Approach to Systemic mycosis

1. APPROACH TO SYSTEMIC
MYCOSIS
MODERATOR
Dr. Rima Moni Doley,
Associate Professor,
Department of Medicine,
AMCH
PRESENTER
Dr. Swdwamshree Boro,
PGT 3rd Year,
Department of
Medicine,
AMCH

2. INTRODUCTION
• Mycosis refers to infection by fungal agents.
• Reasons for the recent rise in mycosis:
– AIDS pandemic
– Widespread use of antibacterial agents
– Cytotoxic and biologic use for autoimmune and
neoplastic diseases
– Hematopoetic stem cell transplantation
• Deep mycoses are caused by primary pathogenic
and oppurtunistic fungal pathogens

3. Primary systemic fungus Oppurtunistic fungus
Coccidioides immitis Cryptococcus neoformans
Histoplasma capsulatum Candida spp.
Blastomyces dermatidis Aspergillus spp.

4. CLASSIFICATION OF MYCOSIS
1. Anatomically- Mucocutaneous &
Deep/Systemic infections
2. Epidemiologically- Endemic & Oppurtunistic
3. Morphologically-
I. Yeast- Candida, Cryptococcus, Trichosporon
II. Mold- Aspergillus, Mucor
III. Dimorphic- Histoplasma, Coccidioides,
Blastomyces

5. HISTOPLASMOSIS
• Etiologic agent- Histoplasma
• Clinical Features
– Asymptomatic
– Flu like symptoms- fever, chills, headache, myalgia,
anorexia, dry cough, dyspnea, chest pain
• a/w arthritis, arthralgia, erythema nodosum

6. • Clinical Manifestations:
1. Acute pulmonary
2. Chronic/ cavitary pulmonary
• Smokers with structural lung disease
• CF- Productive cough, dyspnea, low grade fever, night
sweats, weight loss
3. Progressive disseminated
• RF- Immunocompromised
• CF- RF, Shock, Coagulopathy
4. Fibrosing Mediastinitis
• Uncommon

7. COCCIDIODOMYCOSIS
• Genus- Coccidioides; Species- C. immitis, C.
posadasii
• Transmission- Direct exposure to soil
– Inhalation of spores
• Clinical manifestations-
– Primary pulmonary coccidioidomycosis
– Disseminated disease- skin, bones, joints, soft
tissue, meninges( Coccidioidal meningitis)

8. Primary Pulmonary Coccidioidomycosis
– Fever, cough, pleuritic chest pain, night sweats,
fatigue, failure to improve by antibiotics
– Immunologic response manifestations
• Toxic erythema- diffuse, maculopapular, erythematous
• Symmetrical arthralgia esp lower limbs
• Erythema nodosum
• Erythema multiforme
– Eosinophilia
– Hilar, mediastinal lymphadenopathy, pleural
nodules radiologically
• D/d- CAP

9. Coccidioidal meningitis
– RF:
• Immunosuppressed
• Second or third trimester pregnancy
– Persistent headache, lethargy, confusion
– CSF
• Lymphocytic pleocytosis
– Increased protein
– Hypoglycorrhachia

10. BLASTOMYCOSIS
• Transmission- Inhalation of spores
• Clinical Manifestations
1. Pulmonary Blastomycosis
• Asymptomatic
• Flu like presentation
• Acute pneumonia
• Chronic pneumonia
• ARDS
– Severe in diabetics, immunosuppressed and
multilobular pneumonia

11. – Radiology-
• Lobar consolidation
• Mass lesion
• Interstitial infiltrates
• Milliary pattern
• Nodules
• Cavitation
• Multiple lobe involvement
*Hilar adenopathy, pleural effusion, empyema are
uncommon

12. 2. Disseminated Blastomycosis
• Mainly skin
• Rarely- CNS, GU tract
– D/D- Pulmonary TB, CAP, Malignancy

13. CRYPTOCOCCOSIS
• Genus- Cryptococcus; Species- C. neoformans,
C. gattii
• RF-
– C. gattii in immunocompetent
– C. neoformans-
• Immunocompromised
• hematologic malignancies
• HIV (CD4+ <200/µl)

14. • Clinical manifestation:
1. Chronic meningoencephalitis-
immunosuppressed
• Headache
• Fever
• neurologic symptoms
• Vision loss
• Subacute dementia (indolent)
2. Pulmonary Cryptococcosis
• Cough, increased sputum, chest pain
• a/w diabetes, malignancy, TB
3. Cutaneous (in disseminated)- variable lesions

15. • CSF Analysis
– Lymphocytic pleocytosis
– Increased protein
• Cryptococcal antigen + in CSF/ blood
• Culture- Cryptococcal cells
– Blood, CSF
*IRIS

