CME INDIA Presentation by Admin.
What is Black, What is White?
As reported in the media about the devastating effect of so-called black fungus, there is high level of panic among health care professionals too. It is high time to analyse the reality of Mucormycosis. Physicians should be in alert mode to detect it early and timely referral can save life. We bring you the essentials of Mucormycosis. – Editor.
Dr Vivek Gumber, Sr Resident SMBT medical college, Nashik Ponders:
I don’t know about other parts of India, but here in Nashik region we have a wave of diabetes Covid patients of Mucormycosis. There are so many who are dying due to this. In last year, we haven’t seen a single patient here, but there are so many that amphotericin liposomal is in shortage now despite being very costly and many are not able to afford.
CME INDIA tried to understand the status of “Tsunami of Post Covid nasty fungal infection.”
Most Vital Communication
Dr Chandrakant Tarke, Pulmonologist, Apollo Hospitals, Hyderabad:
1.During first wave, I have observed very few cases of post COVID mucormycosis. During second wave, we are observing many cases of this deadly disease.
First wave was peaked in September 2020. Second wave is ongoing now. Current temperature conditions favourable for survival of these fungi.
2. India has the second largest diabetic population globally, with nearly 70% of these cases being those of uncontrolled diabetes. DKA, CKD patients, dehydration are strong risk factors for Mucormycosis.
3. Sino-nasal mucosal breach in COVID 19 favouring germination of fungal spores.
4. More sick cases, early lung involvement, there is more steroid use in second wave. DM and steroid both can cause neutrophilic dysfunction which favours mucormycosis. Immune dysregulation due to COVID 19 disease might be additional risk factor.
A pre-COVID study showed, 9% of all mucormycosis cases were found to be nosocomial in origin. These patients acquired infection either at the site of the ECG leads or the adhesive tapes, or from contaminated intramuscular injections, or from air in the hospital environment.
Most hospitalized COVID patients require oxygen. Contaminated oxygen sources, cylinders, humidifiers, impurities in industrial oxygen, steamers etc can be potential sources for Mucor infection.
6. Other possible risk factors:
- Genetic predilection.
- Steam inhalation abuse.
- Use of higher antibiotics.
- Use of fluconazole and voriconazole.
- Poor oro-nasal hygiene in hospitalised patients.
- Use of same mask/unhygienic cloth mask for prolonged period.
Dr Akashkumar Singh, Dr. Ankur Bhavsar, Spandan Multispeciality Hospital, Vadodara and Dr Hiren Soni, HOD, ENT dept., GMERS Medical College, Vadodara:
- Current trend and situation – A Medicine & ENT perspective
- We have seen increased cases of mucormycosis recently during second wave of Covid 19 in India. We used to have cases of mucormycosis pre covid era too but incidence was very low and only in immunocompromise patients. After first wave in India we have seen few cases of mucormycosis and we have been able to treat and cure them all barring one exception.
- But situation is very different this time around in second covid wave. We are having many cases of mucormycosis. Probable contributory factors could be uncontrolled DM due to covid 19 and use of high doses of steroid as blanket therapy, use of immunosuppressive drugs like tocilimab. it could also be use of tap water in oxygen humidifier in such cases. In the second wave, almost 50% of our patients are on oxygen therapy with nasal prongs, masks etc in situ and majority of them requiring prolonged oxygen therapy and prolonged steroids adding further to our woes. So, main possible culprit could be immunocompromised status of the patient due to disease and treatment as well as oxygen therapy mode of administration.
- As an ENT, we see cases with symptoms of unilateral headache or facial pain, retroorbital pain, nasal blockage and nasal discharge. All cases of post covid with such symptoms should be subjected to imaging to confirm sinus involvement and beyond. Microbiological examination with KOH shall confirm diagnosis but at times when disease is within the sinus only and not in the nasal cavity or palate makes it difficult to get sample pre-operatively.
