Bakterielle Infektionen bei Immunsuppression < Lungentransplantation bei Mukoviszidose > PD Dr. med. Michael Hogardt M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Immunsuppressiva: Glucocorticoide - Prednisolon (Induktions-, 3-fach Erhaltungstherapie; Therapie Abstoßung/BOS) Glucocorticoide - Prednisolon Calcineurin Inhibitoren (CNI) Cyclosporin Tacrolimus Antimetabolite/Antiproliferative Substanzen Mycophenolat Mofetil Azathioprin Sirolimus Everolimus Antikörper - Anti IL-2, CD3 Medikamenten NW Infektion Tumor M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Angriffspunkte Immunsuppressiva: Basiliximab CD3/CD4 MPA, AZA Glucokortikoide NFkB Transkription proinflam. Gene (Zytokine/Interleukine) modifiziert nach Nat Clin Pract Neprol 2006; 2: 688–699 M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Immunsuppression → Infektionen: Neutropenie Phagozyten B-Zellen HSCT S. aureus, GNS (z.B. P. aeruginosa) Pilze Pneumokokken H. influenzae N. meningitidis Asplenie T-Zellen Mykobakterien, Nokardien Pilze P. jiroveci intrazelluläre MO (CMV/HSV) zytotoxische. Therapie HIV-Infektion Transplantation M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Relevante Pathogene: im Speziellen u. im Allgemeinen klassische CF-Erreger: („die Sinus haben weiterhin CF“) - P. aeruginosa (mucoid; MDR) - S. aureus (MRSA) - A. xylosoxydans (MDR) - S. maltophilia (MDR) - B.-cepacia-Komplex - Nicht-tuberkulöse Mykobakterien (NTM; M. abscessus) - Pilze (Aspergillus spp.; Candida spp.; Secedosporium spp.) Hospitalkeime („perioperative AB-Prophylaxe“): - MRSA - VRE - Acinetobacter spp. - C. difficile Aris RM et al., Am J Respir Crit Care Med. 1997; 155:1699-704. Dobbin C et al., J Hosp Infect. 2004 Apr;56(4):277-82. Hadjiliadis et al., J Heart Lung Transplant, 2007 Aug;26(8):834-8 Vos R et al., Eur Respir J; 2008 May;31(5):1037-45 M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Fishman, Liver Transplantation, 17:S34-S37, 2011 Immunsuppression (Tx) → Infektionen: Bakterielle Infektionen: v.a. in ersten 1-2 Monaten nosokomiale Infektionen bei 137 LTx (39CF): 47,5% NI (follow-up: mean 42d) 30.7% Pneumonien, 14.6% HWI , 13.1% Sepsis,, 11% Wundinf.. Mattner et al., J Heart Lung Transplant. 2007 Mar;26(3):241-9 J Heart Lung Transplant. 2007 Mar;26(3):241-9. Post-operative nosocomial infections after lung and heart transplantation. Mattner F, Fischer S, Weissbrodt H, Chaberny IF, Sohr D, Gottlieb J, Welte T, Henke-Gendo C, Gastmeier P, Strueber M. Source Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany. mattner.frauke@mh-hannover.de Abstract BACKGROUND: Thoracic transplant recipients appear to be at high risk for post-operative infections. Therefore, we investigated the incidence and risk factors of post-operative nosocomial infections (NIs) in lung and heart transplant recipients. METHODS: From January 2002 to December 2003, a cohort of 208 consecutive thoracic transplant recipients (137 lung transplants [LTx], 51 heart transplants [HTx] and 20 combined transplants [CLTx]) were analyzed for post-operative infections and in-hospital mortality. NIs were determined according to CDC definitions. Uni- and multivariate risk factor analyses were performed. RESULTS: Of the 157 NIs, 59 were pneumonia (37.6%), 34 primary sepsis (21.6%), 34 urinary tract (21.6%) and 30 surgical site (19.1%). Despite a total NI incidence of 75.5%, more importantly 56.3% of all patients