Pulmonary Aspergillosis

Spectrum and Managements

Invasive

Prof Viboon Boonsarngsuk

Ramathibodi Hospital, Mahidol University
 Invasive Pulmonary Aspergillosis
Acute Subacute Chronic
<1m 1-3 m >3m

Lancet Infect Dis. 2017;17(11):e357–e66

Acute Invasive Pulmonary Aspergillosis
• Host defenses
–Epithelial inhibition of adherence and germination
Prolonged neutropenia
Immunosuppressive
Chronic respiratory diseases
–Cellular immunity Steroid >of 20
Alteration mg/d or chronic
pulmonary use > 3 m
microbiome
Chemotherapy
Antibiotic
• Alveolar macrophages Organ transplantation
Respiratory infection Pseudomonas,
Multiple
Influenza,organ failure
• PMNs COVID-19
Immune paralysis (compensatory anti-
• T cells inflammatory response syndrome)
Immunodeficiencies Cong, Acquired
–Innate immunity mediators
Semin Respir Crit Care Med 2020;41:80–98
Acute Invasive Pulmonary Aspergillosis

Semin Respir Crit Care Med 2020;41:80–98

Acute Invasive Pulmonary Aspergillosis
• Clinical signs
Fever not respond to ATB
–Non specific
No fever
• Fever, cough, dyspnea, pleuritic chest pain,
hemoptysis
–Abnormal CXR/CT
Acute Invasive Pulmonary Aspergillosis
• Patterns of invasion Neutropenia
Halo sign
Angioinvasive Early within 5-10 d
Perilesional hemorrhage
Consolidation
Airway-invasive Air crescent sign
Starts with recovery from neutropenia

Tracheobronchial Retraction of necrosis lesion

J Clin Diagn Res 2016;10(04):TE01–TE05

Acute Invasive Pulmonary Aspergillosis
• Patterns of invasion

Nonneutropenic patients
Airway-invasive Multiple centrilobular nodules
Consolidation

J Clin Diagn Res 2016;10(04):TE01–TE05

 Acute Invasive Pulmonary Aspergillosis
• Patterns of invasion Obstructive

Bronchoscopic findings + microbiological + pathology

Pseudomembranous

Tracheobronchial

Ulcerative
Clin Microbiol Infect. 2010 Jun;16(6):689-95
Acute Invasive Pulmonary Aspergillosis
• Investigations
–Chest CT
–18F-FDG PET/CT
• High maximum standardized uptake values (SUV)
• In thorax, has no advantages over CT chest

Detection of extrapulmonary lesions

Guiding the duration of treatment
Eur J Nucl Med Mol Imaging 2019;46(01):174–183
Acute Invasive Pulmonary Aspergillosis
• Larger
Investigations
when degenerated (up to 15 m)
Definite Dx by histology when conidial heads are present
–Microscopy
(rarely produced, may be seen in cavity)
• Dichotomous acute angle branching septate
hyphae (3 – 6 m)
• Discriminate from Mucorales but not from the non-
Aspergillus hyalohypomycetes
• Diagnostic yield 30%
Med Mycol 2019;57(Suppl 2):S155–S160
Acute Invasive Pulmonary Aspergillosis
• Investigations
–Histology
Acute Invasive Pulmonary Aspergillosis

J Clin Oncol 2015;33: 501-509

Acute Invasive Pulmonary Aspergillosis
• Investigations
–Culture
• Gold standard
• Low positivity
–Polyenes and azoles resistance

Clin Microbiol Infect 2018;24(Suppl 1):e1–e38

Acute Invasive Pulmonary Aspergillosis
• Investigations
–Galactomannan
• A component of the cell wall of Aspergillus spp.
•  (1→5) - linked galactofuranose
Acute Invasive Pulmonary Aspergillosis

BAL GM

immune

Serum GM
Acute Invasive Pulmonary Aspergillosis
• Investigations • Cut-off index
–Galactomannan –Serum 0.5
–BALF 1.0
Acute Invasive Pulmonary Aspergillosis
• Investigations
–Galactomannan
• Monitoring for invasive aspergillosis during
immunosuppression
Serum: A meta-analysis noted a sensitivity of 79% and
specificity of 86%, with an overall accuracy of 89%

