Presentation on theme: "Invasive mycoses in cystic fibrosis and lung transplant"— Presentation transcript:
1Invasive mycoses in cystic fibrosis and lung transplant Elio CastagnolaInfectious Diseases Unit“G.Gaslini” Children HospitalGenoa - Italy
2Cystic fibrosis (CF)An autosomal recessive disease that cause abnormalities of ion transport of epithelilal cells and presents as a multisystem diseaseChronic infections in the lungs are among the most preminent clinical manifestations and are related with the obstruction of respiratory ways by viscous secretionsMucus hypoxia and stasis may contribute to the propensity for bacterial infections, mainly due to Sthaphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas maltopilia and Burkholderia cepacia.
4Fungi 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 CFA. 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 airwaysPenicillium emersonii and Acrophialophora fusispora are encountered in humans almost exclusively in the context of CFThe 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.
5Allergic Broncho Pulmonary Aspergillosis (ABPA) ABPA is a long-term allergic response to Aspergillus, mainly observed in patients with severe, persistent asthma and in CFIn 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
6Allergic 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 bronchiectasisThe 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)Allergic Broncho Pulmonary Aspergillosis (ABPA)ABPA is a long-term allergic response to Aspergillus, mainly observed in patients with severe, persistent asthma and in CFIn 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 diseaseIn 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
7Criteria 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 ageThis is not surprising since colonization with Aspergillus has been shown to be age-related aslo in children with asthma1999Clin Infect Dis, 2003/2004In 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.
8In 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
9TherapyAttenuation of inflammation and immunological activity: systemic steroidsSide effects tue to long term, high dose steroidsAttenuation of antigen burden from heavy colonization: itraconazole, some effect, butMany drug interactions, long term suppression of adrenal glucocorticoid synthesis (associated with budesonide), liver toxicity
10Other therapeutic options Voriconazole: improvements in serological parameters (IgE) and decrease in steroids administration, some effect on pulmonary function, but not in all patientsTriazoles: many drug interactionProbably necessary TDMNebulized liposomal amphotericin B+ nebulized budesonideUse of anti IgE monoclonal antibodies (omalizumab)
11Effect of A.fumigatus infections in CF without ABPA Retrospective analysis on 230 patientsFEV(1) lower in chronically infected patientsInteractions between A.fumigatus and P.aeruginosa on lung functionHigher 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 ?
12Scedosporium... a new challenge? Voriconazole should be the drug of choice, but the caveats regarding interactions and absence of kinetics data still remains...
13Implanted CVC-related fungal infections Type of CVCInfections/ 100 CVCProportions of candidemiasInfections/ 1000 CVC daysLiteratureCF(3 studies)Totally5-8(95%CI )8-10%1.4%-4.6%(95%CI )Partially21-3747 (*)6.6%(**)(*) 7 episodes in 1 patient!(**) PIVADS in 1 study only, not stratified TIVADS/PIVADSIn patients with CFdisease severityfrequent antibiotic usagecorticosteroid therapydiabetes mellitusall have been associated with an increased risk of candidemia
14Lung transplant becomes the only therapeutic option for end-stage lung disease in CF, but... Type of transplant(n of procedures) (Dummer, 2005)infections per patientinvasive mycoses (%)proportions of infectios (%)most common sitekidney (64)0.9841urinary tractheart (119)1.36827lungheart-lung (31)3.192357liver (101)1.8616abdomen & biliary tract
15AspergillosisIncidence 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: Pediatrics 2008; 121:1286)Clinica featuresAcute inflammatory pneumoniaChronic necrotizing aspergillosisTracheobronchitis affecting the anastomotic site and causing dehiscence of the suturePossibe disseminationNo distinctive radiological features
16Pre transplant colonization 22-58% of FC, 28% of non-FCIn FC 25%-42% of colonized patients will develop invasive disease after LTxIn non fc 34% with IAA.fuigatus the most frequently isolatedRisk of disease without prophylaxis 11 times higher than in non colonized, within 6 months from TxColonization within 1 year after tx, 6 times higher risk of IANo major role of azole prophylaxis
17Post transplant aspergillosis in CF (Helmi et al, Chest 2003; 123: 800) Fungal infection developed in 44% (14/32) of patientstracheo-bronchial aspergillosis was observed in 9 (in 1 associated with pneumonia)isolated pneumonia was observed in 5survival was 21% (3/14)
18CandidaCandida 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 failureInvasive 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 time32 IFD (8%): manly tracheobronchitis (31%), including the anastomotic site, bloodstream (28%) and disseminated (13%) infections
19Other mycosesPneumocystosis (Clin Infect Dis 2002; 34:1098; Clin Microbiol Rev 2004; 17:770)Attack rate % without prophylaxis, 35% symptomatic, 4% severe infectionsBetween 3 and 6 months after TxShort prodromic period (< 5 days)Cryptococcosis (Clin Infect dis 2009; 48:1566)In LTx the incidence is increasingUp tp 6% of patients treated with tacrolimusNon-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
20Indirect 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)
22Nebulized 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 mg, doubled if the patient is incubatetThe frequency could be every 2 weeks (long peristence in the BAL)Clinical studies:ABLC mg for 4 days, then 1/week up to 2 mtsABLC 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 eventsSome programs use 1 dose every 2 weeks lifelongCombination with systemic prophylaxis ?
23Azoles High risk of interactions (Clin Infect Dis 2009; 48: 1441) Therapeutic Drug Monitoring (TDM) is mandatoryVoriconazole TDM in CF LTx (Transpl Infect Dis 2009; 11:211)Usual dose: 200 mg q12h after load,
24Azoles High risk of interactions (Clin Infect Dis 2009; 48: 1441) Therapeutic Drug Monitoring (TDM) is mandatoryVoriconazole TDM in CF LTx (Transpl Infect Dis 2009; 11:211)Usual dose: 200 mg q12h after load,14% neurologic effects, 30% liver toxicityIncreased 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)
25ConclusionsAt present fungal infections do not seem to represent a major challenge in patients with CFABPA 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 transplantThis 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 CFConsidering 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