“MUCORMYCOSIS

IN COVID 19
PANDEMIC”
PRESENTED BY
DR.MASHUQ AHMAD JUMMA
ASSISTANT REGISTRAR
DEPARTMENT OF MEDICINE
MUCORMYCOSIS / BLACK FUNGUS
DISEASE

• is a clinical syndrome caused by a number of fungal species

belonging to the order Mucorales (class zygomycetes).
Common species are Rhizopus,Rhizomucor and Mucor

• It is deadly and aggressive disease with average

mortality rate of 54%

• Microscopycally mucorales have non septate hyphae, broad and

irregularly branched at right angle (90 degree branching)
EPIDEMIOLOGY

⬥ Spread by Inhalation or inoculation of sporangiospore in the skin or mucosa

⬥ Mucormycetes are ubiquitous.Found in air, soil, decaying organic matter,

animal dung etc

⬥ Some studies found seasonal incidence: More in autumn

⬥ In developed country found to occur in immunecompromised state

⬥ In developing country : Sporadic. More common in diabetes and trauma

PREDISPOSING FACTORS

• Covid 19 infection (active / after recovery)

• Diabetes mellitus with or without ketoacidosis
• Corticosteroids and immunomodulators
• Neutropenia and (lymphopenia also)
• Iron overload and chelation therapy
• Haematological malignancy eg: Leukemia,Lymphoma
CONTD…..

• Major trauma or skin injury due to surgery burn or wounds

• Organ transplantation
• Malnutrition
• Premature or LBW baby
• Voriconazole therapy
• Rarely HIV or AIDS
CLASSIFICATIONS

• Rhino-orbito-cerebral
• Pulmonary
• Cutaneous
• Gastrointestinal
• Disseminated
• Others: endocarditis,osteomyelitis,peritonitis,renal infections
RHINO-ORBITO-CEREBRAL

• A disease of immunosupressed seen in diabetic patient (particularly acidotic) and

neutropenic paients on antibiotics.Almost invariably fatal,causing septic necrosis
and infarction of the tissue of the nasopharynx , orbit even bone and brain

• C/F: Facial pain,headache,fever,may have eschars in oral cavity,loosen teeth,jaw

destruction,orbital cellulitis, proptosis, chemosis,blindness, ophthalmoplegia and
other cranial nerve lesions,cerebral abscess,cavernous sinus or internal carotid
artery thrombosis
CONTD…..

• Xray of sinuses may show mucosal thickening and fluid.

• bone destruction may be apparent in CT.
• Endoscopic evaluation of the sinuses should be performed to assess
appearance and to obtain tissue.
 PULMONARY
• Usually secondary to neutropenia and seen in BMT or leukemia patients
receiving chemotherapy

• C/F: mild fever, shortness of breath and cough or haemoptysis.erosion of

blood vessel may cause severe pulmonary haemorrhage

• CXR may show infiltration,consolidation and cavities,sometimes effusion

• Diabetic patient may develop a milder form of chronic pulmonary infection

Case courtesy of Dr Roberto Schubert,
Radiopaedia.org, rID: 17628

REVERSE HALO SIGN

 CUTANEOUS

• Outbreak has been associated with colonized bandages . Cases have occurred
with trauma, burns, insect bites and dissemination from a distant site.

• The appearance is of cellulitis, but if unrecognized the organism penetrates

deeper into the skin and necrosis may follow vascular invasion. May take the
appearance of a chronic ulcer. Infected area may turn black. Later,
dissemination may follow.
GASTROINTESTINAL

• Seen in those suffering from malnutrition, although cases occurred in renal

transplant recipients. Any part of the tract may be infected and it is rapidly
fatal.

• C/F: Abdominal pain, fever, nausea, vomiting, gastrointestinal

bleeding, perforation, peritonitis.
DISSEMINATED

• Occurs when other sites are infected through haematogenous spread.

• Most commonly associated with pulmonary variant and patient with iron
overload, neutropenia and active leukemia.
• C/F: Changes in mental status, coma
• Metastatic skin lesion is an important hallmark in early diagnosis .
• Mostly fatal .
 MUCORMYCOSIS AND COVID DISEASE ASSOCIATION:

( STUDY ANALYSIS )

• Recently incidence of mucormycosis is on the rise among the covid affected patients
worldwide and mostly in INDIA.

• A 2019 nationwide multi-center study of 388 confirmed or suspected cases of

mucormycosis in India prior to COVID-19, Prakash et al found that 18% had DKA
and 57% of patients had uncontrolled DM .
CONTD…

• Similarly, in a data of 465 cases of mucormycosis without COVID-19 in India,

Patel et al has shown that rhinoorbital presentation was the most common
(67.7%), followed by pulmonary (13.3%) and cutaneous type (10.5%).

