Mucormycosis simplified notes.

Welcome to DRD medshortnote. 

Today we will discuss about MUCORMYCOSIS :-

• This topic contains :-

1. Microbiology of mucormycosis
2. Pathophyiology of disease caused by it
3. Clinical features 
4. Diagnosis and investigations 
5. Management

1) MUCORMYCOSIS MICROBIOLOGY : Mucormycosis is caused by Fungi - order Mucorales of subphylum mucormycotina.

• All Fungi are classified morphologically into 4 major classes :-
  

1. Yeasts
2. Yeast like
3. Molds
4. Dimorphic

• Mucorales comes under MOLDS ( ASEPTATE MOLDS )

• mucorales includes :

1. Rhizopus ( most common cause) { R.oryzae & R. delemar }
   
2. Mucor 
3. Rhizo mucor 
4. Cunninghamella
5. Lichtheimia 

image showing aseptate broad hyphae seen under microscope in gomori methenemine silver stain.

 schematic diagram of asexual form of Rhizopus fungi

2) PATHOPHYSIOLOGY OF MUCORMYCOSIS : -

• Mucorales are ubiquitous organism but it is present mainly in humid atmosphere, dust, in kitchen garbage, in soil, on rotten bread, etc.
• Causes infection in - Diabetics , phagocytosis function defect , elevated free iron, glucocorticoid treatment.

• In Diabetics there are 3 mechanisms :-

1. DKA diabetic ketoacidosis causes dissociation of Iron from bound form → so free form of iron increased in blood which enhances fungal survival and virulance.
2. Ketoacids beta hydroxy butyrate →increases host and fungal receptors → fungus adhere and penetrates tissue. 
3. Hyperglycemia also plays major role:- 

• Hyperglycation of iron storing proteins → increases free form of iron 
• Increased GRP78 receptor expression → increased binding & penetration of fungus to host cell.
• Causes defects in phagocytic functions
• Increase expression of CotH mediates fungus penetration via GRP78.

3) RISK FACTORS AND CLINICAL FEATURES:-

• Risk factors :-

1. Diabetes mellitus
2. Malignancy
3. Patient on immunosuppresives ( specially in organ transplant recipients )
4. Neutropenia
5. It may occur in immunologically normal individuals eg. Injury due to Road traffic accidents, via I.V. catheters in nosocomial settings.
6. Newly identified risk factor is COVID 19 infection because of :- Chronic respiratory disease, Corticosteroid therapy; which is used as a lifesaving measure in Cytokine storm; but if it is required for prolonged duration it increases the chances of fungal infections  & in some cases ventilatory care increases the risk
   
7. Higher level of free serum iron. (Iron overload)

• Also look for local risk factor like H/O recent tooth extraction , oral surgical procedures.
  

BUT INTERESTING FACT IS PATIENT RECEIVING PROPHYLAXIS WITH ITRACONAZOLE OR VORICONAZOLE ARE AT INCREASED RISK FOR DEVELOPING DISSEMINATED TYPE( WORST FORM ) OF MUCORMYCOSIS. ( written in Harrison's internal medicine 20th Ed , pg 1538 ) 

➜ Clinical Features :-

•  it presents as a six clinical syndromes 

1. RHINO ORBITAL CEREBRAL DISEASE 
2. PULMONARY 
3. CUTANEOUS 
4. GASTROINTESTINAL 
5. DISSEMINATED &
6. MISCELLANEOUS

 1) Rhino Orbital Cerebral Disease-

• Most common type
• Commonly seen in Diabetic patient 
• Initially non specific symptoms like Facial pain, eye pain, followed by conjunctival suffusion and blurry vision.
• Fever in 50% cases
• Foul smelling Nasal discharge, sinusitis. 
• Headache, cranial nerve involvement.
  
• If untreated infection spreads from Ethmoid sinus to orbit which results in Extra Ocular Muscles function compromise and causes UNILATERAL PROPTOSIS of affected side of eye. 
• If Bilateral eyes involved the outcome is ominous; it suggests development of cavernous sinus thrombosis.
  
• Progression of symptom seen →1st normal area → then erythematous phase +/- edema → violaceous appearance → at last Black necrotic area (Eschar)
• Painful necrotic ulcer in hard palate ( late finding suggests established infection )

 2) Pulmonary Disease :- 

• Second most common type.
• Presents as a DYSPNOEA , COUGH , CHEST PAIN, FEVER.
• Lobar consolidation, Nodules, cavitations and infarction seen on CXR.
• HEMOPTYSIS seen

3) Gastrointestinal Disease :-

• Primarily it occurs in premature neonates suffering from necrotizing enterocolitis.
• In adults it is seen in neutropenia, immunocompromised patient.
• It presents as a nausea, vomiting, abdominal pain and distension.
• GI bleeding and at last stage perforation has higher mortality rates

4) Cutaneous Disease :-

• External implantation of fungus via thorn prick, road traffic accidental injuries, contaminated wound dressings, etc.
• It can involve muscle, fascia, even bone and causes Necrotizing fasciitis in which mortality rate is 80%
• However with aggressive surgical debridement mortality rates are low.

