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How I Manage Pulmonary Infection in the Post-Transplant Patient Joanna Schaenman, M.D., Ph.D. David Geffen School of Medicine at UCLA Los Angeles, CA October 13, 2015 Pulmonary infection : Learning objectives 1.Know the frequent causative agents of pulmonary infection after transplantation. 2.Understand effective strategies for prophylaxis and diagnosis of pulmonary infections 3.Know how to select antibiotic therapy to treat common causes of pulmonary infection Pulmonary infection: the most common infection, highest mortality after solid organ transplantation Person-toperson: Influenza Environmental: Fungi Reactivation: CMV Increased risk with augmentation of immune suppression, patient comorbidities including advanced age Time course of risk for pulmonary infection Induction Maintenance immunosuppression Prophylaxis • Nosocomial infection Transplant Phase 1 First month • Reactivation • Opportunistic • Communityacquired • Opportunistic Phase 2 Months 1-6 Kupeli, Curr Opin Pulm Medicine 2004 Phase 3 >6 months Common etiologies of pulmonary infection BACTERIA • Community or hospital acquired pneumonia • Mycobacteria VIRUSES • Community acquired respiratory viruses • CMV FUNGI • Endemic fungi • Molds (Aspergillus) Case 1: Fever and sepsis physiology 10 years post kidney transplant • 47 yo woman with DM, s/p DDRT • February developed URI symptoms, rash over thighs • Progressive respiratory failure, fever, altered mental status, required intubation Clinical and radiographic presentation of pneumonia is often not specific for a particular pathogen Diagnostic approach to lung infection Direct testing: • Sputum or tracheal aspirate for Gram stain and bacterial, AFB, and fungal cultures • Blood cultures • Consider bronchoscopy for bronchoalveolar lavage • Respiratory virus testing by PCR Indirect testing: • Consider blood or urine testing for surrogate markers including • Coccidioides Ab • Cryptococcus ag • Histoplasma ag • Aspergillus galactomannan • Legionella urine antigen • CMV PCR Low threshold for ordering Chest CT Case 1: Fever and sepsis physiology 10 years post kidney transplant • Empiric therapy: vancomycin, pipercillin/tazobacta m, levaquin • Outside hospital sputum culture positive for Streptococcus pyogenes • Clindamycin added • Patient ultimately did well, complete Chest CT gives more information than CXR, resolution of but is still nonspecific for cause of infection symptoms Yield of bronchoscopy in SOT • Review of 47 kidney and 14 liver transplant recipients in Turkey • 39% bronchial wash cultures were positive (47% in patients off antibiotics) • Higher yield with transbronchial biopsy (58%) • Positive cultures included MTB, Staphylococcus aureus, Moraxella, Klebsiella pneumoniae, E coli, Streptococcus pneumoniae, Pseudomonas, Aspergillus Kupeli et al, Transplant Proceedings 2011; Kupeli et al., Curr Op Pulm Med 2012 Empiric treatment based on risk profile • Community acquired pneumonia Haemophilus influenzae, Streptococcus pneumoniae, Mycoplasma, Legionella, viruses • Fluoroquionolone, or ceftriaxone plus azithromycin • Hospital acquired pneumonia Staphylococcus aureus, Enterobacteraciae, Acinetobacter, Pseudomonas; aspiration • Vancomycin plus pipercillin tazobactam, levaquin • Concern for multidrug resistant organisms ESBL, CRE, MDR Pseudomonas, fungi • Empiric broad spectrum therapy (penem, aminoglycoside, colistin, etc) Mycobacteria MTB MAC (MAI) • Pre-transplant screening recommended • Incidence of MTB 14% in developing countries, 0.5-6% in low endemic areas • Often high mortality Rapid growers (e.g. M. abscessus) Caution for drug-drug interactions with rifampin or rifabutin use Case 2: Fever and sepsis physiology 3 mo. post kidney transplant • 74 yo man with DM, s/p DDRT, ATG induction • February developed URI symptoms, cough, seen in clinic but CXR showed only atelectasis • Admitted with progressive cough, malaise Chest x-ray is often unrevealing in transplant • Progressive respiratory failure, recipients required intubation Case 2: Fever and sepsis physiology 3 mo. post kidney transplant • Empiric therapy: vancomycin, pipercillin/tazobacta m, levaquin, oseltamivir • Nasopharyngeal swab pos for RSV by respiratory viral PCR • Ribavirin added • Progressive Low threshold for further evaluation in respiratory failure, vulnerable patients ARDS Community acquired respiratory viruses (CARV) • • • • • • Influenza Respiratory syncytial virus (RSV) Human metapneumovirus Parainfluenza Adenovirus Rhinovirus • Diagnosis via PCR testing of nasopharyngeal swab or respiratory source • Rx Influenza with oseltamivir