• The predisposing factors associated with mucormycosis in Indians include DM

(73.5%), malignancy (9.0%) and organ transplantation (7.7%)
 CONTD…

• In a recent systematic review conducted until April 9, 2021 by John et al that

reported the findings of 41 confirmed mucormycosis cases in people with COVID-19,
DM was reported in 93% of cases, while 88% were receiving corticosteroids.
 CONTD….

• These findings are consistent with another larger case series of 101 mucormycosis
cases (95 confirmed and 6 suspected) in COVID-19, conducted on May 2021
where 80% cases had DM, and more than two-third (76.3%) received a course of
corticosteroids. Collectively, these findings suggest an unholy trinity of mucormycosis,
diabetes and steroid in people with COVID-19
• Since there are no studies that compared patients of mucormycosis in non-diabetic
COVID-19 who did not receive steroids versus COVID-19 patients who received
steroids and developed mucormycosis, it is difficult to establish a causal effect
relationship between COVID-19 and mucormycosis in relation to corticosteroids.
Nonetheless, there appears to be a number of triggers that may precipitate
mucormycosis in people with COVID-19 in relation to corticosteroids:

• (i) Presence of DM with or without DKA increases the risk of contracting

mucormycosis and DM is often associated with an increased severity of COVID-19
• (ii) Uncontrolled hyperglycemia and precipitation of DKA is often observed due to
corticosteroid intake. Low pH due to acidosis is a fertile media for mucor spores to
germinate. Moreover, steroid use reduces the phagocytic activity of WBC (both first line
and second line defense mechanism), causes impairment of bronchoalveolar
macrophages migration, ingestion, and phagolysosome fusion, making a diabetic patient
exceptionally vulnerable to mucormycosis.

• (iii) COVID-19 often causes endothelialitis, endothelial damage, thrombosis,lymphopenia,

and reduction in CD4+ and CD8+ level and thus predisposes to secondary or
opportunistic fungal infection.
• (iv) Free available iron is an ideal resource for mucormycosis. Hyperglycemia causes
glycosylation of transferrin and ferritin, and reduces iron binding allowing increased
free iron. Moreover, increase in cytokines in patients with COVID-19 especially
Interleukin-6, increases free iron by increasing ferritin levels due to increased
synthesis and decreased iron transport. Furthermore, concomitant acidosis
increases
free iron by the same mechanism and additionally by reducing the ability of
transferrin to chelate iron.
• (v) High glucose, low pH, free iron, and ketones in presence of
decreased phagocytic activity of WBC, enhances the growth of mucor.
In addition, it enhances the expression of glucose-regulator protein 78
(GRP-78) of endothelium cells and fungal ligand spore coating
homolog (CotH) protein, enabling angioinvasion,hematogenous
dissemination and tissue necrosis.
 DIAGNOSIS :

• Diagnosis is challenging. Clinical judgment and inter departmental communications

play crucial role.

• Direct Microscopy: Optical brighteners like blankophor and calcofluor white,

haematoxylin­eosin (HE),Periodic Acid Schiff (PAS) and Grocott gomoris Methenamine
Silver (GMS) Stain highlights hyphae.
• Culture: Tissue swabs, sputum, or BAL cultures are usually nondiagnostic
Direct microscopy of bronchoalveolar lavage & transbronchial biopsy may
increase the yield.
rapid growth (3 to 7 days) on Sabouraud agar and potato dextrose agar
incubated at 30◦ .Aggressive vertical growth toward the lid of the Petri dish –

Lid lifters
(Specimens should be chopped not grounded)
• HISTOPATHOLOGY:
- Hyphae can be seen
- there may be Neutrophilic or granulomatous inflammation
- Invasive disease is characterized by prominent infarcts and angioinvasion.
-Perineural invasion may be present.
- Angioinvasion is extensive in neutropenic patients.

