutrients. For example, Rhizopus delemar (previously R oryzae), one of the main species causing Mucormycosis, encodes 3 cell surface zinc importers.
• In fact, this fungus Rhizopus is used for industrial purposes e.g., for alcohol production due to its fermenting ability.
• A Japanese paper from 1996 that looked at ways to make the fungus work more efficiently (fermenting) in the alcohol industry, found that Rhizopus “does its work well” by producing more glucoamylase while it is grown in a medium rich in zinc.
• In Egypt, attempting to use this property of fungus, they used a fungal biomass to absorb zinc from polluted water.
• Conclusion:
  • The sudden appearance of serious cases of Mucormycosis in the setting of the pandemic necessitates a WIDE search for contributing factors.
  • High sugars, low immunity immunosuppressive therapy including steroids are already known. But there are patients who are getting admitted without these risk factors. 
  • I was in a discussion with some doctors across the country yesterday, and some doctors said <30% of their Mucormycosis patients had diabetes. People in their 30’s were getting admitted with it. This week there were 8 deaths in AIIMS Delhi alone.
  • Bottom line is that there may be other risk factors too. Multiple hypothesis are being raised.
  • One relevant question is: Does the widespread use of zinc supplements have a role?
  • It will be easy to find an answer, by simply analysing the cases seen so far, listing all their medications, medical history and all other parameters, and then comparing them to similar patients who DID NOT have Mucormycosis. (Large no’s need to be studied, to avoid wrong conclusions).
  • Mucormycosis is caused by multiple species of fungi including Rhizopus, Lichtheimia, Apophysomyces (trauma related) etc. Spores are inhaled. Mortality is >30%.
  • One of probably cause of Mucormycosis in Covid is excessive use of zinc.

(Zinc actually acts as growth factor of Mucormycosis. In vitro study it has been seen that zinc chilator (zinc antidote) like clioquinol or phenanthrolene or other zinc chilator inhibit the growth of this fungus. That means zinc deprivement nutrilise the growth. Not only this, difficult to grow this fungus in zinc deficient tissue. Zinc chilator has seen Amphotericin B like action.)

Think OUT OF BOX, see these cases( Being reported widely)

Dr Jaimin Parmar, MD Baroda:

• One of my patients, female 56 yrs. was treated on OPD as she was mild symptomatic Covid She got only 10 mg omnacortil bd for 5 days and developed mucormycosis. She is non-diabetic and not suffering from any other disease. So, no oxygen, no diabetes no other immunocompromised condition.

Dr Hardik, Internist, Ahmedabad:

• Saw similar patient: Mild Covid, No Diabetes, Only therapeutic steroid use for 5-6 days. No Covid worsening symptoms, baseline HbA1c: within normal range, HbA1C during development of Mucor specific symptoms: 12. Post diagnosis of Mucor – random blood sugar: 92 There must be any of one Predisposing Risk factor to develop Mucor.
• One another patient, came to private clinic here at Ahmedabad, with Ptosis, Redness, rhinitis (Mucor specific symptoms) known case of DM, Random 400+, on the third day of admission Fever developed, incidentally RTPCR came Positive. Prior to hospitalization no Covid symptoms. (Seems acquired Covid after getting hospitalization)

Dr V. P. Youmash, Assistant professor KAPV medical college, Trichy: Vaccine Blues:

• We didn’t see such a surge in mucor cases last year Covid wave, though not much treatment protocols modified in present second wave. This is something beyond diabetes, steroids, zinc and oxygen therapy. The one difference between last wave and present wave is introduction of vaccines. Do add an information on vaccine status of affected mucor patient and type of vaccine they received sir.

Dr Vivek, MD, Paediatrician, Baroda:

• We all have read the tweet from HOD rheumatology of AIIMS, she was surprised how he that mucormycosis has been linked to the use of steroids. According to her experience despite using steroids for very long in her rheumatological patients she has hardly seen any Mucormycosis
• I had a discussion with my friend who is into liver transplantation and according to him, in his career of 15 years he has hardly see any mucormycosis in his patients whose immune system is totally knocked off
• We all have been using steroids in nephrotic syndrome and bronchial asthma, how many patients of mucormycosis have we ever encountered?
• We all have listened to the audio clip of a surgeon who explained that the patients are having a clear area of demarcation between the healthy tissue and the necrosed tissue which cannot be possible in a fungal infection alone. According to him the primary event seems to be thrombosis of the feeding artery leading to necrosis of the tissue and secondary invasion by the fungus.
• In the nutshell, it’s a combination of immuno dysregulation and thrombotic events because of Covid, uncontrolled diabetic mellitus and add on effect of immunosuppressant agents which probably is leading to mucormycosis
• Mucor is there in the environment and every one of us is exposed but we never develop the disease because of our immune system, so attributing it to industrial use of oxygen and other such measures probably does not make sense
• So, let’s not blame only the steroids for the occurrence of mucormycosis because they are one of the life-saving drugs available in the treatment protocol of Covid. They have saved more lives than the harm they caused. We probably have to reconsider the duration of anticoagulation therapy that needs to be given in these Covid patients to prevent the thrombosis and subsequent necrosis of the tissues

Dr Anupama Ramkumar, Physician, Clinical Researcher, Ahmedabad:

• The compulsive over steaming is a very persuasive factor to consider!  And several people have religiously been doing it up to two three times a day for the past year!

