CME INDIA Presentation by Dr Anand Malani, MD, Consultant physician, Sangli, Maharashtra.

Mucormycosis – Logical Reasoning and Preventive Aspects.

We are yet stumbling and gasping to breathe in the unending ‘Marathon’ of Covid-19 and finding ourselves encountering new hurdles! Mucormycosis is a new hurdle, and may be few more to come! Natural or Partially Iatrogenic? Let’s apply logical reasoning to find out. This commentary will not deal with medical details or management aspects about mucor. We already have a lot of information coming on a daily basis from different authentic sources.

An India specific epidemic within a Pandemic

  • Mucormycosis is a deadly disease carrying more than 50% mortality despite standard care [1]. The morbidity in survivors is even more. The treatment is as deadly as the disease. The multidisciplinary approach, expensive medicines with high adverse effects, a prolonged course of illness etc. makes it most challenging to manage.
  • So far 12000+ cases reported in Post Covid-19 scenario which is quite significant and in epidemic proportions.
  • We are struggling to provide standard of care, at all levels, due to logistics and other issues.
  • No other country except ours have reported such huge surge in Mucor cases post Covid. Relevant search didn’t reveal a spurt in any affluent country who had more cases of Covid than us.
  • So, it’s an India specific epidemic within a Pandemic, related to the disease of Pandemic. Logically the reasons have to be our own and needs analysis rather than just theories and speculations.

Some age-old proven facts about Mucor and risk factors as per literature [1,2]

  • Mucor spores are ubiquitous, especially in damp/ moist surroundings, unhygienic environments especially organic degrading wastes, dusty environments. We all get exposed to Mucor spores on a frequent and recurrent basis. Exposure gets converted into disease only in a very miniscule proportion of the exposed due to certain risk factors.
  • Diabetes – especially uncontrolled remains the biggest risk factor, Diabetes of a longer duration, ketoacidosis, CKD increase the risk further.
  • Immunocompromised state, Neutropenic conditions are next important risk factors.
  • Steroid use, use of immunosuppressants are proven risk factors.
  • Broad spectrum Antibiotic use is a proven risk factor.
  • Use of Voriconazole is a risk factor.
  • Iron overload states / Use of deferoxamine are known risk factors.
  • Use of Oxygen was never a risk factor.

What are the various theories incriminated for this Mucor epidemic and their rationality or evidence?

  • Steroid use [1,2,4] – A known risk factor. Very much rational and lot of evidence available in literature. Doesn’t need much elaboration.
  • Uncontrolled DM [1,2,4] – A Known risk factor. Again, very much rational and evidence supported. So, doesn’t need much elaboration.
  • Covid and Steroid aggravated DM – It is highly rational and logical. Covid and steroids both aggravate diabetes.
  • Covid induced immunosuppression – Rational theory. Systemic viral infections are immunosuppressive.
  • Covid induced lymphopenia – Irrational theory. In fact, neutropenia is a risk factor and not lymphopenia.
  • Old worn-out Oxygen pipelines – Irrational and unproven! No evidence to support. Less likely to be a source of Mucor spores. The pipelines are usually of copper and guarded at both ends by valves. Contamination by dust is less likely. Besides the first use will flush out all the stuff if at all present.
  • Industrial Oxygen – No evidence to support the theory. It is likely that industrial grade oxygen may contain impurities, but that doesn’t prove the notion. Scientific studies and analysis needed about this.
  • Oxygen humidifiers – No evidence to support the theory. Again, has to be proved.
  • Unsterile Nasal Swab sticks – Somewhat rational but unproven. Use of unsterile unhygienic swab sticks is a possibility in our country. Fake Remdesivir, fake or unauthorized labs and fake swab sticks all can be true. Dirty and unsterile swab sticks can definitely introduce Mucor and some others as well.
  • Use of unhygienic masks – Somewhat rational but unproven. The way in which masks are used by our people is well known. And they use it for a duration at least 10 times of the recommendation. It’s very common to use the same masks for days to weeks of whatever make they are. The masks become moist, dirty and contaminated with all sort of stuff. Microbiological studies, if conducted will definitely reveal some interesting aspects. Moreover, in Covid hospitals, patient continue to use same masks till they are discharged!
  • Excessive Steam inhalation – Can lead to mucosal damage, increased humidity and increased susceptibility. No data available.
  • Elevated Ferritin levels – Rational. Complex metabolics underneath. An elevated iron or ferritin levels is a favorable factor for mucor.
  • Excess use of Zinc [3] – Never was Zinc used as these days. Fungi need zinc to grow. It is a known fact that mammalian cells escape fungal infection by starving the fungus of zinc by complex mechanisms. This aspect needs more research.
  • Ischemic Theory – Somewhat rational but unproven. Thrombosis of feeding arteries as primary event. Then why only Mucor as secondary infection? Rather Mucor is an angio-invasive infection and vascular involvement and ischemia is usually secondary.
  • Use of broad-spectrum antibiotics – Rational reason. Detailed discussion follows and forms the core and purpose of this commentary. A very important and undermined aspect.
  • Use of prophylactic antifungals – Rational reason. Again, discussed later.

