THEEMERGENCEOF PULMONARYMYCOSES:

WHO, WHEN AND HOW?

ANNA ROZALIYANI
Pulmonary Mycoses Working Group, Perhimpunan Dokter Paru Indonesia Dept. of Parasitology, Mycology Division
Faculty of Medicine, Univ. Indonesia Pulmonary Mycoses Centre – FMUI /Persahabatan Hospital
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OUTLINE

I. Background
II. The Risk Factors of PulmonaryMycoses
III. When & How to Treat of Pulmonary Mycoses :
Diagnosis & Treatment Strategies
IV. Summary
 SERIOUS PROBLEMS OF PULMONARYMYCOSIS

• The incidence significantly increase > 200% in last two decades → due to increasing
number of patients at risk: immunocompromised & critically ill patients

• Morbidity &mortality → very high.

• prolongs the length of hospitalization → very high cost
• mortality 40 – 100 %

• Diagnosis is stillchallenging
• Fungi can be colonizers, pathogens, orcontamination
• Clinical symptoms are not characteristic
• Objective evidence usually occurs late
 THE ETIOLOGY OF PULMONARY MYCOSES
The causative fungi vary with the population selected & the
geographical region
o Aspergillus spp, Cryptococcus neoformans, Candida spp → in immuno-
deficience individuals
o Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, in
certain endemic regions

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ROUTE OFTRANSMISSION
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THE RISK FACTORS &

UNDERLYING DISEASES
o Risk factors
• prolonged usage of systemic antibiotic,steroid
• chemotherapy of malignancies
• invasive medical device

o Underlying diseases
• chronic lung disease: COPD, bronchiectasis, asthma,etc
• other chronic conditions:diabetes mellitus, chronic renal disease, auto-
immune diseases, etc.
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DIAGNOSTIC CAVEAT
o Early diagnosis as crucial step in pulmonary mycoses management →
CLINICAL AWARENESS → the most important
o Clinical features not typical & difficult to differentiate with other
pulmonary diseases: shortness of breath, prolonged cough, chest
discomfort, fever, etc.

o The key diagnosis

• recognizing underlying diseases & riskfactors
• careful physical examination
• accurate diagnosis modalities : mycological, radiological &
histological laboratory tests
 KRITERIADIAGNOSISMIKOSISPARU
Pedoman Nasional MikosisParu–PerhimpunanDokter ParuIndonesia (PDPI)

Underlying diseases Symptoms&signs - Microscopic

Risk factors • Physical findings - Serology
• Radiologyfeatures - Molecular based

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MYCOLOGICAL EXAMINATION
o Proper clinical material handling is a crucialstep
(selection of clinical materials, delivery, laboratorytest)

collected transported laboratory

o Type of mycological test

• microscopic test → rapid diagnosis, not sensitive, not spesific
• culture → important for identification &susceptibility test
• serological tests → Ag detection or Ab detection
 OBTAINING ASPECIMEN
Bronchoscopy
Sputum
BAL

Fine needle aspirate

Biopsy

Brush Lung biopsy

 LABORATORY DIAGNOSIS
CONVENTIONAL METHODS
Recovery of Aspergillus species/other fungi
▪ From sterile sites (blood, peritoneal fluid, etc) → proven diagnosis
▪ From multiple non-sterile sites is highly suggestive
• Culture of clinical specimen
• Histopathologic method

NON-CULTUREAPPROACHES

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 NON-CULTUREAPPROACHES
Candida Aspergillus Detection
LA
Mannans Galactoman ELISA
Cell wall 1,3--D-glucans nan 1,3--D- RIA
components chitin glucans Amebocyte lysate assay
chitin Spectrophotometry

Cytoplasmic Enolase
HSP-90 ELISA
antigens Immunoblot

arabinitol D-mannitol GLC

Metabolites Mass spectroscopy

Genomic DNA C-14 lanosterol C-14-lanosterol PCR

demethylase demethylase
sequences
Chitin synthase Alkaline protease
Actin Mitochondrial DNA
Aspartate proteinase HSP-90
Ribosomal RNAgenes Ribosomal RNAgenes 12
 FACING THE PROBLEMS
• How much confidence are we in diagnosis & giving treatment ?
• Early diagnosis is crucial, but patients frequently have the diagnosis at late
stage/critically ill
o Clinicians should remain in CLOSE COMMUNICATION with laboratory
scientists → ensure all steps correctly followed → more accurate diagnosis
→ indicate the appropriate treatment

o The communication breakdown → incomplete clinical data for laboratory

analysis → delay diagnosis → increase diseaseduration
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 THE TREATMENT STRATEGIES

▪ Choose appropriate drugs

▪ Start antifungal early
▪ Think wisely about theresistance
▪ Considere the duration &other problems

ADEQUATE APPROPRIATE
DIAGNOSIS TREATMENT
 DIAGNOSIS & THERAPEUTICSTRATEGIES
4P1rophylaxis Empirical Pre-emptive Definite

Treatment
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Temperature( ° C)
39

