1. Emily A. Blumberg, MD Perelman School of Medicine at the University of Pennsylvania

2.  Research Funding ◦ Achaogen ◦ Actelion ◦ Ansun ◦ Cubist/Merck ◦ Roche ◦ Viropharma/Shire  DSMB ◦ Bristol Myers Squibb ◦ Pfizer  American Board of Internal Medicine Test Development Committee

3.  Deceased donor from India, CMV D-R+  Progressive weight loss since transplant  Admitted with CVA  Incidental finding of newly abnormal chest X- ray  Never had fever and no respiratory symptoms  Meds: Tacrolimus, prednisone, mycophenolate (held), tmp sulfa, valganciclovir, thymoglobulin induction  Exam unremarkable  Routine CBC and chemistries unremarkable

5.  Review of exposures revealed extensive exposure to soil during gardening post transplantation LESSONS LEARNED  Infections occur in the absence of fever and localizing symptoms  Can be true even months-years post transplant  Detailed history is important in making diagnoses

6. Fever, dyspnea, non productive cough  Basiliximab induction, Tacrolimus, Mycophenolate, Prednisone maintenance  Valganciclovir, Tmp sulfa prophylaxis  Pulmonary rehab – exposed to influenza, started on oseltamivir  Presented with progressive SOB/DOE for 3-4 weeks  Initial BAL Klebsiella pneumoniae – treated with cefpodoxime  Persistent dyspnea

8.  BAL  Klebsiella pneumonia  Influenza A  Treated with piperacillin tazobactam, treatment dose of oseltamivir  Still symptomatic  Repeat bronchoscopy

10.  Review of donor chart revealed donor from the Dominican Republic  Subsequent testing donor serology + for Strongyloides LESSONS LEARNED  Recipient history isn’t the only one that matters  Transplant patients can have more than one diagnosis concurrently  Not always clear which is the most important one

11.  Tacrolimus, azathioprine immunosuppression  Trimethoprim sulfamethoxazole and acyclovir for prophylaxis  Exam – fever, rash  Labs – pancytopenia  Normal liver function tests

12.  Diagnosis by chimerism assay  All microbiology testing negative initially, although expired due to persistent bacterial infection when profoundly neutropenic LESSONS LEARNED  Not all fevers are infection  GVHD, Drug fever, rejection, thromboses all may cause fever  Physical exam and labs can be helpful  Consider all the options and test broadly when the answer is not obvious

13. Organ Donor Recipient Blood Donor Hospital Community Pyogenic Bacteria “Opportunistic” Bacteria Community Acquired Viruses “Opportunistic” Viruses Fungi Parasites Protozoa

14.  Cultures  Differentiation of colonization from infection  Viral nucleic acid tests  Interpretation of low viral loads and negative results with high index of suspicion  Fungal assays (e.g., galactomannan, beta D glucan, histoplasmosis antigen, cryptococcal antigen)  Variable sensitivity and specificity based on site/dissemination

15. Pooled sensitivity and specificity of the galactomannan assay for diagnosis of invasive aspergillosis (IA). Christopher D. Pfeiffer et al. Clin Infect Dis. 2006;42:1417- 1727 © 2006 by the Infectious Diseases Society of America

16. Procalcitonin and Bacterial Infection in SOT Yu, et al.Transplant Proc. 2014;46:26-32 Pooled sensitivity 85% (95% CI 75%-92%), specificity 81% (95% CI 72%-88%)

17.  Pro-peptide precursor of calcitonin released by multiple tissues in response to cytokines and endotoxin  Biomarker associated with bacterial infection  Also elevated with end stage organ disease (cirrhosis), pancreatitis, cardiogenic shock, trauma, ischemic bowel  Levels affected by surgery, immunosuppression  Cytolytics may lead to elevated levels  Viral infections typically associated with lower levels  Co-infections may yield confounding results Sandkovsky, et al. Clin Transplant 2015: 29: 689–696

18.  Serial measurements can be used  As clue to bacterial infections in the early post transplant period in patients who did not receive cytolytics  As indicator of response to treatment  May differentiate infection from rejection  But Procalcitonin alone cannot diagnose infection  Serial measurements may be important

19.  There is currently no magic set of tests that will consistently identify who is infected (fever or no fever)  Need to incorporate clinical judgment and physical examination

20. “Timeline” of infection post-transplant NOSOCOMIAL, TECHNICAL OPPORTUNIST IC COMMUNITY ACQUIRED CMV Aspergill us PCP HSV VZV EBV Nocardia Listeria Toxoplasmo sis Tuberculo sis Cryptococc us Endemic mycoses Treatment of rejection Courtesy of Dr. Brian Schwartz

21. Impact of OI prophylaxis on the post- transplant “timeline” CMV Aspergill us PCP HSV VZV EBV Nocardia Listeria Toxoplasmo sis Courtesy of Dr. Brian Schwartz

22.  Testing should reflect clinical suspicion  Include combination of radiography, non invasive testing, and biopsy  Extensive diagnostics may be required unless diagnosis is clear  Step wise testing may result in critical loss of time (especially since outcomes often linked to timing of initiation of appropriate antimicrobials)  But is a broad approach cost effective?  Histopathology may ultimately be the quickest reliable test!

23. Prompt initiation of appropriate antimicrobials makes a difference All antimicrobials come at a cost (not purely financial)

24.  How strong is the suspicion regarding a specific diagnosis?  Have I gotten sufficient samples so that antimicrobials will not affect diagnosis?  What kind of testing will be most helpful?  Will the testing have reduced sensitivity in transplant patients?  How sick is the patient?  What is the anticipated toxicity of the antimicrobials?

25.  Fever usually (but not always) equals infection  Not all infections are associated with fevers  Transplant patients may be the exception to Occam’s Razor (single unifying diagnosis)