PULMONARY MUCORMYCOSISDr. V. Gopala KrishnaiahProfessor & H.O.D of PulmonologyBHASKAR MEDICAL COLLEGE

BACKGROUNDMM refers to rare, severe opportunistic infection with fungi of the order Mucorales. Hence the name mucormycosis

ORGANISMSRhizopus species are the most common causative organisms.Other less frequent species include: Rhizomucor, Absidia, Cunninghamella, Saksenaea, and Apophysomyces

PATHOPHYSIOLOGYMucorales fungi are ubiquitous environmental organisms. Humans are resistant to disease, but immuno-compromised hosts are at risk.The major route of infection is by inhalation of spores. Ingestion or traumatic inoculation are recorded

PATHOPHYSIOLOGYcont.Once the spores begin to grow, fungal hyphae invade blood vessels, producing tissue infarction, massive necrosis with bone destruction. Thus producing the life-threatening, invasive, rhinocerebral, and other organ-centered manifestations.

RISK FACTORSDiabetes mellitus esp. with ketoacidosis Neutropenea, HIV patients Malnourished individuals, especially children Desferoxamine therapy and all causes of iron overloadBurn victims susceptible to cutaneous MMSteroid therapyHematologic and solid malignancies BM transplant recipients Persons in Renal Failure Intravenous drug abusers (at risk for cerebral MM)

FREQUENCYMM is extremely rare,one center showed it was present in 0.7% of patients at autopsy. Rhinocerebral disease is the most common form, hence the name Zygomycosis. Others include pulmonary, cutaneous, gastrointestinal, and disseminated diseases. Very rare cases occur in immuno-competent patients, usually after traumatic inoculation.

AGEMM is found in patients of a wide age range.SEXThere is equal sex distribution, but pulmonary MM shows a male-to-female ratio of 3:1

MORTALITY/ MORBIDITYMucormycosis has a very high mortality rate reaching 50 to 80% even with treatment. Pulmonary and gastrointestinal diseases have higher mortality rate due to late diagnosis. Rhinocerebral disease causes significant morbidity in patients who survive because treatment requires extensive facial surgery.

CLINICAL PICTURE

Mucormycosis is distinguished by its fulminant course with evidence of extensive tissue necrosis.

PULMONARY MUCORMYCOSISPresents nonspecifically with fever, dyspnea, cough and haemoptysis.By comparison, signs of pulmonary and GI MM are nonspecific, which leads to difficulty in diagnosis.

BIOPSYPathognomonic picture of broad, irregular, nonseptate, right-angled, branching hyphae are demonstrated by H&E or fungal stains.

Vascular invasion is characteristic with neutrophil infiltrate BIOPSYMM: HIGH POWER

Histopathology

TREATMENT

1. MEDICAL CAREA.Correction of the underlying abnormality: Diabetic ketoacidosis requires insulin & correction of acidosis Neutropenia requires use of CSF and withdrawal of cytotoxic CH Wean glucocorticosteroids Interrupt desferoxamine B. Prompt institution of IV amphotericin B therapy is critical to survival.

Amphotericin BIs the only antifungal agent with proven efficacy in mucormycosis.The lipid formulations of amphotericin B allows for very high doses while protecting renal function. High doses are required, and nephrotoxicity may result.

2. POSACONAZOLEIn the form of Syrup for Oral Therapy.

In pulmonary disease, excise lesions if they are localized to a single lobe.3. SURGICAL CARE cont.

Finally, mucormycosis carries an extremely poor prognosis. Because of the rapidity with which this disease progresses, prompt diagnosis and aggressive therapy are essential.

Palate

Orbital Mucormycosis

Cavernous Sinus

Male 60 yrs.Occupation Farmer.Presented with high-grade fever with chills for the last 15 days.Persistent cough with scanty mucoid sputum.Breathlessness Grade III for the last 3 days.Scanty urine with burning micturation for the last 2 days.Vomiting for the last 2 days, two episodes.Generalized weakness.

Known case of systemic hypertension on Losar 25 mg twice daily.Diabetes mellitus type II on oral Hypoglycemic drugs.No history of bronchial asthma.Vitals:Temp. 100 FPulse Rate 120 per min.B.P 120/70 mmHg.Respiratory Rate 24 per min.SPO2 100% with 2 liters of O2.

Lab Reports:Total Leukocyte Count(TLC) 21,400 Cells per cumm.ESR 118 mm first hour.Serum Creatinine 2.2 mgs.Serum sodium 121 mmol/L.X-ray chest PA view Right upper lobe consolidation.

On admission:Haemoglobin 11.2 gms.Total Leukocyte Count 15,300 cells per cumm. After 5 days 9,560 cells.Platelet 3,64,000.Random Blood Sugar 331 mgs. 09:00 AM. - 543 mgs 01:00 PM.Blood Urea 96 mgs.Serum Creatinine 2.5 mgs. 1st day of admission -1.2 mgs. After 5 days.