• Molecular based methods:

-PCR, RFLP, DNA sequencing that targets the 18S ribosomal DNA of Mucorales
• Antigen Detection & Specific T cells:
Galactomannan and ß-D Glucan – If negative likely invasive mucormycosis than IPA.
Mucorales-specific T cells - by enzyme-linked immunospot (ELISpot) assay

• Genus & Species Identification:

No strong evidence that identification to the genus/species may be important to guide
treatment. Helps to acquire better epidemiological knowledge and investigation of
outbreaks.
Sequencing of Internal Transcribed Spacer (ITS) of rRNA is the best technique.
• IMAGING : X ray Chest and sinuses, CT chest or abdomen, CT/MRI of Head

• ENDOSCOPY: Sinus endoscopy and GI endoscopy

• OTHERS: CBC and other idividualised blood chemistry and routine workup
including ABG, Iron study, CSF study etc.
• Blood culture rarely helps.
TREATMENT PRINCIPLES:

• Early diagnosis
• Complete removal of all infected tissues with clear margine
• Early administration of active antifungal agents
• Reversal of underlying factors
ANTIFUNGAL THERAPY :

• Duration of Treatment is highly individualized .Depends upon near

normalization of radiograph, negative biopsy specimens and cultures,
recovery from immunosuppression
• (Usually 3-6 weeks I/v followed by 3-6 weeks oral therapy)
CONT..

• Liposomal Amphotericin-B (Polyene) first line recommended agent

Can be given as 5mg/kg/day to 10mg/kg/day, if CNS involved
Surgery + Liposomal Amp B increases survival rates and cure rates .
Other lipid based amphotericin can be used also.
Use of Amphotericin Deoxycholate is effective but discouraged.
 Azoles :

• Posaconazole, Isavuconazole IV and oral can also be used as first line therapy
• Posaconazole IV 300 mg BD at day 1 then 300 mg OD from day 2 .
oral suspension can be used 200 mg 4 times daily .
If toxicity or for renal compromise patient, DR tablet 300mg BD at day 1 then 300 mg OD
• Isavuconazole IV or oral 200 mg TDS for first 2 days then 200 mg OD from day 3

• Fluconazole, Voriconazole , Itraconazole – have no reliable activity.

 SURGICAL INTERVENTION :

• Removal of necrotic tissue with removal of surrounding infected healthy-looking

tissues

• Lobectomy, Pneumonectomy or wedge resection

• (According to Groll A et al.– Mortality might be reduced by 79% )

CONT…

SALVAGE THERAPY:

• If disease is refractory or intolerance towards previous antifungal therapy.

• Isavuconazole is strongly supported as salvage treatment.
• Posaconazole delayed release tablets or infusions are strongly supported for
salvage treatment and when available should be preferred over posaconazole
oral suspension, which in turn is marginally supported for salvage treatment.
 PREVENTION:
• Try to avoid areas with a lot of dust like construction or excavation sites. If you can’t
avoid these areas, wear an N95 respirator

• Avoid direct contact with water-damaged buildings and flood water after hurricanes and
natural disasters

• Wear protective equipment like gloves,shoes,long pant,long sleeved shirt when

necessary

• To reduce the chances of developing a skin infection, clean skin injuries well with soap
and water, especially if they have been exposed to soil or dust.
• Eat healthy , do exercise and boost immunity
• Control hyperglycemia
• Monitor blood glucose level post-COVID-19 discharge and also in diabetics
• Use steroid judiciously – correct timing, correct dose and duration
• Use clean, sterile water for humidifiers during oxygen therapy
• Use antibiotics/antifungals judiciously
PROPHYLAXIS:

• Posaconazole 600mg/day in divided dose.

• Neutropenic or GvHD with immunosuppressive outbreaks –
• Surgery and Past h/o mucormycosis – (Strong recommendation)
 CONCLUSION:

• Increase in mucormycosis in south east asia context appears to be an unholy

intersection of trinity of diabetes , rampant use of corticosteroid and COVID-19
fueled by using cowdung as remedy for covid disease blinded by religious misbelief in
some parts of india. All efforts should be made to maintain optimal glycemic control
and only judicious evidence-based use of corticosteroids in patients with COVID-19 is
recommended in order to reduce the burden of fatal mucormycosis. Early suspicion,
diagnosis and treatment conducted by a group of dedicated experts can save lives.
THANK YOU
Sources:
• 1) 2019 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
• 2) Oxford Handbook of Infectious Disease and Microbiology
• 3) Mucormycosis in COVID-19: A Systematic Review of Cases Reported Worldwide and in India(15 may 2021,journal pre-
proof) Authors: *Awadhesh Kumar Singh, MD, DM1; Ritu Singh, MD1; Shashank R Joshi, MD, DM2; Anoop Misra, MD3-5
• 4) www.cdc.gov
• 5) 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
• 6) Coronavirus Disease (Covid-19) Associated Mucormycosis
(CAM): Case Report and Systematic Review of LiteratureDeepak Garg . Valliappan Muthu . Inderpaul Singh Sehgal . Raja
Ramachandran . Harsimran Kaur . Ashish Bhalla . Goverdhan D. Puri . Arunaloke Chakrabarti .Ritesh Agarwal