What data says?

  • So far more than 12000 patients of Mucor mycosis reported in post-Covid scenario. The details and data, hopefully is being compiled and will be made available. This will form the most important exercise in understanding the reasons, ultimately translating into preventive care.
  • Fortunately, a small analytical study from a central Indian city have revealed following.[3]
  • Total patients – 210. Non diabetic – 20% Oxygen received by – 50% Home treatment in – 35% Steroids use in- 85% Below 40 years- 15%
  • Antibiotics used in – 100% Remdesivir used in – 30% Tocilizumab used in- 1.5%
  • The data can be extrapolated to others as well as it is likely to be more or less similar!
  • Highlights that the presence of diabetes, use of steroids and oxygen are not mandatory ingredients for developing Mucor.
  • Also highlight that the steroids are overused. Any home treated patient shouldn’t be on steroids in most of the cases.
  • And last but not the least, and a thing which can easily get overlooked is that Antibiotics were used in all!
  • So, the common denominator for all Mucor patients was Covid-19 + Antibiotic use. And other major presence was that of Diabetes and Steroid use. And remember the problem is almost restricted to our country as of now!

What are present Indian Practices in treating Covid-19 spectrum?

  • We all know that Covid-19 has to be treated strictly as per State/National guidelines. But does that happen really?
  • The real scenario is very different.
  • For practical purposes let us divide Covid caregivers into different categories, especially for indoor care. And later have a glimpse of ‘Standard of care’ offered by them.
  • Due to pandemic and unprecedented situation, our requirement of ICU beds/ Ventilator beds is extremely high and we had no option other than to convert many existing setups with or without ICUs into Covid facilities.
  • The division of Covid care giving hospitals, facts and the figures, are speculative and representative only but derived from practical experiences of many doctors and patients after talking to them. Actual figures or statistics cannot be obtained. And the comparison is with the highest category.
  • And this may not be taken as undermining or demeaning of the services offered by any category hospital except for CAT E. It is understandable that the deficiency in services is predominantly due to logistics and demand mismatch.
  • CAT A – Existing hospitals already equipped with level III/ III B critical care setups and established practices.
    • Many Premium Corporate hospitals, Post Graduate Educational Institutional hospitals, Premium Govt Institutions qualify for this category.
    • Available to a very a smaller number of patients – less than 5%
    • Standard of care: Highest. Many have facilities of ECMO and Lung transplant.
    • Covid Treatment Protocols and Guidelines: In place and rigorously followed.
    • Other Hospital protocols: In place and rigorously followed.
    • Nursing: High quality trained qualified nurses with 1:1 ratio.
    • Cleanliness and Hygiene: very high
    • Air handling units and AC/Ventilation: Available and as per standard protocols
    • Antibiotic policy: In force and adhered by. Invasive Ventilation survival: Almost equal to Non Covid ARDS or lesser.
  • CAT B – Existing hospitals doing basic standardized critical care converted into Covid hospitals.
    • Moderate or large sized multispecialty hospitals, medical college hospitals, and nursing homes fall in this category.
    • Again, available to a lesser population due to limited number of critical care beds/ Covid beds.
