Invasive mycoses in cystic fibrosis and lung transplant

1
Invasive mycoses in cystic fibrosis and lung
transplant

• Elio Castagnola
• Infectious Diseases Unit
• G.Gaslini Children Hospital
• Genoa - Italy

2
Cystic fibrosis (CF)

• An autosomal recessive disease that cause
  abnormalities of ion transport of epithelilal
  cells and presents as a multisystem disease
• Chronic infections in the lungs are among the
  most preminent clinical manifestations and are
  related with the obstruction of respiratory ways
  by viscous secretions
• Mucus hypoxia and stasis may contribute to the
  propensity for bacterial infections, mainly due
  to Sthaphylococcus aureus, Pseudomonas
  aeruginosa, Stenotrophomonas maltopilia and
  Burkholderia cepacia.

3
(No Transcript)
4
Fungi in the respiratory tract of patients with CF

• The defective mucociliary clearance is associated
  with local immunological disorders. Moreover, the
  prolonged antibacterial therapy and the use of
  corticosteroid treatments also facilitate fungal
  growth.
• A. fumigatus, S. apiospermum and A. terreus for
  filamentous fungi and C. albicans for yeasts are
  the main fungal species associated with CF
• A. flavus and A. nidulans may be isolated
  transiently from CF respiratory secretions, while
  others such as Exophiala dermatitidis and
  Scedosporium prolificans may chronically colonize
  the airways
• Penicillium emersonii and Acrophialophora
  fusispora are encountered in humans almost
  exclusively in the context of CF
• The clinical relevance of the fungal airway
  colonization is mainly unknown, but it would be
  not surprising the discover that filamentous
  fungi contribute to the local inflammatory
  response, and therefore to the progressive
  deterioration of the lung function.

5
Allergic Broncho Pulmonary Aspergillosis (ABPA)

• ABPA is a long-term allergic response to
  Aspergillus, mainly observed in patients with
  severe, persistent asthma and in CF
• In CF bacterial pneumonia and ABPA may present
  with similar clinical features, and their
  differential diagnosis could be very difficult,
  not forgetting that both conditions could be
  present simultaneously.
• Therefore, specific criteria are used to
  establish the diagnosis of ABPA

6
Allergic Broncho Pulmonary Aspergillosis (ABPA)

• Pathogenesis is very complex
• After colonization, Aspergillus germinates to
  form hyphe.
• The response to these antigens is of the Th2
  type, with release of cytokines IL-4, IL-5, and
  IL-13 (maybe driven also by peculiar HLA)
• Recent studies suggest a pivotal role of
  chemokines (especially CCL17 and its receptor
  CCR4)
• The inflammation in the bronchial submucosa
  leads to excessive mucin production,
  extravasation of eosinophils into the bronchial
  mucin, intermittent bronchial obstruction with
  atelectasis, and, over time, to bronchiectasis
• The picture may become even worst if we consider
  that the brochial secretion in CF are
  particularly though and may represent a culture
  media for other pathogens (e.g. Pseudomonadaceae)

• ABPA is a long-term allergic response to
  Aspergillus, mainly observed in patients with
  severe, persistent asthma and in CF
• In patients with asthma clinical manifestations
  are episodic wheezing, expectoration of brown
  mucus plugs, low-grade fever, eosinophilia, and
  transient pulmonary infiltrates due to
  atelectasis. Central bronchiectasis occurs in
  some patients after several years of disease
• In CF bacterial pneumonia and ABPA may present
  with similar clinical features, and their
  differential diagnosis could be very difficult,
  not forgetting that both conditions could be
  present simultaneously.
• Therefore, specific criteria are used to
  establish the diagnosis of ABPA

7
Criteria for the diagnosis of ABPA

• Using these criteria in CF patients the incidence
  of ABPA is approximately 7 (ranging 2-15),
  increasing after the 6th year of age
• This is not surprising since colonization with
  Aspergillus has been shown to be age-related aslo
  in children with asthma

