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Fungal infections in CF.pptx

  1. 1. The Challenges of Fungi in Cystic Fibrosis Michael Tracy, M.D. Clinical Assistant Professor March 10, 2018
  2. 2. Microbes in Cystic Fibrosis Bacteria Fungi Viruses Staph MRSA Pseudomona s Burkholderia NTM Influenza RSV Rhinoviru s Aspergillu s Candida
  3. 3. Everyone is exposed to fungi • Every day we breath: • >20,000 times/day • We inhale: • ~10,000 liters of air/day • 1 cubic meter of air can contain: >50,000 fungal spores Chotirmall SH et al. 2018. Mycopathologia.
  4. 4. Many species of fungi cause disease Romani L. 2004. Nat Rev Immunol.
  5. 5. Rising awareness of fungi in CF • Increased life expectancy • Increased percentage of immunocompromised CF patients • Detection methods are improving
  6. 6. So many fungi – where do we focus? Chmiel JF, et al. 2014. Ann Am Thorac Soc
  7. 7. 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.
  8. 8. Similar prevalence in recent studies 0 5 10 15 20 25 30 35 40 45 Aspergillus spp Scedosporium spp Prevalence (%) Prevalence of fungi in CF patients in USA, France & Germany USA France Germany Hong G, et al. 2017. J Clin Microbiol. Coron N, et al. 2018. Mycopathologia. Ziesing S, et al. 2016. Med Mycol.
  9. 9. 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.
  10. 10. We found fungi – now what? • Colonization? • Allergy? • Infection?
  11. 11. 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.
  12. 12. Wide spectrum aspergillosis Inhalation of Aspergillus spores Healthy Lung No infection Efficient Clearance Adapted from: van de Veerdonk FL, et al. 2017. Nat Rev Microbiol. Asthma/CF lung APBA Hypersensitivity CF Lung Bronchitis & Aspergilloma Colonization/Infection
  13. 13. 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.
  14. 14. 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.
  15. 15. ABPA: Treatment Anti-inflammatory Antifungal Anti-IgE • Oral steroids • IV steroids • Concerns: • Diabetes • Bone health • Oral Triazole • Inhaled Amphotericin • Concerns: • Toxicity • Drug interaction • Omalizumab • Concerns: • Cost • Anaphylaxi s • Injections
  16. 16. non-ABPA: Colonization or Infection? Liu JC, et al. 2013. J Cyst Fibros.
  17. 17. 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.
  18. 18. 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.
  19. 19. Scedosporium species • Aka Lomentospora prolificans • Colonizers & Pathogens • Environmental exposures – Soil and water • Eradication is difficult – Highly resistant • Treatment - often several agents: – Triazole(Voriconazole) – Echinocandin (caspofungin) – Inhaled amphotericin Before Treatment After Treatment Schwarz C, et al. 2018. Mycopathologia.
  20. 20. Candida species Schwarz C, et al. 2018. Mycopathologia. • 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.
  21. 21. 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?
  22. 22. Resources to learn more • CFF.org – Dr Okorie & Dr. Moss • NACFC 2017 Archives – S10 – Chair: Dr Moss & Dr Elborn
  23. 23. Thank you!

Hinweis der Redaktion

  • Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacia complex, Stenotrophomonas maltophilia, and
    Achromobacter species
  • Humans are constantly exposed to fungi,
  • fungal kingdom comprises over 1,000,000 species

    but only a limited number of fungi cause severe infections.

