Viral Infections in HCT Patients

1. Viral Infections in HCT Patients Marcie Riches, MD, MS Associate Professor University of North Carolina February 19, 2019

2. Overview CMV • Background • Importance in transplant patients • Relevance to forms completion Influenza

3. Virus From Merriam-Webster dictionary: “ any of a large group of submicroscopic infective agents that are usually regarded as nonliving extremely complex molecules, that typically contain a protein coat surrounding an RNA or DNA core of genetic material but no semipermeable membrane, that are capable of growth and multiplication only in living cells, and that cause various important diseases in humans, animals, and plants”

4. Early Infectious Mortality in HCT: 2014 - 2015 Related Donor Unrelated Donor Infections were reported as the primary cause of death in 20% of allogeneic HCT in the first 3 months after transplant

5. Viral Infections • Most viral infections, particularly early after HCT, are caused due to prior exposures • Examples: Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus (HSV), BK Virus, Human Herpes Virus-6 (HHV-6), Varicella Zoster Virus (VZV) • Reactivation of virus can lead to disease • CMV reactivation ≈ Viremia ≈ identification of CMV in the blood • CMV disease (infection) = involvement in sites other than blood (ex. CSF, colon) • Respiratory viruses: common in the community • Enteric Viruses: fecal-oral routes of spread

6. Timing of Viral Infections after HCT More common Less common Adapted from Tomblyn et al, BBMT 2009; 15(10): 1143-1238 and BMT 2009; 44(8):453-5

7. Burden of Viral Infections after HCT • Estimated that more than 35% of patients receiving an unrelated donor or umbilical cord blood experience at least one viral infection in the first 3 months after HCT1 • Ongoing analyses in CIBMTR INWC to exam viral infection burden in matched related and haplo-identical transplant cohorts 1Ballen et al, BBMT 2016; 22(9): 1636 - 1645

8. Prevention of viral infections • Most centers use a combination of prophylaxis and pre-emptive measures to prevent viral reactivation/infection1 • Hand hygiene and contact/droplet precautions • Respiratory viral prevention • Enteric viral prevention • Vaccinations • Generally not effective much before 3 months post-transplant 1Pollack et al, BBMT 2011; 17(5): 664 - 673

9. Antiviral Prophylaxis: F2100 R5.0 q419 - 21 • The option of “None” means the patient did not receive anyantiviral drug from the start of the preparative regimen through Day +45 • Clinically, this would be highly unusual

10. HSV and VZV Prophylaxis • Acyclovir from start of conditioning1 until • Engraftment, or • Mucositis resolves, or • Day 30 • Continue longer for patients with frequent recurrence of HSV disease • For VZV positive patients • Continue prophylaxis until 1 year post-transplant • Continue longer if cGVHD or on-going immune suppression • Consider early vaccination with HZ/su vaccine (Shingrix) after autologous HCT2 1Tomblyn et al, BBMT 2009; 15(10): 1143-1238 and BMT 2009; 44(8):453-5 2Stadtmauer et al, Blood 2014; 124(19):2921 - 9

11. Cytomegalovirus (CMV) • Risk of reactivation/infection affected by • donor/recipient CMV serostatus1,2 • Use of CMV safe blood products • Pre-emptive therapy • Prophylaxis3 • Letermovir decreased clinically significant CMV infection in CMV+ recipients 1Tiera et al, Blood 2016; 127(20): 2427 – 2438 2Ramanathan et al, BMT 2016; 51(8): 1113-1120 3Marty FM et al. N Engl J Med; 377(25):2433-2444

12. CMV • Monitoring • Blood test, usually weekly • Generally PCR based test to give quantitative measure of CMV burden

13. CMV • Disease • Evidence of CMV in tissues/organs • Ex. CMV colitis • Treatment • Indications • Viremia: Varies by center based upon test used, sensitivity of test, clinical picture, and risk factors • Disease • Options for therapy • Oral (ex Valganciclovir) • IV therapy (ex Ganciclovir or Foscarnet) • Cellular therapy (ex CMV-CTLs) Le et al, Thera Clin Risk Manag2017; 13: 1585-1593