Eur J Clin Microbiol Infect Dis 2008;27: 245-251

 Acute Invasive Pulmonary Aspergillosis
• Investigations
–Galactomannan
• Evaluation for suspected pulmonary invasive
aspergillosis
Serum: neutropenia 60-80% BALF: sensitivity 33-100%
nonneutropenia < 50% specificity 52-100%

PLoS One 2012;7(08):e43347

Acute Invasive Pulmonary Aspergillosis
• Investigations
–Galactomannan
• Monitoring therapy for invasive aspergillosis
Acute Invasive Pulmonary Aspergillosis
• Investigations
–Galactomannan
• False positivity
Acute Invasive Pulmonary Aspergillosis
• Investigations
–-D-glucan
• (1→3)--D-glucan (BG)
• Lack of specificity

Clin Microbiol Infect 2018;24(Suppl 1):e1–e38

Acute Invasive Pulmonary Aspergillosis
• Investigations
–Antibody
• A mean time of antibody production was 10 days
• Immunosuppressive status
• No role in the diagnosis of IPA

Med Mycol 2017;55(01):48–55

Acute Invasive Pulmonary Aspergillosis
• Investigations
–Polymerase Chain Reaction
• Sensitivity of
–Serum 73 – 86%
–BAL 77 – 96%
• Detection of gene mutations associated with azole
resistance
J Clin Microbiol 2017;55(11):3210–3218
Acute Invasive Pulmonary Aspergillosis
• Investigations
–The lateral flow device
• AspLFD, OLM Diagnostics, Newcastle-on-Tyne, United
Kingdom
• Aspergillus galactomannan LFA, IMMY, Norman, OK
• Point of care test
• Detecting an extracellular glycoprotein secreted by
Aspergillus
• Sensitivity > 70%
Mycoses 2019;62(03):230–236
Acute Invasive Pulmonary Aspergillosis
• Diagnosis
–EORTC/MSG criteria for severely
immunosuppressed patients
–AspICU investigator group for critically ill
patients

Am J Respir Crit Care Med 2012;186(01):56–64

Clin Infect Dis. 2020 Sep 12;71(6):1367-1376
Acute Invasive Pulmonary Aspergillosis
• Diagnosis

Clin Infect Dis. 2020 Sep 12;71(6):1367-1376

Acute Invasive Pulmonary Aspergillosis
• Diagnosis
BALF XXX
–Proven
• Specimen from a unusually sterile site: culture, PCR or DNA
sequencing positive for Aspergillus sp. BALF XXX
• Histopathologic, cytopathologic, or direct microscopic
examination of a specimen obtained by needle aspiration or
biopsy in which hyphae are seen accompanied by evidence of
associated tissue damage qualifies for an invasive mold disease
but not for an invasive aspergillosis in the absence of Aspergillus
identification by culture or molecular diagnosis.
Acute Invasive Pulmonary Aspergillosis
• Diagnosis
–Probable
Acute Invasive Pulmonary Aspergillosis
• Diagnosis
–Probable Pneumonia not response to ATB Bronchoscopy
Acute Invasive Pulmonary Aspergillosis
• Diagnosis
–Possible
• Immunosuppressed patient
–Host factor + clinical features
• ICU patients
–Aspergillus colonization
Acute Invasive Pulmonary Aspergillosis
• Diagnosis
–Failing to meet the criteria does not exclude a
fungal infection
–These definitions should not be employed in
daily clinical practice
Acute Invasive Pulmonary Aspergillosis
• Treatment
–Antifungal monotherapy

12-wk survival rate in probable and proven IPA

Acute Invasive Pulmonary Aspergillosis
• Treatment
–Voriconazole
• Therapeutic drug monitoring
–1-5.5 mg/L after 2 -5 d of Px
• Adverse events
–Transient visual events
–Increase in liver enzymes
–Phototoxicity
–Hallucination
–Drug interaction
Clin Microbiol Infect 2018;24(Suppl 1):e1–e38
Acute Invasive Pulmonary Aspergillosis
• Treatment
–Isavuconazole
• Compared with voriconazole
–Survival similar
–Side effects less
–Activity against Mucorales