16. CANDIDIASIS
• Candida spp.
• Clinical manifestations
– Mucocutaneous
– Deeply invasive candidiasis
• Difficult to diagnosis
candidemia and
dissemination by blood
from local seeding
• CHROM agar- Selective &
differential media
Different Candida species in
CHROM agar

17. ASPERGILLOSIS
• RF-
– Neutropenia
– ICU
– Severe COVID 19
– Underlying respiratory disease- Pulmonary TB,
COPD, Asthma
– ECMO
– Immunomodulatory agents

18. • Clinical manifestations:
– Lung, sinus, heart, eye, brain & skin are involved
1. Invasive aspergillosis
2. Chronic
1. Chronic pulmonry aspergillosis
2. Chronic Aspergillus sinusitis
3. Allergic
1. Allergic Bronchopulmonary Aspergillosis (MC)
2. Severe asthma with fungal sensitization (SAFS)
4. Saprophytic
1. Aspergilloma
2. Maxillary fungal ball

19. ALLERGIC BRONCOPULMONARY ASPERGILLOSIS
• CF:
– Recurrent exacerbations of asthma
– Uncontrolled with usual anti asthmatic therapy
– Sputum- brownish mucus plugs, haemoptysis
• Diagnosis:
– Asthmatics
– Peripheral blood eosinophilia >500/microL
– Pulmonary infiltrates in chest radiograph
– HRCT thorax- string of pearl, signet ring
– Sputum culture +
– Total IgE against A. fumigatus >1000 IU/ml
• D/D- Pulmonary TB, Bronchiectasis, CAP

20. MUCORMYCSIS
• Order- Mucorales
• In uncontrolled diabetes, glucocorticoid use,
neutropenia
• Clinical Syndromes
– Rhino orbital cerebral
– Pulmonary
– Gastrointestinal
• GI bleed, pain and distension, may progress to perforation
• Endoscopy- Fungating mass in stomach
– Disseminated

21. Rhino orbital cerebral disease
• MC
• Eye/ facial pain, facial numbness, conjunctival
swelling, vision blurring, proptosis, chemosis,
necrotic ulceration in mouth
• Inspection- initially infected tissue looks
normal f/b erythematous phase with or
without edema f/b violaceous and finally
black necrotic eschar
• Blind bx of normal appearing sinus helps

22. • Diagnosis
– Culture
– Biopsy with Histopathology- Most sensitive and
specific
– Radiographic evidence
• Pulmonary
–Lobar consolidation
–Cavity
–Mass

23. When to suspect systemic mycosis?
• History
– Present
– Past History- Pulmonary Tuberculosis, Diabetes,
Malignancy on Chemotherapeutic drugs, Auto
immune diseases on immunosuppressants, Organ
and stem cell transplant
– Drug History
• Immunosuppressants, Chemotherapy drugs, Biologics
– Family History- Blastomycosis

24. • Exposure History
– Soil- Coccidiodomycosis, Aspergillosis,
Blastomycosis
• Travel History
• Occupational History

25. INVESTIGATIONS
1. Specimen collection- depends on the site
involved
2. Direct Microscopy:
a) Wet mounts:
• KOH- Yeast cells, hyphae, pseudohyphae
• Gram stain- yeast & yeast like fungus
• India ink- negative stain
–Cryptococcal capsule- CSF
• Calcoflour white stain- Blastomyces & mixed
infection

26. C. neoformans capsule in
India Ink
Hyphae seen in KOH stain

27. b) Histopathological examination:
• PAS, Gommori Methenamine silver, H&E stain
• Fungal elements from tissue biopsy
c) Frozen section Biopsy:
• Intra operative diagnosis of suspected
malignancy
d) Lactophenol cotton blue:
• microscopic appearance of fungi from isolates
grown in culture

28. 3. Fungal Culture- Blood, CSF, Sputum, BAL fluid
– Isolation and identification
– SDA (mc)
– niger seed agar- selective media for cryptococcus
– CHROM agar- selective & differential media for
Candida species

29. 4. Immunological methods
– Antibody detection- ELISA, Agglutination test, CFT
• Prognosis & response to anti fungals
– Antigen detection- Latex agglutination
* In early stages & impaired immunity or immunity not
sufficient to raise significant antibody levels
• Cryptoccus- Serum, CSF
• Blastomyces- Urine, blood, CSF, BAL fluid
• Aspergillus- BAL
• Histoplasma

30. – Immunohistochemistry-
• Ag detection on the cells of tissue sections
4. Antifungal Susceptibility Testing
5. New Techniques
– AccuProbe
– PNA Fish
– MALDI TOF mass spectrometry

31. TREATMENT
• Antifungals
– Antifungal antibiotics
• Polyene- Amphotericin B
– Azoles
– Echinocandins- Caspofungin, Anidulafungin,
Micafungin
– Flucytosine