Depending upon the involvement surgical removal technique differs
|Only sinus involvement||Endoscopic sinus surgery|
|Only palate and alveolar arch||Intra oral approach and partial maxillectomy|
|Orbital involvement with vision||Endoscopic sinus surgery with orbital decompression|
|Orbital involvement without vision||Maxillectomy with orbital exenteration|
|Rhino cerebral involvement||Debridement with neurosurgeon|
- According to occuloplatic surgeons early exenteration gives better results in containing the disease.
- Apart from this surgical debridement which will confirm the diagnosis as well as therapeutic major part of the treatment lies with physician for control of DM, DKA and administration of Amphoterecin B preferably Liposomal, Isavuconazole or posconazole subsequently. In current scenario, we are facing scarcity of Ampho B depriving patients of treatment. Cost is another factor as liposomal ampho B and after that continuation of Isavuconazole/posconazole for a month only medication will be around 5-6 lacs in expenditure.
- With 50% mortality documented with mucormycosis according to literature and rise of cases in post covid patient and lack of medicine point towards very grim situation.
Dr Suresh Kumar, Infectious disease Specialist, Apollo Hosp:
- A study soon to be published shows overall 0.27 and ICU 1.6% incidence of mucormycotic. Although ID Physicians see a huge number due to referral bias the true denominator is unknown. This incidence is far below the generally accepted threshold of about 8% used in Haematology oncology.
Dr Nishith Kumar Pulmonologist Ranchi:
- At least in our centre we are strictly adhering to guidelines. We’re using injectable steroid in recommended doses (0.5-1mg/kg methylprednisolone in divided doses). Also, we’re initiating injectable steroid in only hypoxic patients. Also, we’re regularly monitoring blood sugar levels in all our admitted patients who have been put on steroid & trying to keep it under strict control using insulin. I have seen Doctors using pulse therapy (methylprednisolone 500mg – 1gm iv OD x3 days/ Inj Dexamethasone 8mg TID) and continuing oral corticosteroid for 2-3 weeks even in non-hypoxic/stable patients post discharge.
- We need to be very careful with steroids use as it is a double-edged sword.
Dr Atri Gangopadhyay, Pulmonologist, Ranchi:
- I have received 1-2 patient of same problem. It is very serious condition with high mortality
- However, the magnitude of problem has been hyped to the level of fear mongering, which should be discouraged
Dr Vinay Dhandhania, Diabetologist:
- One major factor is steroid induced diabetes post Covid is not being managed properly, not being monitored. Very high blood sugar in immunocomprised state appear to be a major factor. I have seen recently 3 cases.
Dr T R Hem Kumar, Diabetologist, Bengaluru:
- First, it is due to starting steroids for all in this second wave as we see prescriptions with steroids from day one.
- Second is indiscriminate use of antibiotics particularly gram positive.
- Third reason could be Budesonide, its use has picked up (inhaler should be safer option).
- Fourth is Failure to control high sugars.
Dr Sanjeev, DM, Heamatology, Asso. Prof SGPGI (With inputs from Dr Amit Keshri, consultant, ENT):
- We are discussing about it in last 6 months, our ENT department is seeing 3-4 cases each week
- Mucor of Paranasal sinus and Skull base cases request are pouring in.
- 3 cases in 3 days. All from Lucknow. Be vigilant in DM patient while treating Covid. Early Diagnosis is key.
Dr Rajiv Awasthi, Consultant Physicians, Diabetologist, Lucknow:
- As far as I am concerned, I have not come across a single case till now.
- Reasons for Surge seems to be the indiscriminate use of steroids in inappropriate doses.
- As far as the inhalation therapy is concerned, many of diabetic and non-diabetic patients have been taking inhalation therapy for years but we didn’t see it.
- It may due to profound impact of viral disease and steroids with “use of same masks repeatedly for weeks as moisture from breath, ruptured linen Fibre’s make a good ground for fungal growth.”
- And last possibility in my opinion is that, there might be something unusual in this viral infection at cellular level which is causing disruption in immunity against fungal attack.