Lancet 2016;387(10020):760–769
Acute Invasive Pulmonary Aspergillosis
• Treatment
–Polyenes
• Liposomal amphotericin B
–Standard (3mg/kg/d) vs high doses (10m/kg/d) x 14 d
then standard dose
» Survival rate 58% vs 50%

Mycoses 2011;54(05):e449–e455
Acute Invasive Pulmonary Aspergillosis
• Treatment
–Echinocandins
• Caspofungin
1st line X
• Anidulafungin
2nd line 
• Micafungin

Antimicrob Agents Chemother 2019;63(08):63

Acute Invasive Pulmonary Aspergillosis
• Treatment
–Combination antifungal therapy
• Voriconazole + anidulafungin vs voriconazole
– No significance in survival rate
1st line in high prevalence of azole resistance
in disseminated IA
in cerebral infection (azole + LAmB)
2nd line 
Antimicrob Agents Chemother 2019;63(08):63
Acute Invasive Pulmonary Aspergillosis
• Treatment
–Antifungal susceptibility testing
• Azole-resistance 1.7 – 6%
– Cross resistance
• The correlation between in vitro antifungal susceptibility
testing and clinical response is less clear
• The ordering of antifungal susceptibility testing is up to the
discretion of the clinician and is not yet routine, except in
the case of suspected resistance
Antimicrob Agents Chemother. 2018, 63:e01634-18
Acute Invasive Pulmonary Aspergillosis
• Treatment
–Duration
• Depends on the severity of immunosuppression,
the quality of the response to treatment, and the
site of the disease
• at least 6 – 12 wks

Clin Infect Dis 2016;63(04):e1–e60

Acute Invasive Pulmonary Aspergillosis
• Treatment
–Surgery
• Limited role
–Hemoptysis after failure of embolization
–Insufficient response to antifungal therapy

Clin Infect Dis 2016;63(04):e1–e60

Acute Invasive Pulmonary Aspergillosis
• Treatment and prophylaxis
Acute Invasive Pulmonary Aspergillosis
• Treatment
–Tracheobronchial
• Voriconazole or LAmB + bronchoscopic
debridement + inhaled AmB
• Duration at least 3 m or until complete resolution

Clin Infect Dis. 2016;63(4):e1–e60.

Acute Invasive Pulmonary Aspergillosis
• Acute community-acquired aspergillus pneumonia
–Mulch pneumonitis: Massive exposure to airborne
Aspergillus spores that overwhelm the immune
response of the lung
–Post-influenza: Lower levels of exposure following
influenza infection
–COPD patients: Patients with COPD and systemic
corticosteroid therapy
Expert Rev Respir Med. 2015;9(1):89–96.
Acute Invasive Pulmonary Aspergillosis
• Acute community-acquired aspergillus pneumonia
–Chest imaging shows a diffuse miliary pattern or
unilateral upper-lobe consolidation with cavitary
disease
–Mortality rate almost 50%
–Diagnosis is made by isolation of Aspergillus from
bronchoscopic samples
–Treatment Voriconazole
Expert Rev Respir Med. 2015;9(1):89–96.
 Invasive Pulmonary Aspergillosis
Acute Subacute Chronic

Lancet Infect Dis. 2017;17(11):e357–e66

 Chronic Invasive Pulmonary Aspergillosis
• Host
–Non immunocompromised host
–Underlying lung diseases
• Cavitary lesion
• Chronic obstructive pulmonary disease
• Sarcoidosis
• Pneumoconiosis
• Lung cancer
• Post radiation
Eur Respir J 2011;37(4):865–72.
 Chronic Invasive Pulmonary Aspergillosis

• Clinical presentation
–Indolent
–Non specific – cough  hemoptysis
–Fatigue, wt loss, night sweats, shortness of
breath, and fever

Mycoses 2014;57(5):257–70
 Chronic Invasive Pulmonary Aspergillosis

• Spectrum

Eur Respir J. 2016;47(1):45–68

 Chronic Invasive Pulmonary Aspergillosis
Aspergillus Aspergilloma Chronic
nodule cavitary PA
One or more nodules Solid oval opacity Progression of cavity
< 3 cm within a preexist overtime with para-
No cavity Ing lung cavity cavitary infiltration
“Monod” or “air Volume loss
crescent” sign