remained free from any infection. CLTx patients had a higher risk of developing NIs (odds ratio [OR] 4.97; 95% confidence interval [CI] 1.74 to 15.34). Risk factors for NIs were volume reduction procedures in LTx (OR 2.6; 95% CI 1.13 to 6.30) and re-do Tx (OR 5.25; 95% CI 1.41 to 26.8). In LTx patients, pre-operative colonization with gram-negative rods was found to be a risk factor for post-transplant pneumonia (OR 3.7; 95% CI 1.19 to 11.37). Presence of NI (OR 2.53; 95% CI 1.07 to 6.25) was a risk factor for mortality, as was cystic fibrosis (OR 3.20; 95% CI 1.27 to 7.92) and ventilation prior to transplantation (OR 4.00; 95% CI 1.28 to 12.09). Transplant Proc. 2011 May;43(4):1290-1. Airway pathogens during the first year after lung transplantation: a single-center experience. Kovats Z, Sütto Z, Muraközy G, Bohacs A, Czebe K, Lang G, Renyi-Vamos F, Klepetko W, Müller V. Department of Pulmonology, Semmelweis University, Budapest, Hungary. tskovacs@freemail.hu After lung transplantation, a high level of immunosuppression is needed to prevent rejection. This demand renders recipients more sensitive to infections. As pulmonary infections are a major clinical problem during the first postoperative year after lung transplantation, preventive treatment and regular surveillance examinations are needed for immediate, adequate therapy. We describe the airway pathogens registered during the first posttransplantation year among our 12 lung transplant recipients since December 2008. Samples were obtained for microbiologic analysis from the upper and lower respiratory tracts and from serum as part of routine care. During the first year after transplantation the most frequent pathogens were fungi (Candida albicans 82%; Aspergillus 50%), Pneumocystis (8%), gram-negative bacteria (Pseudomonas spp 60%; Klebsiella 25%, Acinetobacter 17%; Escherichia Coli 17%; and Enterococcus faecalis 25%), and Staphylococcus aureus (50%, including methicillin-resistant strains 25%). This pathogen spectrum in the first postoperative year after lung transplantation was similar to other centers. Colonization with Pseudomonas or fungi presented early and was prevalent among our patients. Clin Transplant. 2010 May-Jun;24(3):341-8. Epub 2009 Aug 27. The impact of invasive fungal diseases on survival after lung transplantation. Arthurs SK, Eid AJ, Deziel PJ, Marshall WF, Cassivi SD, Walker RC, Razonable RR. Division of Infectious Diseases, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA. Recipients of lung transplants are at high risk of infectious complications. We investigated the epidemiology of infections after lung transplantation and determined their impact on survival. We retrospectively reviewed the medical records of patients who underwent lung transplantation at Mayo Clinic (Rochester) during 1990-2005. Survival analyses were performed using Kaplan-Meier estimation and Cox proportional hazard modeling. Sixty-nine lung transplants were performed during the 16-yr study period. The mean (+/-SD) patient age was 50.5 +/- 9.7 yr; 45% were male. During the mean (+/-SD) follow-up period of 1188 (+/-1288) d, the cumulative percentage of patients with infections were: bacteria (52%), cytomegalovirus (CMV) (49%), other viruses (32%), fungi (19%), mycobacteria (7%), and Pneumocystis jiroveci (1%). The median survival time after lung transplantation was 5.02 yr. Kaplan-Meier estimation