Dr. Firoz Memon, Internist, Raipur:
- I have seen 2 cases of Mucor mycosis in last one week. Liposomal Amphotericin B started.
Dr Anil Motta, Sr Consultant, Internal Medicine Hospital:
- My personal observation & inference, as also discussed with my colleagues is that Mucor mycosis is not so rampant here, though lot of serious fungal infections seen. Candida; Aspergillosis etc.
- My observation is that Mucormycosis is more seen in:
- Tobacco growing zones
- Cotton growing zones
- Coastal zones.
Dr Subodh Banzal, DM, Endo:
- I have talked to leading ENT Surgeons Indore all of them operating 4 to 5 cases of mucor mycosis daily for last 4 weeks. All of them post Covid.
- Bombay hospital, choithram, Apollo, chl, Akash and almost all big hospitals in Indore have such cases. Dr Gwaliorkar senior ENT Surgeon of Bombay hospital Indore said he has been operating such cases for last one month but recently they are coming like Rain!
Dr Venkatesh Molio, Maregoan:
- In Goa, we have not seen many cases so far, Just one case.
- But I think it follows peak of cases and we have not peaked as yet.
- In Maharashtra, they are witnessing a rise in cases of mucor now.
Dr Santosh Malpani, Diabetologist:
- I think contamination is seed in the soil of immuno compromised patient. Hygiene is very important. To summarise, important factors:
- Abundance of spores.
- Suppressed Host defence (mainly mucosal).
- Conducive atmosphere favouring germination of spores.
Dr Hemdhankar Sharma, Nodal officer, JLNMCH:
- We haven’t seen many cases. Only one case was brought to our notice of eye lesions, with complete loss of vision. We are on alert mode.
CME INDIA Learning Points
Mucormycosis quoted as diabetes-defining illness, is one of the most devastating complications in uncontrolled diabetics with mortality rates ranging between 40-80%. India contributes to 40% of the global burden of this “rare mould” infection.
- In most of the history of intravenous dexamethasone for COVID‑19 disease has been found. The strongest predisposing factor appears to be hyperglycemia in undiagnosed or uncontrolled diabetics. Hyperglycemia leads to increased expression of the endothelial receptor GRP78, resulting in polymorphonuclear dysfunction, impaired chemotaxis and defective intracellular killing.
- An important virulence trait of Mucorales is the ability to acquire iron from the host.
- In DKA, free iron becomes readily available in the serum. This excess endogenous iron is efficiently taken up by the Mucorales through siderophores or iron permeases, further enhancing their virulence.
- When steroids are used, it can cause impairment in the neutrophil migration, ingestion, and phagolysosome fusion.
- Coupled with the potential implications of steroid-induced hyperglycemia, the diabetic COVID 19 patient receiving corticosteroids is exceptionally vulnerable to the development of mucormycosis.
- Thus, SARS COV 2 itself may serve as a risk factor – chronic respiratory disease, corticosteroid therapy, intubation /mechanical ventilation, deranged glucose metabolism, which may lead to secondary fungal infection.
- COVID patients should be evaluated for undiagnosed diabetes, checked for strict glycemic control and closely monitored for secondary infections.
- The two most important manifestations of Mucormycosis in this setting are rhino-orbital-cerebral and pulmonary.
- The clinical hallmark is tissue necrosis manifested as a necrotic lesion, eschar or black discharge in the nasal or oral cavity. Orbital, ocular and cranial nerve involvement are ominous signs that must be taken seriously.
- There is no biomarker for mucormycosis and hence a negative galactomannan and beta-d-glucan are useful pointers to rule out other mould infections. A false positive galactomannan due to generic piperacillin tazobactam use etc. can lead to the erroneous diagnosis of invasive aspergillosis.
- Although challenging, the need to distinguish Mucor from bacterial infections and from aspergillosis in a timely fashion is of essence.
- Treatment with voriconazole for suspected invasive aspergillosis increases the pathogenicity of Mucor with obvious dire consequences.
How Presenting Now?