14. Epstein-Barr Virus (EBV) • About 90 – 95% of adults are EBV+ • Associated with certain types of lymphoma and nasopharyngeal cancers • Following alloHCT, associated with development of post-transplant lymphoproliferative disorder (PTLD) • Risk factors for PTLD • T-cell depletion • Use of anti-T-cell antibodies • Alternative donors (UCB, Haplo) Landren et al, Blood 2009; 113(20): 4992-5001

15. EBV • Replication occurs in B-cells • Rituximab as pre-emptive therapy in EBV Viremia • PTLD • Treatment • Rituximab • Decrease immune suppression • EBV-CTLs Overall survival from diagnosis of PTLD in 267 patients (EBV+ n=222; EBV- n=45) reported to the CIBMTR between 2002 and 2014 Naik et al, BBMT 2018; 24(3): S370 Liu et al, BBMT 2018; 24(7): 1341-1349

16. Human Herpes Virus-6 (HHV-6) • Infects > 90% of persons during childhood • Studies report reactivation in 35 – 72% of patients1-3 • Depends on stem cell source • Complications of reactivation • Encephalitis • Cognitive decline4 • Increased CMV reactivation • Delayed engraftment 1Zerr et al, BBMT 2012; 18(11): 1700-1708 2Betts et al, BBMT 2011; 17(10): 1562-1568 3Scheurer et al, BMT 2013; 48(4): 574 - 580 4Zerr et al, Blood 2011; 117(19): 5243-5249

17. HHV-6: Monitoring and Treatment • PCR for viremia • Consider in high risk patients • Reactivation generally occurs early • Threshold to initiate antiviral therapy unclear • Ganciclovir or Foscarnet effective • Assessment of PCR in CSF needed in patients with mental status changes

18. HHV-6 CNS isolates • Identified in 123 patients after allogeneic HCT reported to CIBMTR between 2007 and 2015 • 76 (61%) received UCB • 45 received ATG/Alemtuzumab peri-transplant • 109 cases occurred by day +60 • Overall survival following identification of a CNS viral isolate • With HHV-6 (n = 123) • Without HHV-6 (n = 42) = Other viruses identified Abidi et al, BMT 2019 (in press)

19. Community Respiratory Viruses • Multiple viruses • RSV, Influenza, Parainfluenza, Adenovirus, Metapneumovirus, Rhinovirus, Coronavirus • Incidence varies by virus and season • Mortality rates of 10 – 50% if progress to lower respiratory tract infection (LRTI) • Prevention • Avoid exposure • Good hand hygiene • Rapid diagnosis with multiplex PCR

20. Respiratory Syncytial Virus (RSV) • 2 – 17% incidence • Increased between fall and spring • Progress to LRTI in 17 – 84% • Risk factors • Older age, Myeloablative conditioning, CMV+, Mismatched or URD, GVHD • Treatment • Aerosolized ribavirin but variable success1 • May consider use of Palivizumab or IVIG • 1Shah and Chemaly, Blood 2011; 117(10): 2755-2763

21. Influenza Virus • Seasonal outbreaks • LRTI in 7 – 35% • 15 – 28% fatal • Yearly immunization critical • Includes family and close contacts • Immune response up to 50% less in HCT patients1 • Treatment with neuraminidase inhibitors • 1Ljungman and Avetisyan, BMT 2008; 42(10): 637-641

22. Other Community Respiratory Viruses • Para-influenza Virus (PIV) • Affects 2 – 8% of patients • Increase in summer • Predominantly PIV 3 • Progresses to LRTI in 20 – 40% • 30% mortality rate • Treatment • Controversial regarding benefit of Ribavirin • Impact of IVIG unknown • Rhinovirus • 30 - 35% incidence • Progression to LRTI >50% • Coronovirus • True incidence unknown • Human Metapneumovirus (hMPV) • 5 – 10% incidence • Progression to LRTI in 20 – 40% • Possible utility of Ribavirin