of one-, three-, and five-yr survival was 80%, 61%, and 50%, respectively. Overall, 37 (54%) patients died due to graft rejection and failure (35%), invasive fungal diseases (16%), post-transplant lymphoproliferative disorder and other malignancies (14%), cardiovascular diseases (5%), CMV disease (3%), bacterial infection (3%), or other causes (24%). Survival analysis using Kaplan-Meier estimation showed that invasive fungal disease (Aspergillus sp., n = 9, Candida sp., n = 2, Alternaria sp., n = 1, Rhizopus sp., n = 1, and/or Mucor sp., n = 1) was significantly associated with mortality (p = 0.0104). After adjusting for age and graft rejection, invasive fungal disease remains a significant predictor of mortality (p = 0.0262). CONCLUSION: Nosokomiale Infektionen („big 4“) ausgeprägte Immunsuppression Immunsuppression Exposition Fishman, Liver Transplantation, 17:S34-S37, 2011 M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Immunsuppression (Tx) → Infektionen: 12 LTx (7CF) RT-Keimspektrum (Surveillance-Ansatz, follow-up: 1 Jahr) 82% C. albicans; 50% Aspergillus spp., 60% Pseudomonas spp.; 25% Klebsiella spp., 17% Acinetobacter spp.; 17% E. coli; E. faecalis 25%, 50% S. aureus (MRSA 25%), 8% Pneumocystis, 2% CMV, 1% EBV Kovacs et al., Transplant Proc. 2011 May;43(4):1290-1 96 LTx-Patienten (3CF), Infektionraten kumulativ über 16J : 52% Bakterien, 49% CMV, 32% s. Viren, 19% Pilze, 7% Mykobakterien, 1% P. jiroveci Arthurs et al., Clin Transplant. 2010 May-Jun;24(3):341-8 7 M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Infektionen nach Lungentransplantation (pLTx): 21 CF-Patienten LTx – 31 Infektionen als Komplikation pLTx Kanj et al., Chest, 1997 Oct;112(4):924-30 M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Nash et al., Transpl Infect Dis 2010; 12:551-4 Burkholderia-cepacia-Komplex: [17 Spezies; v. a. B. cenocepacia (III), B. multivorans (II); B. dolosa (VI)] nach LTx ÜR in Frühphase signifikant  bei BCK+ - 85% vs. 95% nach 3 Mo.; v. a. B. cenocepacia ;nach 5J ÜR ~ BCK+/- Boussaud et al., Thorax. 2008 Aug;63(8):732-7 B. cenoc. ÜR 20%↓, 75% Tod im 1J, in 87% Sepsis - andere BCK-Spezies ÜR ~ BCK-negativen Kontrollgruppe De Soyza et al., J Heart Lung Transplant. 2010;29:1395-404 16 P. BCK+, pLTX 14 P. BCK+ (identischer Klon) - signifikant reduz. ÜR innerhalb 5J für B. cenocepacia - andere BCK-Spezies (ÜR im 1J leicht ↓; 5 J ~ BCK-negative P.) Alexander et al., Am J Transplant. 2008;8:1025-30 2 “long-term survivors” after LTx u. B.cenocepacia-Sepsis Nash et al., Transpl Infect Dis 2010; 12:551-4 M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Burkholderia gladioli: (Ø BCK) B. gladioli: TW-Abszess, Empyem, Sepsis pLTx CF-P., Tod Kahn et al., Pediatr Infect Dis J. 1996 Jul;15(7):637-9 2 CF-P., pLTx, Wundinfektion (Sternum) u. Bakteriämie mit B. gladioli (prä LTx-Stamm) Kanj et al., Chest, 1997 Oct;112(4):924-30 retrosp. Auswertung (6J), 251 LTx-Patienten, davon 33 CF-P. B. g.-positiv; 3 CF-P. LTx: 1 x Medastinalabszess pLTx Kennedy et al., J Cyst Fibros. 2007; 6(4):267-73 invasive Rhinosinusitis, Bakteriämie, pLTx bei CF-P.,Tod Quon et al., Can Respir J. 2011;18(4):e64-5 1x Mediastinalabszess, LTx (non-CF) Church et al., J Heart Lung Transplant, 2009 May;28(5):511-4 1x dissiminierte B. g.-Infektion, Ltx (non-CF) Thompson et al., Transpl Infect Dis. 2011 Dec;13(6):641-5 M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