or zanamivir • Consider ribavirin for RSV, especially in lung transplant CMV pneumonitis • Donor positive/Recipient negative is highest risk • Risk decreased with Valcyte prophylaxis • Lung>heart>liver>kidney • Diagnosis via PCR testing, viral culture, or histopathology • Treat with IV ganciclovir Kotloff et al., 2004; Kotton, 2010 Case 3: Fever 1 year post kidney transplant • 52 yo woman with DM, s/p DDRT • H/o TB peritonitis • November developed fever, chills, myalgias, fatigue, no improvement with course of levaquin • No neurologic complaints or findings Broad diagnostic differential for lobar pneumonia Case 3: Fever 1 year post kidney transplant • Empiric therapy: vancomycin, meropenem, levaquin • Sputum culture positive for Cryptococcus gattii, Aspergillus flavus • BAL positive for Cryptococcus and CMV; LP negative “Bad news comes in threes” (the Transplant • Started on ID motto), not “Occam’s Razor” Voriconazole Clinically Important Fungi Yeast Endemic Fungi Candida Cryptococcus PCP PCP is less common with routine TMP/SMX prophylaxis Molds Coccidioides Histoplasma Blastomycosis Aspergillus Scedosporium , others Agents of Mucormycos is Distribution of fungal infections by transplant type TRANSNET Surveillance cohort Pappas et al., CID 2010 McPherson: Henry's Clinical Diagnosis and Management by Laboratory Methods, 2011 Distribution of dimorphic endemic fungi Histoplasmosis distribution in the Americas Coccidioidomycosis. • Environment is main source for exposure, but can also be donor-derived • Reports suggest that number of infections are increasing • Sensitivity of serologic testing is lower in immunosuppressed patients Proia, et al. AJT 2009 Diagnosis of invasive fungal infections is challenging • Clinical and radiographic presentation is not specific for fungal infection • Need culture for identification and sensitivity testing • Noninvasive testing can be helpful: Aspergillus GM, antigen testing, future PCR or breath testing Empiric antifungal treatment • Endemic fungi (non-severe) • Fluconazole, itraconaozle • Aspergillosis • Voriconazole* • Agents of mucormycosis • Liposomal Amphotericin B • Severe invasive fungal infection • Liposomal Amphotericin B, possibly combination Rx *Watch for drug-drug interactions with tacrolimus And last but not least…parasites • Strongyloides: Donor derived or reactivation Think about the etiology of pulmonary infections: Person-toperson BACTERIA Environmental VIRUSE S Reactivation FUNGI To devise strategies for prevention: Vaccination, Antibiotic prophylaxis (TMP/SMX, Valcyte, azoles), Patient education Pulmonary infection : Learning objectives • Causative agents of pulmonary infection after transplantation include bacteria, viruses, and fungi • Prophylaxis for PCP and CMV has decreased pneumonia incidence • Diagnosis is important and should include sputum testing, BAL or FNA when appropriate, and noninvasive tests • Antibiotic therapy should be based on culture-based diagnosis when possible, and on suggested clinical syndrome when unable to make clear diagnosis References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Fishman JA. Infections in immunocompromised hosts and organ transplant recipients: Essentials. Liver Transpl. 2011 Oct 26;17(S3):S34–7. Küpeli E, Eyüboğlu FÖ, Haberal M. Pulmonary infections in transplant recipients. Curr Opin Pulm Med. 2012 May;18(3):202–12. Kupeli E, Akcay S, Ulubay G, et al. Diagnostic Utility of Flexible Bronchoscopy in Recipients of Solid Organ Transplants. TPS. Elsevier Inc; 2011 Mar 1;43(2):543–6. Kotloff RM, Ahya VN, Crawford SW. Pulmonary Complications of Solid Organ and Hematopoietic Stem Cell Transplantation. American Journal of Respiratory and Critical Care Medicine. 2004 Jul;170(1):22–48. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. CLIN INFECT DIS. 2007 Mar 1;44(Supplement 2):S27–S72. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. American Journal of Respiratory and Critical Care Medicine. 2005. p. 388–416. Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. American Journal of Respiratory and Critical Care Medicine [Internet]. 2003 Feb 15;167(4):603–62. McGrath EE, McCabe J, Anderson PB, American Thoracic Society, Infectious Diseases Society of America. Guidelines on the diagnosis and treatment of pulmonary non-tuberculous mycobacteria infection. Int. J. Clin. Pract. 2008 Dec;62(12):1947–55. Ison MG. Respiratory viral infections in transplant recipients. Antivir. Ther. (Lond.). 2007;12(4 Pt B):627– 38. Kotton CN, Kumar D, Caliendo AM, et al., International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation. Transplantation. 2010 Apr;89(7):779–95.