23. Viral Organisms: 2100 R5.0 Several new viruses added in 2017 Split out certain viruses into 2 categories based upon infections

24. Sites of Infection

25. Infection Reporting 2100 R5.0

26. Report as New Infection: Viruses Testing negative for 14 days or more? New Infection Testing negative for 60 days or more? New Infection Cytomegalovirus Herpes Simplex Virus BK Virus JC Virus Epstein-Barr Virus • Adenovirus • Enterovirus • Herpes/Varicella Zoster Virus • Influenza Virus • Parainfluenza Virus • Rhinovirus • Respiratory Syncytial Virus

27. Clinical Example • 61 year old woman with SAA day +106 status post MUD HCT following Flu/Cy/ATG conditioning admitted with fever and respiratory symptoms including hypoxia requiring 2 – 3 LPM O2 by nasal cannula. Exam found small lymph nodes in the neck and decreased breath sounds • CBC: 3.7>10.8<40, ANC 2.8, ALC 0.5 • Respiratory Viral panel obtained (nasal swab) • Imaging obtained: • CT neck: 1.4 cm left cervical LN • CT chest: right pleural effusion • Ground glass opacities in bilateral upper lobes

28. Case continued Day 8 Day 4 Day 1 = admit • Due to lack of improvement, patient had bronchoscopy • Neck lymph node was increasing in size as well • Excisional biopsy obtained • EBER stain on LN positive by IHC

29. Case continued • Patient with confirmed PTLD due to EBV • Treatment • Tapered immune suppression • Rituximab 375 mg/m2 weekly x 4 weeks So, how do we report this scenario to CIBMTR?

30. How to complete the forms for this patient… • 2100 R5.0 • Coronovirus • Date of infection = date respiratory viral panel obtained • Site = Sinus and/or upper respiratory tract • No evidence of Coronovirus on the BAL so would not report Lung (lower respiratory tract) • EBV • Date of infection = Date of the bronchoscopy/BAL results • Site = Lung EBV – triggers the F2150

31. Form 2150: CMV/EBV/ADV/HHV-6/BK • Triggered in the following circumstances: • Organism of EBV, ADV, BK regardless of site • Organism CMV or HHV-6 if at any site other than just blood • Rationale • Serious infections that need additional study • Goal: • Collect information on diagnosis, risk factors, and treatment/response to therapy

32. Form 2150: Diagnosis • Collect information on tests with a positive result supporting the diagnosis • Tests performed 7 days before and up to 14 days after the reported date of infection • Allows us to have global picture of certainty of diagnosis • Because of the range of infections, there are several questions • Skip pattern is built into the form

33. Form 2150: Diagnosis Patient had PCR detected disease in the lung from the BAL fluid Date = Date of the bronchoscopy Questions 7, 8, 9, 10, 11 will not show based upon answers Question 12: No tissue was cultured (skip to 17)

34. Form 2150 continued Skips to question 20

35. Form 2150 continued Question 32 – 50: Laboratory values obtained ± 7 days of diagnosis

36. Form 2150 continued Patient on Valtrex from day 0 and continued throughout course of infection *No date required if therapy started 7 days prior to infection*

37. Form 2150 continued Questions 66 – 75 are all “No” in our clinical scenario Enter first day Rituximab given yyyy mm dd 4 weekly doses so this may be “no” if completed by 33 days from infection diagnosis Infection d+106, form completed ~6 months post: Infection Resolved

38. Summary • Viral infections are common after transplant • Associated with significant morbidity and mortality • Infection data are important to continue to improve post-HCT outcomes for our patients • Can design interventions for better prevention and better treatments • The data you provide are critical, particularly for the rare and/or serious infections Thank You