- Facial swelling
- Sinus tract on face
- Discolouration of skin (necrosis)
- Infection in dangerous area of face
- Foul smelling nasal discharge
- Nasal congestion
- Erythematous to violaceous to black necrotic eschar in nasal cavity
- Intraoral pus discharge
- Ulceration & Blackening of mucosa
- Exposed palatal bone
- Sinus tract
- Loosening of teeth
- Unhealed tooth socket
- Mobility of maxilla
- Vision loss
- Peri orbital cellulitis
- Exophthalmos (Proptosis)
- Cranial nerve involvement
- Rapidly progressive neurological deficit
Fever/ Cough/ Chest pain/ Dyspnoea/ Haemoptysis
Abdominal pain/ Nausea/ Vomiting/ Gastrointestinal bleeding
- Lab parameters: CBC/ ESR/ FBS, PPBS, HbA1C/ LFT/ RFT with electrolytes/ HIV, HbsAg / CSF (if indicated).
- Nasal endoscopic examination Black necrotic eschar tissue
- Radiographic Examination:
- X-Ray PNS and OPG may be normal.
- Contrast enhanced CT scan with 3D Reconstruction findings: 1. Erosion and thinning of Hard Tissues Enlargement of masticatory muscle 2. Mucosal thickening of sinuses Changes in Fat Planes.
- MRI with contrast findings: 1. Optic neuritis Intracranial involvement 2. Cavernous sinus thrombosis Infratemporal fossa involvement.
- Potassium hydroxide (KOH) wet mount and fungal culture/sensitivity from biopsy obtained during debridement or from nasal swab obtained during diagnostic nasal endoscopy.
- Thus, rapid diagnostic methods include biopsy, KOH mount and Calcofluor stain.
- Mucor is difficult to routinely culture.
- Biopsy remains the mainstay of diagnosis
(Compilation by Dr Chandrakant Tarke, Apollo Hospitals, Hyderabad.)
1. Surgery: FESS+- Exentration/debridement
2. Medical management options:
a). Liposomal Amphotericin B: Drug of choice
- Common brands: PHOSOME, AMBISOME 50 mg vial
- Dose: Any organ (except CNS) 5 mg/kg, For CNS 10 mg/kg.
- For sino-orbital: e.g., 60 kg person ×5 mg= 300 mg (6 vials of 50 mg)
- In 500 ml 5%Dextrose over 4-6 hours i.v. once daily for 3 to 6 weeks, followed by oral Posaconazole. Treatment duration 3 to 6 months. Repeat CT PNS and orbit before switching over to oral therapy and before stopping treatment.
- (Potassium monitoring required, hypokalaemia is frequent with Ampho B)
- Common brands: PICASA, POSATRAL, CRITPOSA
- Oral suspension: 200 mg (5 mL) PO TID. OR
- Tablet: 300 mg PO BID on Day 1, then 300 mg PO qDay
- IV: 300 mg IV BID on Day 1, then 300 mg IV qDay
- Common brands: CRESEMBA372mg isavuconazonium sulfate (equivalent to 200mg isavuconazole)
- Dose: Initial: 372 mg PO/IV TID x6 doses (48 hr)
- Maintenance: 372 mg PO/IV OD
d). Conventional (Deoxycholate) Amphotericin B:
- Nephrotoxic/Anaphylaxis risk, vial 50 mg
- Test dose: 1 mg IV x1 infused over 20-30 min,
- Load: 0.25-0.5 mg/kg IV infused over 2-6 hr
- Maintenance: 1-1.5 mg/kg IV qOD over 4 to 6 hours.
- Fever/chills are minimized by premedication with diphenhydramine 25 mg iv or oral and/or hydrocortisone injection 60 minutes before.
(creatinine, potassium, magnesium monitoring)
- TAB POSACONAZOLE 300 twice daily on day 1 followed 300 mg once daily… (100 mg 3 tablets).
- This regimen is followed in neutropenic or immunocompromised patients to prevent invasive mucor or aspergillus.