    • Standard of care: Moderate to High but limited to the number of existing critical care beds.
    • Covid Treatment Protocols and Guidelines: Mostly in place and followed. Some centers deviate for self- benefits!
    • Other Hospital protocols: Mostly in place and followed.
    • Nursing: Moderate level. Ratio is much lesser than 1:1especially in Covid ICUs.
    • Cleanliness and Hygiene: Moderate to high.
    • Air handling units and AC/Ventilation: May or may not be available
    • Antibiotic policy: Not always available. Not always followed.
    • Invasive Ventilation survival: Much lesser than CAT A.
  • CAT C – Existing hospitals not having Critical care set ups converted into Covid hospitals.
    • Self-explanatory.
    • Available to majority of population.
    • Standard of care: Low to Moderate
    • Covid Treatment Protocols and Guidelines: Mostly in place and followed. Some centers deviate for self- benefits!
    • Other Hospital protocols: May not be in place except if NABH.
    • Nursing: Low. Very few trained nurses available and even fewer in Critical care. Ratio is very low. Even 1:10 is luxury at some places.
    • Cleanliness and Hygiene: Poor to Moderate.
    • Air handling units and AC/Ventilation: Unavailable.
    • Antibiotic policy: Usually not in place
    • Invasive Ventilation survival: Very low.
  • CAT D – Newly formed or assembled Covid Hospitals.
    • Self-explanatory.
    • Available to majority of population.
    • Standard of care: Low.
    • Covid Treatment Protocols and Guidelines: Mostly in place and followed. Some centers deviate for self- benefits!
    • Other Hospital protocols: Doesn’t exist!
    • Nursing: Low. Very few trained nurses available and even fewer in Critical care. Ratio is very low. Even 1:10 is luxury at some places.
    • Cleanliness and Hygiene: Poor to Moderate.
    • Air handling units and AC/Ventilation: Unavailable.
    • Antibiotic policy: Usually not in place.
    • Invasive Ventilation survival: Very very low.
  • CAT E – Triple E or Exempt Exempt Exempt category.
    • Self-declared or unqualified Covid caregivers in Non- hospital / Day care Or Home care settings.
    • This does form a quiet large group, catering to very large volume of patients, especially in rural settings.
    • Unorganized, Unmonitored, Unaccounted, Unaudited, Unfearing, Understanding, Unlearning, Uncaring.
    • Standard of care: What is that?
    • Covid Treatment Protocols and Guidelines: Not for us? We have our own.
    • Other Hospital protocols: what is a protocol?
    • Nursing: why?
    • Cleanliness and Hygiene: Not applicable. Air handling units and AC/Ventilation: Not applicable.
    • Antibiotic policy: We have our own policy!
    • Invasive Ventilation survival: What is that?

Some poor practices observed on a consistent basis- Very relevant as risk factors for Mucormycosis.

  • Very poor cleanliness and hygiene due to staff shortage.
  • Very poor ventilation.
  • Poor housekeeping.
  • Failure to follow sterile practices.
  • Poor nursing.
  • Lack of oral-nasal hygiene in most patients. Severe the disease lesser the oral care and   hygiene!
  • Use of cotton mattresses and bedsheets. Changed with a very less frequency. Prone to becoming moist and dirty. Patients sleep prone on same pillow.
  • Disposable bedsheets changed or discarded only after discharge.
  • Heaps of biomedical and organic waste like food waste lying for extended times.
  • Unconsumed food lying for days together.
  • Patients using same masks till discharge.
  • Deviations from following protocols.
  • Poorly controlled Diabetes.
  • Antibiotic misuse.
  • Steroid overuse/abuse.

