Invasive mycoses in cystic fibrosis and

lung transplantElio 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

1999Clin 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.

Criteria for the diagnosis of ABPAUsing 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 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

transplant (n of

procedures) (Dummer, 2005)

infections per patient

invasive mycoses

(%)

proportions of infectios

(%)

most common

site

kidney (64) 0.98 0 41urinary

tract

heart (119) 1.36 8 27 lung

heart-lung (31)

3.19 23 57 lung

liver (101) 1.86 16 23abdomen & biliary

tract

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 mycosesPneumocystosis (Clin Infect Dis 2002; 34:1098; Clin Microbiol Rev 2004; 17:770)

Attack rate 6.5-43% without prophylaxis, 35% symptomatic, 4% severe infections

Between 3 and 6 months after Tx

Short prodromic period (< 5 days)

Cryptococcosis (Clin Infect dis 2009; 48:1566)

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

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