„Impact of Burkholderia on lung transplantation“ Burkholderia gladioli: Murray et al., Am J Respir Crit Care Med, 2008, 15;178:363-71 „Impact of Burkholderia on lung transplantation“ BCK negative B. multivorans (II) B. gladioli M. Hogardt, Winterschool – Obergurgl 5-8 März 2012 11

NTM in (3-15%) im RT-Trakt bei CF-Patienten nachweisbar (vor LTx) Nicht-tuberkulöse Mykobakterien bei: [USA v.a. MAC; Europa v.a. M. abscessus, SWM: Umwelt/Wasser, SK] NTM in (3-15%) im RT-Trakt bei CF-Patienten nachweisbar (vor LTx) Jordan et al., 2007 146 CF-P. nach LTx: NTM-Prävalenz 13.7%, invasive Infektion in 3.4% Chalermskulrat W et al., Thorax. 2006; 61(6):507-13 Titel des Vortrags/Name des Vortragenden/Datum

J Heart Lung Transplant.2006 Dec;25(12):1447-55. outcome Death/Asp Death/Asp Death/Pneu Death/Mab Thirty-one centers (50%) responded (Appendix B). Of a total of 5,200 transplantations performed, 17 patients were identified with M abscessus for a cumulative incidence of 0.33%. Most centers did not report any cases (n 24), whereas 5 centers reported 1 patient, 1 center reported 4 patients, and our center reported 8 patients. Eleven patients were from North America, 2 were from Europe, and 4 were from Australia. Four of these cases have previously been reported.2,3 The cumulative incidence for centers reporting at least 1 case is 0.94% (17/1,806), whereas our center’s incidence was 1.54% (8/521). Death J Heart Lung Transplant.2006 Dec;25(12):1447-55. Titel des Vortrags/Name des Vortragenden/Datum

Nicht-tuberkulöse Mykobakterien bei: [USA v. a. MAC; Europa v. a. M Nicht-tuberkulöse Mykobakterien bei: [USA v.a. MAC; Europa v.a. M. abscessus, SWM: Umwelt/Wasser, SK] 3 von 4 CF-Patienten Hautinfektion und Abszesse nach LTx, follow-up 7 Jahre Gilljam M J Cyst Fibros. 2010; 9(4):272-6 nach LTx: v. a. Haut- und Weichteilinfektionen, Allograftinfektion (s. dissiminierte Infektionen) M.-abscessus-Komplex: M. massiliense + M. abscessus (+ M. bolettii) Leao SC et al., Int J Syst Evol Microbiol. 2011; :2311-3 M. massiliense: 89.8% CLA-E, neg. Sputum (88%), HRCT+ (82%) M. abscessus: 48.7% CLA-E, neg. Sputum (25%), HRCT+ (42%) M. abscessus: besitzt intakte induzierbare CLA-R (erm41) J Clin Microbiol. 2001 Feb;39(2):816-9. Fatal pulmonary infection due to multidrug-resistant Mycobacterium abscessus in a patient with cystic fibrosis. Sanguinetti M, Ardito F, Fiscarelli E, La Sorda M, D'Argenio P, Ricciotti G, Fadda G. Source Istituto di Microbiologia, Università Cattolica del S. Cuore, Ospedale Pediatrico Bambino Gesù, Rome, Italy. msanguinetti@rm.unicatt.it Abstract We report a case of fatal pulmonary infection caused by Mycobacterium abscessus in a young patient with cystic fibrosis, who underwent bipulmonary transplantation after a 1-year history of severe lung disease. Fifteen days after surgery he developed septic fever with progressive deterioration in lung function. M. abscessus, initially isolated from a pleural fluid specimen, was then recovered from repeated blood samples, suggesting a disseminated nature of the mycobacterial disease. Drug susceptibility testing assay, performed on two sequential isolates of the microorganism, showed a pattern of multidrug resistance. Despite aggressive therapy with several antimycobacterial drugs, including clarithromycin, the infection persisted, and the patient died. Kim et al., Microbiol Immunol. 2010; 54(6):347-53 Koh et al., Am J Respir Crit Care Med., 2011;183:405-10 Kim et al., Microbiol Immunol. 2010 Jun;54(6):347-53. M. Hogardt, Winterschool – Obergurgl 5-8 März 2012 14

Nokardien [Gram+ verzweigte Stäbe, keine NF (Exposition)!, SK] Nokardiosen nach OrganTx: 0.7% bis 3% v.a. Pneumonien (Infiltrate / Abszesse) bei Tx-Patienten (N. asteroides, N. farcinica, N. alba, N. nova) Dissemination in ZNS und Haut Mortalität bei TX-Patienten (~) American Journal of Transplantation 2004; 4: 47–50 Peleg et al., Clin Infect Dis. 2007; 15;44(10):1307-14 5 Nokardiosen/4000 Tx-Patienten (0,3% über 25J) Wismayr et al., Transpl Int. 2005 Nov;18(11):1308 4 Nokardiosen /410 LTx-Patienten (1% über 17J) Khan BA et al., Clin Transplant, 2008;22(5):562-6 0.6% Nokardiosen unter 5126 TX-P. (LTx: 3.5%) Peleg et al., Clin Infect Dis 2007 May 15;44(10):1307-14 Problem: klinisches Bild, Radiologie unspezifisch; mikrobiologischer Erregernachweis (Kultur/PCR) schwierig, SXT-Prophylaxe kein absoluter Schutz (in bis zu 69% der Pat. trotz SXT) M. Hogardt, Winterschool – Obergurgl 5-8 März 2012 15