1st Day2nd Day4th DaySerum Sodium126 mmol/L128 mmol/L134 mmol/LSerum Potassium3.1 mmol/L3.7 mmol/L3.3 mmol/L

Serum Chloride96 mmol/L100 mmol/L110 mmol/L

LFT :Total Bilirubin 0.6 mg.ALT 35AST 43 Alkaline phosphatase 88Total proteins 5.6 grams.Albumin 2.2 grams.Globulin 3.4 grams.A/G Ration 0.6

CT Scan of the Chest:Right upper lobe consolidation with cavity.Ultrasound abdomen Normal study.Sputum per AFB Negative.Sputum per Gramstain Gram positive cocci in pairs and short chains. Sputum per culture and sensitivity Sterile.

Bronchoscopy:Right upper lobe mass lesion, pedunculated with mucus plug bleeding on touch.

Bronchial washings, brushings, and biopsy taken from right upper lobe bronchus mass lesion

Sent for AFB Smear, Fungal elements, Cytology and Histopathological examination which reveals plenty of pus cell with few lymphocytes; Sheet of epitheloid cells seen in one area, No evidence of Caseation or Langhans giant cells; No malignant cells; AFB Negative; No Fungal Elements seen.

HISTOPATHOLOGY REPORTMATERIAL : Bronchial Biopsy for HPE.

GROSS DESCRIPTION: Received four pieces of gray whit soft tissue varying in size from 2 to 4 mm. All embedded in one.

MIRCOSCOPIC EXAMINATION:Section of biopsy tissue show bronchial mucosa, lined by columnar epithelium and few lobules of cortilagenous tissue.

There are multiple fungal colonies, consisting of broad fungal hyphae with perpendicular branching and no septation.

They are admixed with fibrinous material and collections of neutrophils. No definite stromal infiltration is seen.

HISTOPATHOLOGY REPORT (Continued)HISTOCHEMISTRY: PAS STAIN show positive staining of the fungal elements. They are short, broad, filamentous and show thick cell walls, without septations.

IMPRESSION: FEATURES ARE SUGGESTIVE OF FUNGAL BAL, BROCHUS. FEATURES ARE IN FAVOUR OF MUCORMYCOSIS. ADVISED FUNGAL CULTURE FOR CONFIRMATION OF THE SPECIES.

TREATMENTANTIFUNGAL THERAPYLiposomal and lipid complex amphotericin BAmphotericin B has proven efficacy in the treatment of mucormycosis.Liposomal formulation (e.g, AmBisoome) is the drugh of choice based on efficacy and safety.Lipid preparations of amphotericin B are used at 5 mg/kg/d.Liposomal amphotericin B is amphotericin B encapuslate in a bilayer of liposomes.

TREATMENT (CONT)Amphotericin BAmphotericin B is produced by strain of Sterptomyces nodosus and can be fungistatic or fungicidal.Amphotericin B binds to sterols (e.g, ergosterol) in the fungal cell membrane causing intracellular components to leak, with subsequent fungal cell death.Amphotericin B deoxycholate can also be used for the treatment of mucormycosis, especially in settings of cost restraints.The typical doses of this drug are required, and nephrotoxicity may result.Monitor the renal function of patients taking amphotericin B; doubling of serum creatinine over the baseline levels is an indication for changing to liposomal amphotericin B.

TREATMENT (CONT)Amphotericin B lipid complex (Abelcet)Amphotericin B lipid complex is amphotericin B in phospholipid complexed form.

This is an alternate therapy to liposomal amphotericin B.

Installation of intrabrochial amphotericin B lipid complex.

TREATMENT (CONT)PosaconazolePosaconazole, a triazole, is currently considered a second-line drug for tratement of mucormycosis and the typical dose is 400 mg twice daily (total of 800 mg/d).Administration with a high-fat meal/food and acidic beverages enhances absorption of the drug.Patients on posaconazole should avoid antacids, especially proton pump inhibitors.Posaconazole has also been used as sequential therapy after the initial administration and control of the disease with liposomal amphotericine B.Posaconazole is a triazole antifungal agent that blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation.Posaconazole is available as an oral suspension (200 mg/5 mL).

TREATMENT (CONT)Combined therapyPre-clinical and limited retrospective clinical data suggest that combination therapy with lipid formulations of amphotericin and an echinocandin improves survival during mucormycosis.

A definitive trial is needed to confirm these results.

TREATMENT (CONT)Other antifunal agentsOther azoles (e.g, fluconazole, voriconazole) have not shown significant activity against mucormycosis fungi. Of note, despite the use of voriconazole prophylaxis in high-risk patients (e.g, transplant recipients)m], breakthrough zygomucosis has been reported.

Surgical interventionDebridement of necrotic tissue in combination with medical therapy is mandatory for patient survival.Excise pulmonary lesions if they are localized to a single lobe.

TREATMENT (CONT)Adjunctive therapiesHyperbaric oxygen therapy after surgical debridement has been used, especially in case of cutaneous disease and rhinocerebral disease in diabetics.High oxygen concentrations may improve neutrophil function, inhibit the growth of Mucorales, and improve wound healing.

Duration of therapy and long-term monitoringSuccessful courses of therapy typically last 4-6 weeks and require cumulative doses that are equivalent to greater than 2 g of amphotericin B deoxycholate.Posaconazole offers another treatment option.

PrognosisRhinocerebral disease: Mortality ~62%Pulmonary disease:Mortality ~76%, higher in severely immunosuppressed.

Cutaneous:Mortality ~10%

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