In these patients eosinophilia is not a useful
diagnostic tool because the patients may have
elevated peripheral blood eosinophils from other
causes such as Pseudomonas aeruginosa infection.
8

• In patients with asthma clinical manifestations
  are episodic wheezing, expectoration of brown
  mucus plugs, low-grade fever, eosinophilia, and
  transient pulmonary infiltrates due to
  atelectasis.
• Central bronchiectasis occurs in some patients
  after several years of disease.
• Without adequate treatment the evolution is
  toward progressive, irreversible lung damage,
  leading to pulmonary fibrosis

9
Therapy

• Attenuation of inflammation and immunological
  activity systemic steroids
• Side effects tue to long term, high dose steroids
• Attenuation of antigen burden from heavy
  colonization itraconazole, some effect, but
• Many drug interactions, long term suppression of
  adrenal glucocorticoid synthesis (associated with
  budesonide), liver toxicity

10
Other therapeutic options

• Voriconazole improvements in serological
  parameters (IgE) and decrease in steroids
  administration, some effect on pulmonary
  function, but not in all patients
• Triazoles many drug interaction
• Probably necessary TDM
• Nebulized liposomal amphotericin B nebulized
  budesonide
• Use of anti IgE monoclonal antibodies
  (omalizumab)

11
Effect of A.fumigatus infections in CF without
ABPA

• Retrospective analysis on 230 patients
• FEV(1) lower in chronically infected patients
• Interactions between A.fumigatus and P.aeruginosa
  on lung function
• Higher risk of exacerbation of pulmonary disease,

Respiratory deterioration not responding to
antibacterials in patients colonized with
A.fumigatus, in absence of criteria for diagnosis
of ABPA a new clinical syndrome in CF or the
first stage of ABPA ?
12
Scedosporium... a new challenge?
Voriconazole should be the drug of choice, but
the caveats regarding interactions and absence of
kinetics data still remains...
13
Implanted CVC-related fungal infections

• In patients with CF
• disease severity
• frequent antibiotic usage
• corticosteroid therapy
• diabetes mellitus
• all have been associated with an increased risk
  of candidemia

14
Lung transplant becomes the only therapeutic
option for end-stage lung disease in CF, but...
15
Aspergillosis

• Incidence 6-16 of transplant, 2.4 cumulative
  incidence at 1 year, late onset (gt 3 months)
  infection is becoming more frequent and is
  associated with rejection (intensified
  immunosuppression) and retransplantation (Clin
  Chest Med 2009 30 307. Curr Infect Dis Rep
  2009 11 209. Pediatrics 2008 1211286)
• Clinica features
• Acute inflammatory pneumonia
• Chronic necrotizing aspergillosis
• Tracheobronchitis affecting the anastomotic site
  and causing dehiscence of the suture
• Possibe dissemination
• No distinctive radiological features

16

• Pre transplant colonization
• 22-58 of FC, 28 of non-FC
• In FC 25-42 of colonized patients will develop
  invasive disease after LTx
• In non fc 34 with IA
• A.fuigatus the most frequently isolated
• Risk of disease without prophylaxis 11 times
  higher than in non colonized, within 6 months
  from Tx
• Colonization within 1 year after tx, 6 times
  higher risk of IA
• No major role of azole prophylaxis

17
Post transplant aspergillosis in CF(Helmi et al,
Chest 2003 123 800)

• Fungal infection developed in 44 (14/32) of
  patients
• tracheo-bronchial aspergillosis was observed in
  9 (in 1 associated with pneumonia)
• isolated pneumonia was observed in 5
• survival was 21 (3/14)

18
Candida

• Candida is frequently isolated from the
  respiratory tract however, it rarely causes
  invasive pulmonary disease.
• The risk of invasive candidiasis seems be
  associated with concomitant bacterial infections
  or multiple organ failure
• Invasive infections due to Candida (Transplant
  Infect Dis 2009 11112 transplantation 2000
  70112)
• 384 L/HLTx from 1980 to 2004, with a decreasing
  incidence in process of time
• 32 IFD (8) manly tracheobronchitis (31),
  including the anastomotic site, bloodstream (28)
  and disseminated (13) infections