Pneumocystis jiroveci: in 5-15% nTX Infektionshäufigkeit abhängig von Durchführung SXT-Prophylaxe! (ab 2Wo nach TX für 2-12Mo, lebenslang) Möglichkeit nosokomiale Übertragungen ! Diagnostik verlässlich (BAL): Mikroskopie, quantitative real-time PCR M. Hogardt, Winterschool – Obergurgl 5-8 März 2012 16

Clostridium difficile Search: C. difficile lung transplantation 1. Clostridium difficile-related pancolitis in lung-transplanted patients with cystic fibrosis. Patriarchi F, Rolla M, Maccioni F, Menichella A, Scacchi C, Ambrosini A, Costantino A, Quattrucci S. Clin Transplant. 2011 Jan-Feb;25(1):E46-51. doi: 10.1111/j.1399-0012.2010.01316.x. PMID: 20642799 [PubMed - indexed for MEDLINE] 2. Clostridium difficile colitis in children following lung transplantation. Rosen JB, Schecter MG, Heinle JS, McKenzie ED, Morales DL, Dishop MK, Danziger-Isakov L, Mallory GB, Elidemir O. Pediatr Transplant. 2010 Aug;14(5):651-6. Epub 2010 Jun 10. PMID: 20561346 [PubMed - indexed for MEDLINE] 3.Clostridium difficile colitis in lung transplantation. Gunderson CC, Gupta MR, Lopez F, Lombard GA, LaPlace SG, Taylor DE, Dhillon GS, Valentine VG. Transpl Infect Dis. 2008 Jul;10(4):245-51. Epub 2008 Feb 29. PMID:18312477 [PubMed - indexed for MEDLINE] 4. Clostridium difficile colitis in cystic fibrosis patients with and without lung transplantation. Theunissen C, Knoop C, Nonhoff C, Byl B, Claus M, Liesnard C, Estenne MJ, Struelens MJ, Jacobs F. Transpl Infect Dis. 2008 Jul;10(4):240-4. Epub 2007 Jul 12. PMID: 17630999 [PubMed - indexed for MEDLINE] M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Clostridium difficile C. difficile in 30-50% der CF-P., (Keimträger signifikant häufiger als bei non-CF-P., CDAD/CDC sehr selten CDAD 2-3x häufiger in LTx-CF vs. LTx-Non-CF, komplizierte CDC nur bei LTx-CF, 2 von 49 LTx-CF Patienten verstarben an Colitis Theunissen C et al., Transpl Infect Dis. 2008;10(4):240-4 78 LTx in Pädiatrie, 4 P mit CDC (alle CF-Patienten), Inzidenz unter CF-P. 8.9% Rosen JB et al., Pediatr Transplant. 2010;14(5):651-6 202 LTx (davon 15 P CDC, follow-up über 2.7J (0-13.6J) kumulative Inzidenz 14.7% (signifikante Assoziation zu BOS) and illustrate our experience in the diagnosis and management of these patients. Gunderson CC et al., Transpl Infect Dis. 2008;10:245-51 3 Fallberichte schwere C. d. assoziierte Colitis nach LTx-CF (Diagnose klinische/Bildgebung, MiBi, keine CMV-Enteritis) Patriarchi F, Clin Transplant. 2011:;25(1):E46-51 M. Hogardt, Winterschool – Obergurgl 5-8 März 2012

Zusammenfassung: nosokomiale Infektionen in Frühphase nach LTx (div. Spezies) (Häufigkeit zu anderen chirurgisch/ICU-betreuten P.-Kollektiven vergleichbar) muliresistente Gram-negative Erreger (Acinetobacter spp. etc) (nosokomiale) CD-Infektionen: bei CF-P. häufiger komplizierte Colitiden signifikant red. ÜR nach LTx für B. cenocepacia u. B. gladioli Nokardiosen: selten, aber ggf. unterschätztes Problem M. abscessus: Infektionen selten bei adäquater AB Haut- und Weichteilinfektionen, Dissiminierung möglich M. Hogardt, Winterschool – Obergurgl 5-8 März 2012 19

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