Large cavities with Chronic

extensive surrounding
fibrosis fibrosing PA
Volume loss Eur Respir J 2016;47(1):45–68
J. Fungi 2020; 6: 106
Chronic Invasive Pulmonary Aspergillosis

Aspergilloma
Chronic Invasive Pulmonary Aspergillosis

Chronic cavitary pulmonary aspergillosis

 Chronic Invasive Pulmonary Aspergillosis

• Diagnosis
Aspergillus nodule

Simple Aspergilloma

Am J Medicine 2021;133:668−74
 Chronic Invasive Pulmonary Aspergillosis
Aspergillus Aspergilloma Chronic
nodule cavitary PA
Surgery Observe Antifungal therapy
Observe Symptomatic  surgery Itraconazole 200 mg bid
Progress  itra/vori Lung reserve Voriconazole 200 mg bid
Bleeding, BPF 4 – 6 months
BA embolization Relapse
Intracavitary AmB Surgery when failed med

Chronic
Treatment
fibrosing PA
Eur Respir J 2016;47(1):45–68
 Chronic Invasive Pulmonary Aspergillosis

• After treatment
–Decrease in the cavity wall thickness and pleural
thickness and disappearance of the fungal ball
correlated the most with a favorable clinical
response to therapy
–Change in the size of the cavity itself didn't
show any correlation
Chest 2016;150 :139–147
 Chronic Invasive Pulmonary Aspergillosis

• After treatment
–A. fumigatus IgG and precipitins levels may
decrease but do not usually return to normal
–Declining levels of ESR and hrCRP

J. Infect. 2006;52:e133-7.
 Chronic Invasive Pulmonary Aspergillosis
Aspergillusbronchitis
• Aspergillus bronchitis
–Chronic superficial infection of the bronchial tree in a
non-immunocompromised patient (bronchiectasis or
CF)
–Bronchoscopic finding: thick tenacious mucus with
bronchial plugging, bronchial erythema, or ulceration.
–Histology: superficial invasion of mucosa by
Aspergillus hyphae
Ann N Y Acad Sci. 2012;1272:73–85.
 Chronic Invasive Pulmonary Aspergillosis

• Aspergillus
Aspergillus bronchitis
bronchitis
–Diagnostic criteria
• Microbiology: demonstration of Aspergillus in the
airways at least twice (sputum culture or PCR)
• Chronic (>4 weeks) pulmonary symptoms
• No significant immune system deficiency
– Immune def  invasive aspergillus tracheobronchitis

Ann N Y Acad Sci. 2012;1272:73–85.

 Chronic Invasive Pulmonary Aspergillosis

• Aspergillus
Aspergillus bronchitis
bronchitis
–Treatment
• Itraconazole
• Voriconazole
• At least 4 months
–Relapse rate 50%

Ann N Y Acad Sci. 2012;1272:73–85.

 Invasive Pulmonary Aspergillosis
Acute Subacute Chronic

Lancet Infect Dis. 2017;17(11):e357–e66

 Subacute Invasive Pulmonary Aspergillosis

• Similar clinical and radiological features with

chronic cavitary PA
–More rapid progression (1 – 3 months)
–Occur in mildly immunocompromised patients
• DM, malnutrition, alcoholism, advanced age,
prolonged corticosteroid use, COPD, CNT disease,
radiation therapy, non-tuberculous mycobacterial
infection, HIV infection
 Subacute Invasive Pulmonary Aspergillosis

• Treatment
–Medication as acute IPA
–Duration as chronic IPA (6 months)

Eur Respir J 2016;47(1):45–68

Conclusion
 Invasive Pulmonary Aspergillosis
Acute Subacute Chronic
Aspergilloma
Angioinvasive
Aspergillus nodule
Airway-invasive
Chronic cavitary PA
Tracheobronchial
Chronic fibrosing PA
Acute community-acquired aspergillus pneumonia
Aspergillus bronchitis