19
Other mycoses

• Pneumocystosis (Clin Infect Dis 2002 341098
  Clin Microbiol Rev 2004 17770)
• Attack rate 6.5-43 without prophylaxis, 35
  symptomatic, 4 severe infections
• Between 3 and 6 months after Tx
• Short prodromic period (lt 5 days)
• Cryptococcosis (Clin Infect dis 2009 481566)
• In LTx the incidence is increasing
• Up tp 6 of patients treated with tacrolimus
• Non-aspergillus filamentous fungi (J Heart Lung
  Transpant 2008 27 850)
• Colonization in 14.5 of LTx, a median of 415
  days from the procedure, mainly zygomycetes, 1
  case of probable IFD

20
Indirect diagnosis

• Serum 1-3 bera-D-Glucan no data
• Serum Galactomannan no data in a wide
  meta-anaysis (Clin Infect Dis 2006 421417)
• Only 1 study in LTx Cochrane Review 2009 high
  risk of false positive in the early days after
  LTx in FC (Am J Transplant 2004 4796)
• Galactomannan in BAL fluid Sensitivity 82.
  Specificity 96, (Clin Vacc immunol 2008 15
  1760)

21
Drugs
22
Nebulized amphotericin B for prophylaxis(Int J
Antimicrob Agents 2008 32 (Suppl 2) s161

• Nebulized lipid preparations of amphotericin B
  greater deposition in the lungs and longer
  half-life (compared with deoxy-AmB)
• Unclear the correct dose 24-28 of the
  administerd dose is deposited in the trnsplanted
  lung(s) recommended 25-50 mg, doubled if the
  patient is incubatet
• The frequency could be every 2 weeks (long
  peristence in the BAL)
• Clinical studies
• ABLC 50-100 mg for 4 days, then 1/week up to 2
  mts
• ABLC vs deoxy-AmB similar efficacy (11 vs 14),
  better tolerability (14 vs 29)
• ABLC 50 mg pre Tx, 50 mg every 48 hrs up to 2
  weeks after estubation, 1/week for 3-13 weeks
  after Tx fluconazole allowed for the 1st month
  6 months f.u. in 60 pts 1 (1.7) colonization, 4
  (7) mild adverse events
• Some programs use 1 dose every 2 weeks lifelong
• Combination with systemic prophylaxis ?

23
Azoles

• High risk of interactions (Clin Infect Dis 2009
  48 1441)
• Therapeutic Drug Monitoring (TDM) is mandatory
• Voriconazole TDM in CF LTx (Transpl Infect Dis
  2009 11211)
• Usual dose 200 mg q12h after load,

24
Azoles

• High risk of interactions (Clin Infect Dis 2009
  48 1441)
• Therapeutic Drug Monitoring (TDM) is mandatory
• Voriconazole TDM in CF LTx (Transpl Infect Dis
  2009 11211)
• Usual dose 200 mg q12h after load,
• 14 neurologic effects, 30 liver toxicity
• Increased levels of tacrolimus (dose reduction by
  factor 4)
• Posaconazole and tacrolimus in CF LTx (Ther Drug
  Monit 2009 31 396) daily tacrolimus reducted
  by a factor 3 (2 mg/day)

25
Conclusions

• At present fungal infections do not seem to
  represent a major challenge in patients with CF
• ABPA and CVC-related candidemias are the most
  frequent clinical features, but invasive
  infections due to Aspergillus and Scedosporium
  are described with increasing frequency,
  especially after lung transplant
• This scenario may change in the (next) future
  because of the overall increase in patients
  survival and therefore it is possible that fungal
  pathogens become (soon) a challenge also in CF
• Considering the peculiarity of pharmacokinetics
  of drugs in CF and the great number of drugs
  administered to these patients, specific studies
  are needed in order to identify the correct
  schedules and the possible risk of adverse events
  due to drugs interactions