Steroid and antibiotics abuse

  • Recently came across a stunning regime for mild Covid cases managed by category E healthcare provider in a rural setting. And many variants of this regime are followed at many places by Cat E. The regime-
    • After establishing diagnosis of Covid or suspected Covid Inj Meropenem bid x 3 days, followed by
    • Inj Pip-Taz 4.5 bid x 3 days, and
    • Inj Methyl Prednisolone 40/60/250 mg bid x n days.
    • The charges for such regime are much higher than even of Covid ICUs. The sole reason behind the game. Imagine the dangers involved! No wonders why Mucor hits even mild non-admitted Covid cases.
  • One more example, this time from a Covid hospital.
    • Patient receiving Inj MPS 40 mg bid even on his 25th day of admission along with a parenteral antibiotic!
    • Overall, antibiotics are misused by many including all categories with probable exception of category A.
    • Meropenem is the most abused drug in this pandemic in our country. The next shortage might of this drug!
    • Antibiotics are not useful in treating Covid! They are used to treat or prevent secondary infections. They do find mention in our ‘State protocol’ as per disease severity along with option of ‘As per local hospital policy.’ This remark is being totally ignored by many and are used without any definite indications, and the use is justified by citing reasons of following the protocol!
    • The other reason for meropenem use is having a ‘sense of security’, although false. Meropenem isn’t going to change the course of Covid. And likely to cause harm when used without a proper indication.
  • Besides Meropenem, all higher antibiotics are misused in many of the hospitalized patients by being used irrationally without any proper indication or policy.
  • Besides higher antibiotics in hospitalized patients, almost every mild and non-hospitalized patient of Covid also receives a cocktail of medicines including 2 antibiotics. Many receive a combination of Doxycycline [a broad-spectrum antibiotic] and Azithromycin.
  • Coming to ‘Steroids’ they are the next most abused/misused drugs with the ‘guidelines’ going for a toss!
  • Covid treatment is judged as incomplete without steroids by many. It’s not unusual to find it added to Doxy + Azithromycin combination. At many places, especially the category E will use steroids as already discussed. A shot of DEXA is a common practice everywhere.
  • Many hospitals are also using prophylactic anti-fungal agents, Fluconazole and Voriconazole along with steroids for prevention of Candidiasis.

What is the result of covid + Broad Spectrum Antibiotics +- steroids +- Uncontrolled Diabetes?

  • Severe suppression of oral+gut microbial flora.
  • On the background of an immunosuppressive state!
  • Steroid induced macrophage dysfunction and suppressed NK cells, impaired neutrophilic chemotaxis and phagocytic functions as well as other complex immune functions are underlying mechanisms. These along with overgrowth of pathogenic microbes/fungi ultimately results in invasive fungal infection [4]. The growth of fungi is aided by excess iron and zinc as well!
  • Human oral microflora consists of approximately 700 different organisms! Bacteria being predominant, also includes almost 100 fungi, and viruses as well [5].
  • These do not cause disease in healthy individuals. Rather the complex interplay and symbiotic association is responsible for local immunity and prevent growth or invasion by pathological microbes [5].
  • With use of powerful broad-spectrum antibiotics, the microflora is damaged/disturbed and results in overgrowth of pathogenic organisms. And the immunity is at its low due to reasons stated above. The ultimate result is an epidemic of Mucor!
  • The use of prophylactic antifungals Fluconazole and Voriconazole are more harmful. These will suppress the local fungal flora but have no action against mucor! [1].

So, what are the preventive strategies?

  • As discussed, the reasons for Mucormycosis are multifactorial with contribution from environmental factors, host factors and human interventions!
  • All treating hospitals, medics, paramedics need to improve on many fronts. Doesn’t need any heroic or very expensive measures but a conscious and judicious approach.
  • Bringing the E category under radar and curbing on malpractices wherever identified is needed and a real challenge!