Dr Ashok Kumar, DM Neuro, Ranchi:

• We know only 5 facts, rest are speculations:
  1. Mucormycosis cases have suddenly increased in this Second wave of COVID-19. There may be some causal association. Prolonged Lymphopenia?
  2. Impaired surface defence in Upper respiratory tract mucosa (IgA?)
  3. Known association to Uncontrolled Hyperglycemia, ketoacidosis. High prevalence of Diabetes in middle age Indians.
  4. Some contribution by Corticosteroids (systemic, Inhalational).
  5. High incidence in India.
  6. What is unique here to cause sudden rise in cases of this rare infection. Not in other countries. Is it the warm, humid climate? Some cultural practice?
  7. Relation to Iron and Acidosis.
• Any hypothesis to explain this phenomenon must use only minimal number of causative factors. Because all these factors have come Simultaneously to create a unique environment which led to growth of this fungus in so many patients. Factor number A, B, C or D may create unique combination. But, if we invoke Factors A to J, total 10, Murphy’s law will apply. Probability of 10 to come together is very low. So, what are those 2 – 3 causative factors and what is unique about India? Or is it some drug/chemical used here which makes Iron available to the fungus or causes acidosis?  
• In last few months, millions of COVID-19 have taken IVERMECTIN. Many have taken herbal preparations like Giloy. These 2 substances have been in India alone, much less in other countries. Almost unique for India. Or localised area of Hypoxia in tissues in COVID-19 causing Lactic acidosis? We can do MR Spectroscopy of to look for Lactate peaks in tissues around Paranasal sinuses. One thing certain is that the Fungus does not attack a patient. It is always there in environment. It comes in only when INVITED.

Dr Swati Srivastava, Prof Med, SMS Med College, Jaipur:

• Is there a contribution to higher cases of mucor linked to increased occurrence of Covid in rural background? Till last year rural areas were relatively safe? Now with immunosuppression following Covid and treatment are they more vulnerable because they are more exposed to mucor spores, in manure, soil, dust, dung, compost, rotting vegetation?

Dr Mridul Das, Diabetologist physician, Agartala,Tripura

• Present concept of MM in SARS-CoV-2 infected & recovered patient depicted as:
  • Rampant steroid use
  • High sugar level
  • Use of unsterilized apparatus & water of oxygen therapy
  • Unhygienic environment & lifestyle.
  • These points may be pronounced more for India than other countries.
• But there are some studies and literature stating SARS-CoV-2 itself is immuno depressant like HIV, which destroys the T-cells massively. Now, question is whether SARS-CoV-2 is genetically engineered in lab with property of auto-mutations and incorporating genome of HIV which will alter the natural immunity. If so, why other countries are not suffering from MM like India? Or, present common Indian mutant type B.1.617.2 is something special to destroy the immunity more?

Dr Suresh Kubavat, Physician, Kailash Cancer Hospital, Muni Seva Ashram, Goraj, Vadodara, Gujarat:

• Why same fungus and not others, at different geographical locations? This cannot be a coincidence.
• Excessive prophylactic Zinc mounting to build a favourable Milieu intérieur for Mucor in patients’ body? Study on zinc stores in such patients would be helpful.
• The vascular theory looks more logical and needs to be addressed stringently.
• Anti-coagulants and antiplatelets both equally important according to my cardiology friend.
• Rhizopus organisms have an enzyme, ketone reductase, which allows them to thrive in high glucose, acidic conditions.
• Iron overload itself may predispose to Mucormycosis.
• Individuals with diabetic ketoacidosis have elevated concentrations of free iron in their serum, which supports the growth of Rhizopus oryzae at an acidic, but not at an alkaline, pH.
• CD4 cells (Helper Lymphocytes) which is responsible for Cell Mediated Immunity and CD8 cells (T suppressor lymphocytes) . CD4 and CD8 both are decreased in COVID 19 infection.

CME INDIA Learning Points

By Dr S K Gupta, MBBS MD(Med) CFM (France) Senior Consultant Physician Hosp, Delhi: Looks logical and tempting but…

How many cases of Mucormycosis or Black fungus in India till now?