    pathogenesis of fungal infections involves several virulence factors that allow fungal survival and persistence in the host, eventually leading to tissue damage
  • Fungal infection is a real problem, but diagnostic criteria are lacking
    Scope of the non-ABPA fungal disease remains to be appreciated
    Optimal detection not standardized
    Multi center studies showing higher prevalence than registry data
    Need to differentiate phenotypes of infection vs colonization
    Extends to yeasts and uncommon filamentous fungi
    New methods and biomarkers will be key in discriminating between colonization, allergy and infection are needed to study antifungal therapies
  • Cystic fibrosis fungal biodiversity grouped according to frequency of isolation (x axis) and established pathogenicity (y axis). The fungi are further divided in terms of chronicity as illustrated. The most frequently isolated filamentous fungi, Aspergillus fumigatus and Scedosporium species complex, and yeast Candida albicans are highlighted and further discussed in text. Low-chronicity genera:
    A. = Aspergillus; C. = Candida; E. = Exophiala; P. = Pneumocystis; R. = Rasamsonia. High-chronicity genera: A. = Aspergillus (flavus, nidulans, niger); A. = Acrophialophora (fusispora); C. = Candida;
    E. = Exophiala; N. = Neosartorya; P. = Pseudallescheria; S. = Scedosporium; T. = Trichosporon
  • optimal testing is not standardized
  • Hong G, et al. 2017. J Clin Microbiol.
    Coron N, et al. 2018. Mycopathologia.
    Ziesing S, et al. 2016. Med Mycol.
  • Aspergillus-sensitization
    Non-ABPA Aspergillus-colonization
    Aspergilloma (rare)
    Invasive aspergillosis (rare)
  • Stevens, DS, et al. 2003. Clin. Infect. Dis.
  • For over 35 years, systemic glucocorticosteroids have been the mainstay of treatment of ABPA
     effective first line treatment for APBA in both asthma and CF.
    Optimal dosing and duration is not as clearly defined

    With recurrent exacerbations, treatment with an antifungal should be considered. Most of the focus of discussion regarding antifungals has been on using them as an adjuvant to systemic glucocorticosteroid therapy.Adding an antifungal agent to the regimen may have a steroid-sparing effect, reducing the need for steroids to control inflammation
    Azoles are used to reduce the fungal burden in the airway. It is then expected would result in decreased inflammation and reduced disease severity and progression
    Interact with CFTR modulators and steroids

     monoclonal antibody to IgE that binds to free serum IgE, interfering with IgE binding to its high-affinity receptor on mast cells and basophils,

  • Controversy persists over the significance of non-ABPA Aspergillus colonization.
    Further study iis warranted before treatment recommendations can be issued (if necessary) for the non-ABPA Aspergillus– colonized population.

    Aspergillus bronchitis
    Invasive aspergillosis
  • A 21-year-old male patient with CF, chronic pseudomonal colonization, and previously diagnosed end-stage lung disease presented with an acute pneumonia 
    Antibiotic treatment did not result in a clinical improvement. 
    Aspergillus fumigatus in the sputum and BAL as well as a new significant infiltration in the right lung led to the decision of an antifungal treatment with voricona- zole (2 9 200 mg daily) for 3 months resulting in a complete remission of the pneumonia and improve- ment of the clinical situation.

  • second most frequent colonizing, allergenic or invasive fungal pathogens

    Case: Scedospo- rium apiospermum being considered as a fungal pathogen causing—or participating with Pseu- domonas to—pneumonia in this patient with CF, an empiric treatment with initially intravenous caspo- fungin and oral voriconazole was started. 

    Voricona- zole caused after a 2-week treatment course adverse drug reactions, so the regimen was adapted to intravenous caspofungin and oral posaconazole. This treatment led to stabilization, but not to a sufficient improvement of the clinical status. Finally, inhaled liposomal amphotericin B
  • 8yo female patient with CF was referred to our center for further evaluation of a chronic exacerbation with dramatic loss of lung function. She was previously treated with several antipseudomonal antibiotic regimens and with non- tuberculous mycobacteria (NTM) effective poly- chemotherapy due to the detection of Mycobacterium avium. The initial workup included a bronchoscopy

    The bronchoscopy revealed multiple whitish plaques in the left upper lobe bronchus (Fig. 7). In fungal cultures grew a unique species which was identified as Candida lusitaniae. Treatment was performed with caspofungin intravenously for 14 days. In a second bronchoscopy, the endobronchial plaques have vanished after the treatment and the patient’s clinical status was improved significantly. However, C. lusi- taniae could be detected from sputum samples even after this treatment, enabling recurrent fungal infections.