- Pulmonary mucormycosis: 50-70%.
- Rhinocerebral: 30 – 70%.
- CNS involvement: >80%.
- Disseminated: > 90%.
- AIDS: almost 100%.
- Hyperbaric oxygen may have to be considered.
Duration of therapy:
- Inj antifungal 2-3 weeks or more depending on clinical severity.
- Liposomal antifungal may be used if AmB toxicity develops.
- Overlap of injectable and oral antifungals for 3-4 days followed by oral antifungals.
- Oral antifungal to be continued 1 week after biopsy is negative.
- Regular follow up initially monthly for 3 months then SOS.
CME Tail Piece
1. Chelating agent is known to increase the risk of mucormycosis is Deferoxamine
2. Mechanism by which Deferoxamine increase the risk of mucormycosis
- The deferoxamine and iron bind together to form feroxamine
- This is a siderophore for the species Rhizopus allowing increasing iron uptake by the organism and hence increasing their growth and tissue invasion
3. Risk factor for Mucormycosis
- Diabetes mellitus with Ketoacidosis
- Use of Deferoxamine
- Increased iron stores
- Treatment with glucocorticoids
- COVID-19 infection with diabetes and glucocorticoid use
- Injection drug use
- Hematological malignancies
4. Not all patients with Mucormycosis have pre-existing diabetes
Only 30-40% of patients have pre-existing diabetes. Some of the others are diagnosed to have new onset of diabetes. In the era of COVID-19, the development of Mucormycosis has been rampant, especially in patients having steroid-induced diabetes
5. Rhino-oculo-cerebral Mucor mycosis is common with diabetes
6. Statins have an inhibitory effect on the growth of these fungi. Exposure of R. oryzae to statins at concentrations below their MICs decreases virulence both in vitro and in vivo as per one study.
7. Be Alert for the early clinical features of Rhino-cerebral mucormycosis
- Nasal discharge- often blackish
- Nasal congestion
- Sinus pain
8. About imaging techniques, CT scan is useful for bony erosions. However, MRI is more useful to detect intracranial involvement
9. The advantage of liposomal AmpB compared to conventional-Liposomal AmpB is less nephrotoxic and hence larger doses can be given without nephrotoxicity
10. Amongst the various mucormycosis The Cunninghamella species has the worst prognosis
11. The most common predisposing factor for the development of mucormycosis in patients with COVID-19 infection-
- Hyperglycemia is the strongest risk factor
- 47% of Indians are unaware of their underlying diabetes
- Many of them are found to have diabetes and severe hyperglycemia secondary to COVID-19 itself and administered glucocorticoids
12. Hyperglycemia provides a conducive environment for infections
13. Glucocorticoids increase the risk of infections by impacting Polymorphs function – it leads to Impairment in the neutrophil migration ingestion, and phagolysosome fusion
14. ICMR Advisory
- Lim S, Bae JH, Kwon HS,et al. COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat Rev Endocrinol 2021; 17:11–30.
- Ibrahim AS, Spellberg B, Walsh TJ, et al. Pathogenesis of mucormycosis. Clin Infect Dis 2012; 54 (Suppl 1): S16-22.
- Treatment Protocol for Mucormycosis In Adult Patients – By Expert Committee of Civil Hospital, Ahmedabad.Dr. Kamlesh Upadhyay: (Professor and Head, General medicine) 2) Dr. Ila Upadhya: (Professor and Head, ENT) et al.2021
- Sarkar S, Gokhale T, Choudhury SS, Deb AK. COVID-19 and orbital mucormycosis. Indian J Ophthalmol 2021;69:1002-4. © 2021 Indian Journal of Ophthalmology | Published by Wolters Kluwer – Medknow
- https://shrtm.nu/JUYE/ Dr Om Lakhani ,Zydus Hospital ,Ahmedabad
- Chakrabarti A, Chatterjee SS, Das A et al. Invasive zygomycosis in India: experience in a tertiary care hospital. Postgrad Med J 2009; 85: 573–81.
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