The Challenges of Fungi in

Cystic Fibrosis

Michael Tracy, M.D.

Clinical Assistant Professor
March 10, 2018
Microbes in Cystic Fibrosis

MRSA
Pseudomonas

Bacteria
Burkholderia Staph
NTM

Influenza Candida

Viruses Fungi
RSV Rhinovirus Aspergillus
Everyone is exposed to fungi
• Every day we breath:
• >20,000 times/day

• We inhale:
• ~10,000 liters of
air/day
>50,000
• 1 cubic meter of air can fungal spores
contain:

Chotirmall SH et al. 2018. Mycopathologia.

Many species of fungi cause disease

Romani L. 2004. Nat Rev Immunol.

Rising awareness of fungi in CF
• Increased life expectancy

• Increased percentage of immunocompromised CF

patients

• Detection methods are improving

So many fungi – where do we focus?

Chmiel JF, et al. 2014. Ann Am Thorac Soc.

How often do we find fungi in CF?
• Historically, reported prevalence varies greatly
– Aspergillus spp: 0 to 36%
– Scedosporium spp: 0 to 9%

• Appears to be increasing over time

• Multi center studies are showing a higher prevalence

of fungi than CF registry data

Hong G, et al. 2017. J Clin Microbiol.

 Similar prevalence in recent studies
Prevalence of fungi in CF patients in USA, France & Germany
45

40

35
Prevalence (%)

30

25

20

15

10

0
Aspergillus spp Scedosporium spp
USA France Germany
Hong G, et al. 2017. J Clin Microbiol.
Coron N, et al. 2018. Mycopathologia.
Ziesing S, et al. 2016. Med Mycol.
What are risk factors for fungal colonization
in CF?
• CF lung disease
– Impaired mucus clearance
– Immunogenic dysfunction

• Decreased lung function

• Older age
• Inhaled and oral antibiotic use
• Inhaled steroid use
• Macrolide antibiotics Stolz et al. 2015. NEJM.
Sudfeld CR, et al. 2010. J Cyst Fibros.
Hong G, et al. 2018. J Cyst Fibros.
We found fungi – now what?

• Colonization?

• Allergy?

• Infection?
Aspergillus species
• Over 100 species
– A. fumigatus most common
• Everywhere in the environment
– Soil, water, decomposing material

• Wide spectrum of Aspergillus-associated disease

– Allergic bronchopulmonary aspergillosis (ABPA) is now well
described in CF
– What is the role of A. fumigatus in the non-ABPA CF lung?

Chotirmall SH et al. 2018. Mycopathologia.

Wide spectrum aspergillosis
Inhalation of Aspergillus spores

Healthy Lung Asthma/CF lung CF Lung

Efficient Clearance Hypersensitivity Colonization/Infection

No infection APBA Bronchitis & Aspergilloma

Adapted from: van de Veerdonk FL, et al. 2017. Nat Rev Microbiol.
ABPA: Minimal diagnostic criteria
• Clinical deterioration
• Total serum IgE > 500 IU/mL
• Immediate cutaneous reactivity to Aspergillus or in
vitro demonstration of IgE antibody to A. fumigatus
• One of the following:
– Precipitins to A. fumigatus  or in vitro demonstration of IgG
antibody to A. fumigatus
– New or recent abnormalities on chest radiography (infiltrates or
mucus plugging) or chest CT (bronchiectasis) that have not
cleared

Stevens, DS, et al. 2003. Clin. Infect. Dis.

ABPA: Challenging diagnosis
• Overlapping features with other factors causing CF
exacerbations

• New biomarkers are emerging: “blood tests for ABPA”

– Basophil Activation Test + IgE + IgE for A.fumigatus
– CF pts into 3 groups:
• Nonsensitized
• A.fumigatus–sensitized
• ABPA

Mirkovic B et al. 2016. JACI.

ABPA: Treatment
Anti-inflammatory Antifungal Anti-IgE

• Oral steroids • Oral Triazole • Omalizumab

• IV steroids • Inhaled
Amphotericin
• Concerns: • Concerns: • Concerns:
• Diabetes • Toxicity • Cost
• Bone health • Drug • Anaphylaxis
interaction • Injections
non-ABPA: Colonization or Infection?

Liu JC, et al. 2013. J Cyst Fibros.

Criteria for “highly probable”
CF fungal infection

1. Increased sputum production

2. Multiple isolation of the same fungal species
– At least two culture-positive samples in 6 months
3. Pulmonary infiltrate(s) on chest CT scan or X-ray
4. Treatment failure with antibiotic therapy
5. Unexplained lung function decline
6. Exclusion of new/other bacteria
7. Exclusion of ABPA

Schwarz C, et al. 2018. Mycopathologia.

Aspergillus infections: Treatment
• No consensus in CF

• Azole therapy is first line

– Voriconazole
– Posaconazole

• Growing concern for Azole resistance

• Amphotericin
• Caspofungin

Schwarz C, et al. 2018. Mycopathologia.

Scedosporium species
• Aka Lomentospora prolificans
• Colonizers & Pathogens
Before Treatment
• Environmental exposures
– Soil and water

• Eradication is difficult
– Highly resistant

• Treatment - often several agents: After Treatment

– Triazole(Voriconazole)
– Echinocandin (caspofungin)
– Inhaled amphotericin

Schwarz C, et al. 2018. Mycopathologia.

Candida species
• C.albicans most common
– Frequently found in sputum
– Oral/genital candidiasis
– Infections of devices/lines
• Colonization associated with:
– Hospitalizations
– Exacerbations
– Declines FEV1 and BMI
• If colonized, clinical role unclear
– no evidence for treatment

• Other species may be more pathogenic

– Remains unusual cause for infection
Chotirmall SH, et al. 2010. Chest.
Schwarz C, et al. 2018. Mycopathologia.
Future Questions
• When and how to do fungi become pathogenic?
– When they enter the airway?
– When they colonize?
– When they sensitive?
– When they infect?

• Should we eradicate?

• Which antifungals? For how long?

Resources to learn more
• CFF.org
– Dr Okorie & Dr. Moss

• NACFC 2017
Archives
– S10
– Chair: Dr Moss & Dr
Elborn
Thank you!