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Invasive mycoses
in cystic fibrosis and
lung transplant
Elio Castagnola
Infectious Diseases Unit
“G.Gaslini” Children Hospital
Genoa - Italy
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.
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.
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
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
1999
Clin Infect Dis, 2003/2004
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.
• 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
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
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)
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 ?
Scedosporium... a new challenge?
Voriconazole should be the drug of choice,
but the caveats regarding interactions and
absence of kinetics data still remains...
Lung transplant becomes the only therapeutic
option for end-stage lung disease in CF, but...
Type of
infections per
transplant
patient
(n of procedures)
invasive
proportions of
most
mycoses (%) infectios (%) common site
(Dummer, 2005)
kidney (64)
0.98
0
41
urinary tract
heart (119)
1.36
8
27
lung
heart-lung (31)
3.19
23
57
lung
23
abdomen &
biliary tract
liver (101)
1.86
16
Aspergillosis
• Incidence 6-16% of transplant, 2.4% cumulative incidence at 1 year, late onset (> 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; 121:1286)
• 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
• 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
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)
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: 11:112;
transplantation 2000; 70:112)
• 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
Other mycoses
Pneumocystosis
Attack rate 6.5-43% without prophylaxis, 35% symptomatic, 4%
(Clin Infect Dis 2002; 34:1098; Clin Microbiol Rev 2004; 17:770)
severe infections
Between 3 and 6 months after Tx
Short prodromic period (< 5 days)
Cryptococcosis
In LTx the incidence is increasing
Up tp 6% of patients treated with tacrolimus
Non-aspergillus filamentous fungi
Colonization in 14.5% of LTx, a median of 415 days from the
(Clin Infect dis 2009; 48:1566)
(J Heart Lung Transpant 2008; 27: 850):
procedure, mainly zygomycetes, 1 case of probable IFD
Indirect diagnosis
• Serum 1-3 bera-D-Glucan: no data
• Serum Galactomannan: no data in a wide meta-anaysis (Clin
Infect Dis 2006; 42:1417)
• 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; 4:796)
• Galactomannan in BAL fluid: Sensitivity 82%. Specificity 96%,
(Clin Vacc immunol 2008; 15: 1760)
Drugs
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:
1. ABLC 50-100 mg for 4 days, then 1/week up to 2 mts
2. ABLC vs deoxy-AmB: similar efficacy (11% vs 14%), better tolerability (14%
vs 29%)
3. 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 ?
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; 11:211)
• Usual dose: 200 mg q12h after load,
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; 11:211)
• 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)
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