32. Fig: Target sites of Antifungals

33. AZOLES
MYCOSIS FLU- ITRA- VORI- POSA- ISAVU-
HISTOPLAS
MOSIS

COCCIDIOD
OMYCOSIS
    
BLASTOMYC
OSIS
  
CRYPTOCOC
COSIS
  
CANDIDIASI
S
  
ASPERGILLO
SIS
   
MUCORMYC
OSIS
 

34. COCCIDIOIDOMYCOSIS
CLINICAL PRESENTATION TREATMENT
Asymptomatic infection None
Focal primary pneumonia Fluconazole/ Itraconazole 400mg/d X
6mths
Diffuse pneumonia AmB f/b Triazole x6mths to a yr
Chronic pneumonia Triazole X 1 y
Meningitis Lifelong triazole

35. BLASTOMYCOSIS
• Immunocompetent
– Mild/moderate- Itraconazole X 6mths
– Severe-
• Lipid AmB (until clinical improvement) f/b Itraconazole
X 6-12 mths
– CNS – Lipid AmB x 4-6 wks f/b Itra-/flu-/vori- x
12mths (at least)

36. • Immunosuppressed
– Lipid AmB x 7-14 days f/b Itraconazole x 12 mths
• Pregnant-
– Lipid AmB x 6-8 wks

37. CRYPTOCOCCOSIS
• Immunocompetent-
Pulmonary Chronic meningoencephalitis
Fluconazole (200-400 mg/d) x
3-6 mths
• AmB (0.5-1 mg/kg/d)
+ Flucytosine (100mg/kg/d) x 6-10 wks
• Alt- AmB + Flucytosine x 2 wks f/b
Fluconazole (400mg/d) x 10 wks

38. • HIV – Induction & lifelong maintenance phase
1. Without CNS
• Fluconazole+ Flucytosine x 10 wks f/b lifelong
fluconazole
2. With CNS
• AmB (0.7-1 mg/kg/d) + Flucytosine x 2 wks
F/b Fluconazole (400mg/d) for 10 wks
F/b 200 mg/d lifelong
• Alt: Fluconazole (400-800 mg/d) + Flucytosine x 6-10
wks
F/b Fluconazole (200 mg/d)

39. CANDIDEMIA & SUSPECTED
DISSEMINATED CANDIDIASIS
• Amphotericin B-
– Deoxycholate- 0.5- 1 mg/kg/d
– Lipid formulations- 3-5 mg/kg/d
• In echinocandin resistance in C. auris
• Azoles
– Posaconazole- prophylaxis in neutropenic
– Fluconazole- MC used
– Voriconazole

40. • Echinocandins
– First choice if concern for resistance
– First line for multi drug resistant C. auris
– Caspofungin, Anidulafungin, Micafungin
• Candida meningoencephalitis
– Polyene+ flucytosine

41. ASPERGILLOSIS
Primary treatment Secondary treatment
Invasive Vori-, isa-, posa- Lipid AmB, Caspofungin,
micafungin
Prophylaxis Posa-, itra- Mica-, aerosolised AmB
Chronic
pulmonary
Vori-,itra- Posa-, IV Mica-, IV AmB
Fungal asthma Itra- Vori-, Posa-
Single
aspergilloma
Surgical resection Itra-, Vori-, AmB
intracavitary
*Oral corticosteroid is the cornerstone of ABPA

42. MUCORMYCOSIS
Drugs Dose
Amphotericin B deoxycholate 1-1.5 mg/kg/d
Liposomal AmB 5-10 mg/kg/d
AmB lipid complex 5 mg/kg /d
First line anti fungal
Second line anti fungal
1. Isavuconazole
2. Posaconazole

43. • Combination therapy
– Echinocandin + lipid polyene
– Lipid polyene + azole
– Triple therapy

44. • 38 YO male, CRPF by occupation came with
– Weakness of all the limbs for 1 month which was gradually
progressive
– Urinary and stool incontinence for 15 days
– Fever and headache for 15 days
• ICTC positive
• CSF – raised protein, lymphocyte pleocytosis
• Serum Cryptoccal antigen- positive
• MRI Brain with screening of whole spine- Toxoplasmosis and
Syrinx formation
• Diagnosis- CRYPTOCOCCAL MENINGITIS
CASE DISCUSSION

45. • He was started on Amphotericin B1 mg/kg/day
IV for 2 weeks and Tab Trimethoprim+
Sulphamethoxazole followed by Tab
Fluconazole 400 mg/ day for 8 weeks.
• ART was started after 1mth
• He could slowly walk with residual weakness
post therapy after about 3 weeks with a
walking stick.

46. REFERENCES
• Harrison’s Principles of Internal Medicine 21st
Edition
• Textbook of Medical Mycology 4th edition