Nearly 8000 cases till now with maximum number of cases in Maharashtra, which has reported 1,500 cases of mucormycosis so far. Next is Gujrat, Bihar, Etc. as on 22 May 2021.

What is the risk of Mucor in Covid?

Very little 0.0034%. Ratio of total cases of Covid in India Vs Total cases of Mucor – shows ~3 cases of Mucor per 10000 cases of Covid. Not to be scared so much.

What has led to an increasing number of Mucor cases in current scenario ?

1️. Covid itself is the biggest contributory factor for mucormycosis because Covid leads to -Lymphopenia and decreased cell mediated immunity (Decreased CD4 and CD8 cell count) -Inflammatory Cytokines release in Covid also promotes mucormycosis.

2️. Sustained High Blood Sugar levels because of prolonged over and excessive use of steroids provides perfect bleeding ground for fungus in setting of compromised immunity. So, suppressed immunity in milieu of High Sugar creates perfect combo for growth of Black Fungus.

Why cases of Mucor were not reported in First wave of Covid?

Because use of Corticosteroids was not as rampant during First wave. Secondly, overall number of cases during first wave were much lesser.

Why not so many cases of Mucor reported from USA despite highest case load of Covid?

Because India remains the Diabetes Capital of the world. Secondly, Unlike India, Steroids are not available freely in Western Countries. Thirdly, more people in India have uncontrolled diabetes because of reluctance to accept Insulin.

Is Mucormycosis a contagious disease?

No, it does not spread from person to person by droplet infection or airborne transmission.

It does not increase risk of Surgeon HCW to get infection from patient.

Spores are present in Atmosphere or even in Nasal cavity as commensal but cause infection only when immunity dips.

What is the age group of patients getting Mucor?

All age groups and even non-Covid patients can contract Mucormycosis. However, those above 40, who are also diabetic, are more prone. Children are at lesser risk only because majority of children only have mild Covid infection that does not require the use of steroids.

Role of Industrial Oxygen contributing to Mucor?

No definite evidence for the same. Few cases of Mucor also seen in those who never required oxygen.

Role of Humidified oxygen in Mucor?

Humidified oxygen is essential for life. Keep Humidifier bottle clean. Fill it with sterile water. Sterilize oxygen tubes using Hypo solution or use disposable Tubes.

Some cases of Mucor being reported after recovery from Covid in post-recovery period also?

Yes, initial two weeks after recovery from Covid remain risky especially among Diabetics with High Sugar levels.

Some cases of Mucor being seen in those who never had Covid?

Possibility of having asymptomatic Covid in such cases remains high in current scenario.

Role of high Zink in Mucor?

No definite Evidence. But association can’t be ruled out.

Early warning symptoms of Black Fungus?

Unilateral Headache, facial numbness, Loose tooth,  pain in teeth Nasal blockade, crusting in nose Bleeding from Nose Diplopia, dropping of eye lid could be late symptom.

Are patients of Mucor Toxic and Sick looking?

No, initially patient may report only mild symptoms of headache facial numbness and nasal blockade.

How to make Early diagnosis of Mucor?

Regular ENT check-up is the Key:

• Simple rigid nasal endoscopy can pick up early cases. Earliest sign could be loss of pain sensation on touching endoscope in nasal mucosa.
• Physicians should not hesitate to refer the patients for ENT check-up even for early symptoms of Unilateral Headache Facial numbness, toothache, facial palsy, ptosis, diplopia apart from nasal blockade etc.!
• Note: Nasal secretions, Sputum and Blood are poor samples for detection of Mucor
• Scraping or Biopsy from nose remains good for diagnosis of Mucor by  by KOH preparation, Gram stain, culture to see fungal hyphae.

CME INDIA Tail Piece

By Dr A. K. Singh, Kolkata.

• The primary reason that appears to be facilitating Mucorales spores to germinate in people with COVID-19 is an ideal environment of:
  1. Low oxygen (hypoxia)
  2. High glucose (diabetes, new-onset hyperglycemia, steroid-induced hyperglycemia)
  3. Acidic medium (metabolic acidosis, diabetic ketoacidosis [DKA])
  4. High iron levels (increased ferritins)
  5. Decreased phagocytic activity of white blood cells (WBC) due to immunosuppression (SARS-CoV-2 mediated, steroid-mediated or background comorbidities) coupled with several other shared risk factors including prolonged hospitalization with or without mechanical ventilators
  6. DM remains the leading risk factor associated with mucormycosis globally

Reference

1. Awadhesh Kumar Singh, Ritu Singh, Shashank R. Joshi, Anoop Misra.Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India,Diabetes & Metabolic Syndrome: Clinical Research & Reviews,2021,,ISSN 1871-4021,https://doi.org/10.1016/j.dsx.2021.05.019.

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