The following preventive measures are to be emphasized again and again:

  • Use steroids only when indicated. Do not use in non- hypoxic patients or non-inflammatory states. Use Dexamethasone 8 mg once a day for 10 days or Methylprednisolone 40 mg twice a day for 10 days as recommended. Don’t exceed the dose, duration without any specific or compelling reason. If needed to continue after 10 days for compelling indications, then use oral form in modest doses.
  • Use antibiotics with caution. Mild Covid doesn’t need any antibiotics. Even evidence for Doxycycline and Azithromycin is not great and the use may be discouraged. Indoor patients, even the severest ones without ventilator can be managed by oral antibiotics like Amoxiclav. Parenteral antibiotics may be used if risk of secondary infection is high. Antibiotics like Piperacillin-Tazobactam, Meropenem, Teicoplanin etc. should not be used empirically. Use only as per culture-sensitivity reports, and empirically only in compelling indications when there is no culture evidence or no time to wait for reports like bacterial sepsis/shock.
  • Prophylactic use of routine anti-fungals should be discouraged.
  • Aggressive control of blood sugars by use of Insulin. Check blood sugars multiple times a day of all patients irrespective of their diabetic status and try to maintain blood sugars below 180 mg% at all times. Many times, need Insulin infusion. Don’t miss ketoacidosis and hypovolemia. Checking HBA1C on admission will be helpful.
  • Maintain good oral-nasal hygiene for all admitted patients.
  • Maintain excellent hygiene in wards/ ICUs. The nursing and helper staff has to be trained appropriately. Have an SOP and monitoring system in place.
  • Good housekeeping includes changing disposable bedsheets and pillow covers more frequently or daily.
  • Change of patient`s mask daily. A surgical mask is sufficient.
  • Effective and rapid disposable of all types of wastes.
  • Hygienic use of oxygen delivery devices or interfaces. Use disposable circuits and tubings/masks for oxygen delivery. Never reuse.
  • Good ventilation. Need not always be ACs or AHUs although preferred.

Most of the measures can be remembered by a simple Mnemonic:

M – More airy and non humid environment.
U – Universal aseptic precautions.
CCorticosteroids with caution.
OOral hygiene.
RRestricted use of antibiotics.
M – MASK Hygiene.
YYes to protocol based treatments.
C – Clean treating environment.
O – Oxygen delivery hygiene.
SSugar control.
I – Inspect oral and nasal cavity. Intervene early.
S – Stop overuse of drugs of questionable efficacy.

Final Points

  • The ‘common denominator’ for ‘Mucor in the pandemic’ has to be explored in detail by doing extensive scientific data mining from the current cases and come out with some definite reasons with evidence ultimately translating into preventing guidelines.
  • Our state guidelines also need to emphasize and incorporate a negative list- ‘Things not to be done while treating Covid’, and add a note on proper antibiotic selection on case-to-case basis.
  • If the trend of ‘Antibiotic and Steroid’ misuse/abuse continues, we are not far away from many more epidemics of pan drug resistant drug organisms with patients succumbing to trivial infections! We will have nobody except us to blame!

CME INDIA Tail Piece

A. Pathophysiology of Invasive Mucormycosis.

B. Usual Predisposing Factors

Predisposing ConditionPredominary Site of Infection
Diabetes mellitusRhinocerebral, sino-orbital, cutaneous
MalignancyPulmonary, sinus, cutaneous, sino-orbital
Hematopoetic stem cell transplantationPulmonary, disseminated, rhinocerebral
Solid organ transplantationSinus, cutaneous, pulmonary, rhinocerebral, disseminated
Intravenous drug useCerebral, endocarditis, cutaneous, disseminated
Deferoxamine therapyDisseminated, pulmonary, rhinocerebral, cutaneous, gastrointestinal
TraumaCutaneous, ocular
Courtsey: https://www.infectiousdiseaseadvisor.com/

References:

  1. Mucormycosis (Zygomycosis): https://emedicine.medscape.com/article/222551-overview#a7
  2. Mucormycosis https://rarediseases.org/rare-diseases/mucormycosis/
  3. Mucormycosis epidemic in india:out of the box menu https://cmeindia.in/mucormycosis-epidemic-in-india-out-of-the-box- menu/
  4. Update on mucormycosis pathogenesis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081484/
  5. Oral microbiome: Unveiling the fundamentals https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503789/



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