5) Disseminated Disease :-

• Hematogenous spread may occur from any infected site
• most common site of dissemination is brain.
• Has a higher mortality rates.
• Also seen in patient on itraconazole prophylaxis.
  

 6) Miscellaneous type :- 

• May affect bone, mediastinum, trachea, kidney, peritoneum.
• Peritonium is involved in case of peritoneal dialysis.

 

4) DIAGNOSIS AND INVESTIGATION :-

• 1) Lab investigations:-

• Complete blood count :- see for neutropenia
  
• Inflammatory markers :- ESR
• FBS, PPBS, HbA1C
• LFT, RFT with electrolytes

• 2) Nasal endoscopic examination :-

• Black necrotic eschar tissue

• 3) radiological examination :-

1. CECT Contrast enhanced CT scan :- bony erosion, hard palate erosion, mucosal thickening irregular patchy enhancement.
2. MRI PNS with contrast:-Nasal involvement :- Ischemia and non enhancement of turbinates" Black turbinate sign", fluid collection and opacification of sinuses in advance disease; Optic involvement :- Optic neuritis, stretching of optic nerve and tenting of posterior pole suggests severe inflammation, patch enhancementr of orbital fat seen , Other finding :- cavernous sinus thrombosis, intra cranial involvemen
3. Pulmonary CECT :- multiple nodules, pleural effusion and thick walled cavity differntiates it from covid 19 lung involvement.
   
4. X Ray PNS has limited value

• 4) Histo pathological finding :- 

• Tissue specimen from nasal/ sinus mucosa , turbinectomy , partial maxillectomy, alveolectomy, partial/ total palate resection 10% formalin used to preserve biopsy specimens.

• 5) Microscopy and culture :-

• Sample collection - in Rhino OrbitalCerebral involvement :- Endoscopic collection of debrided tissue , transport in sterile water for Microscopy and culture ; for other portion in formol saline for Histopathology.
• For pulmonary mucormycosis :- broncho alveolar lavage, CT guided biopsy.
• In microscopy - broad ribbon like Aseptate hyphae seen.
  

• 6) Molecular method :- 
• PCR test but it is not FDA approved. 

5) MANAGEMENT OF MUCORMYCOSIS :-

• Successful treatment requires 3 steps :

1. Early initiation of therapy.
   
2. Rapid correction of underlying condition causing it. (e.g. Correcting hyperglycemia, stopping or stepping down immunosupression , avoid iron administration. )
   
3. Surgical debridement.
   

• Primarily antifungal therapy is based on Polyene antifungal

➤  Anti fungal options for mucormycosis :-

１) FIRST LINE ANTIFUNGAL THERAPY :-

1} Amphotericin B deoxycholate :- (AmB deoxycholate)

• Starting dose 1mg / kg / day.
  
• It is inexpensive, clinically ecperienced,
• FDA approved for mucormycosis.
• BUT disadvantage is that it is Highly nephrotoxic
• It has a poor CNS penetration so not as effective as Liposomal compounds

2} Liposomal amphotericin B :- (LAmB)

• Starting dosage 5mg / kg / day 
• For CNS mucormycosis dosage is increased up to 7.5 to 10mg / kg/ day.
• It is less nephrotoxic than Amphotericin B deoxycholate.
  
• Better penetration on CNS 
• Better outcome than amphotericin B deoxycholate and Amphotericin B lipid complex.
• Only disadvantage is that it is expensive

3} Amphotericin B lipid complex :- (ABLC)

• Dosage is 5mg / kg/ day.
• It is less nephrotoxic than amphotericin B deoxycholate.
• But it is expensive
  

２) SECOND LINE THERAPY / SALVAGE OPTION:-

1} Isavuconazole :-

• Recommended dosage is 200mg of isavuconazole (372mg of isavuconazonium sulphate ), load q8h x 6 followed by once daily dosing.
• FDA approved for treatment of mucormycosis.
• For empirical therapy when in doubt about septate vs aseptate fungal infection.
• Slow cidal activity. 
• Higher MIC needed
• In some centres alternatively used as a parenteral route unresponsive to AmpB

2} Posaconazole :-

• Dosage is 400 mg four times a day.
• Lower MIC needed than isavuconazole.
• Not used for initial therapy
• Potential use for salvage therapy. and in some centres alternatively used as a parenteral route unresponsive to AmpB

➤ DURATION OF TREATMENT :-

• Parenteral antifungal 2 to 3 weeks or more depending on clinical severity.
• Overlap of injectable and oral antifungal for 3-4 days followed by oral antifungal.
• Oral antifungal to be continued 1 week after endoscopic biopsy is negative 
• Regular follow up should be maintained at least once a month for 3 month.
  

other modalities used but efficacy yet not determined are :- 

• Hyperbaric oxygen 
• Recombinant cytokines infusion
• Neutrophilic transfusion

supportive care :- 

• To minimize nephrotoxicity due to amphotericin B preload patient with 500ml to 1000ml Normal Saline.
  
• Sodium bicarbonate used for acidosis.
• Debridement of all necrotic wound for eradication of disease.