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CT
37

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PCR +
Disease likelihood

Galactomannan + Culture + Tissue +

10
Granulocytes (log10x109/L)

0
Remote Possible Probable disease Proven
1

0.1

-14 -7 0 7 14 21 28 35 42 49 56 63
Days after transplant
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 Initial Treatment of PulmonaryAspergillosis
• Primary treatment recommendation :voriconazole
• 6 mg/kg IV Q12H for 1 day, followed by 4 mg/kg IV Q12H; oral therapy can be used
at 200-300 mg Q12H or with weight-based dosing
• Initiate antifungal therapy early in patients with strongly suspected IPA; diagnostic
evaluation can occur simultaneously
• Alternative options: isavuconazole, liposomal AmB (or lipid formulations)
• Echinocandins NOT recommended unless azole and polyene antifungals are
contraindicated
 Why Voriconazole?
• Randomized, open-label trial in immunocompromised patients with definitive or probable invasive
aspergillosis (N = 277)
Voriconazol Conventional AmB
Outcome at Wk 12 in mITT Population,%
e (n = (n = 133)
144)
Overall response 52.8 31.6
▪ Complete response 20.8 16.5
▪ Partial response 31.9 15.0
Overall survival* 70.8 57.9
*HR: 0.59 (95% CI: 0.40-0.88; P = .02)

▪ Significantly fewer severe potentially drug-related AEs with

voriconazole vs AmB: 13.4% vs 24.3%, respectively (P = .008)
clinicaloptions.com
 Voriconazole
ADVANTAGES
• The current gold standardfor
invasive aspergillosis[1]
• Oral and IVformulations are both
generic
• DISADVANTAGES
• Need for TDM, unpredictable
pharmacokinetics[1-3]
• When to useweight-based dosing;
oral bioavailability
• Increasing concern over the risk of skin
cancer[4]
• Toxicities: hallucination, fluorosis[5,6]
 Isavuconazole

• ADVANTAGES DISADVANTAGES
• Spectrum similar to posaconazole • Prodrug requires loading doses
• Broad in vitro activity against a • Potential confusion over
range of medically important fungi administration
(eg, Candida and Aspergillus • Very little prophylaxis data
species, Cryptococcus neoformans)
• Role should be clarified byfurther
• QD dosing of oral and IV formulations
studies
(no cyclodextrin in theIV)
• Treatment indications for invasive
aspergillosis and mucormycosis
 SECURE: Isavuconazole vs Voriconazole for Primary Treatment of Invasive Aspergillosisand

Other Molds • International, randomized, double-blind phase IIItrial (N =527)

100 Isavuconazole
Voriconazole
80 P < .001
Patients (%)

59.8
60
42.4
40 35.0 36.4

23.3
18.6 20.2 19.6
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n/N = 48/258 52/258 28/143 30/129 50/143 47/129 109/257 155/259
0
All-Cause Mortality All-Cause Mortality at OverallResponse Drug-Related
at Day 42 (ITT)* Day 42 (mITT)† at EOT TEAEs

*Primary endpoint in patients who received ≥ 1 dose of study drug. †Subset of ITT patients with proven or probable invasive mold disease.
 Initial Treatment of InvasiveCandidiasis
• “An echinocandin is recommended as initialtherapy”
• Anidulafungin: 200 mg loading dose, then 100 mg/day
• Micafungin: 100 mg/day
• Caspofungin: 70 mg loading dose, then 50 mg/day

Alternative Key Considerations

Acceptable in selectpatients
Fluconazole
(eg, not critically ill, fluconazole-resistant Candida speciesunlikely)
Reasonable in cases of intolerance, limited availability of other antifungals;
Lipid AmB
recommended for suspected azole- and echinocandin-resistant Candidainfections
Voriconazole Effective but little advantage overfluconazole
Treatment ofMucormycosis

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JENISMIKOSISPARUDIKAITKAN DENGANGAMBARAN KLINIS, FAKTORRISIKO,
DIAGNOSISDANTERAPI

Pedoman Nasional Mikosis Paru –Perhimpunan Dokter Paru Indonesia (PDPI)

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 JENISMIKOSISPARUDIKAITKAN DENGAN GAMBARAN
KLINIS,FAKTOR RISIKO,DIAGNOSIS DANTERAPI

Pedoman Nasional Mikosis Paru –Perhimpunan Dokter Paru Indonesia (PDPI) 24

 PULMONARY MYCOSIS CENTRE FMUI – PERSAHABATANHOSPITAL
BURDENOFPULMONARYMYCOSISIN INDONESIA
(COLLABORATION RESEARCH OF DEPT. OF PULMONOLOGY, MICROBIOLOGY, PARASITOLOGY, PDPI & ARSABAPINETWORKING)
One sucheffort is to develop
a pulmonary mycosiscenter
- an integrated center for
diagnostic and treatment
- the center of excellence,
research, and community
services

PDPI PERHIMPUNAN DOKTERPARUINDONESIA

ARSABAPI ASOSIASI RUMAH SAKIT & BALAI KESEHATANPARUINDONESIA
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SUMMARY
EARLY RECOGNITION & DIAGNOSIS
of pulmonary mycosis

• A cornerstone to improve the quality of management towards a

comprehensive approach
• Continuous effort is highly needed to overcome the gap of
knowledge, limited diagnostic facilities, and managementof
pulmonary mycosis
 BERSATU
MELAWAN
C PENYAKIT
JAMURPARU

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TERIMA KASIH