1. Bad Bugs: Managing Challenging Infections Post-Transplant Respiratory Viruses
Michael G. Ison, MD MS FIDSA
Division of Infectious Diseases & Organ Transplantation
Transplant & Immunocompromised Host Infectious Diseases Service
TID 2015 Meeting – Cancun, Mexico
13 October 2015

2. As of 9/7/15; °Paid to Northwestern University.
Disclosures
Research Support°
Chimerix, Gilead, GlaxoSmithKline, Jansen/Johnson & Johnson
Paid Consultation
Biota, Chimerix, Farmark, Genentech/Roche, Shionogi
Unpaid Consultation
Adamas, BioCryst, Biota, Cellex, Clarassance, GenMarkDx, GlaxoSmithKline, MP Bioscience, MediVector/Toyama, NexBio, Romark,TheraClone, T2 Diagnostics, Vertex, Visterra
Data & Safety Monitoring Board Participation
Abbott, Jansen/Vertex
As of 9/7/15; °Paid to Northwestern University.

3. Respiratory Viruses in Transplantation
Case-Based Discussion of Common Respiratory Viral Infections in Transplantation
Influenza
Respiratory Syncytial Virus
Parainfluenza Virus

4. Case 1: Should We Vaccinate?
34 year old Hispanic Female who underwent an uneventful living donor kidney transplant 3 months prior
Alemtuzumab and steroids for induction
Tacrolimus and Mycofenolate mofitil for maintance
Valganciclovir (CMV D+/R-) and TMP-SMX for prophylaxis
Past Medical History
ESRD secondary to IgA nephropathy
Lives in the suburbs of Chicago with her husband and 3 children (10, 7 and 5 years old)
She is in for her 3 month protocol biopsy and asks about whether it is ok for her to get a influenza vaccine?

5. Case 1: Should We Vaccinate?
You recommend:
Injectable influenza vaccine for the patient
Defer influenza vaccine until 6 months post-transplant
Injectable influenza vaccine for the children
A and C

6. Case 1: Should We Vaccinate?
You recommend:
Injectable influenza vaccine for the patient
Defer influenza vaccine until 6 months post-transplant
Injectable influenza vaccine for the children
A and C

7. Prevention of Influenza: Vaccines in SOT
Concerns
Early studies showed poor efficacy
Case reports of rejection associated with vaccination
Influenza vaccine is safe & effective in SOT
>40 published studies of influenza vaccine in heart, lung, kidney, and liver transplant recipients
Consistent findings:
NO association with increased risk of rejection or graft dysfunction
Reduced serologic response compared to healthy controls
Some studies, mostly in kidney transplant recipients, showed similar serologic responses
Can safely be used in “operationally tolerant patients”
No one IS protocol associated with decreased responses
Sirolimus ≤ Calcineurin inhibitor based therapy
MMF ≥ Azathioprine
Present, but reduced, influenza-specific responses to vaccines
Kumar et al. Am J Transplant ;11:

8. Prevention of Influenza: Vaccines in SOT
Limitations of Current Data
No data in alemtuzumab-induced recipients
Limited data of protective efficacy against culture/PCR-proven influenza
Birdwell et al. Am J Kidney Dis ; 54:

9. Prevention of Influenza: Vaccine Recommendations
Kumar et al. Am J Transplant ;11:

10. Case 2: Fever in February
Our same 34 year old Hispanic Female living donor kidney transplant patient presents in early February with:
3 days history of fever and cough
No significant sick contacts
She was appropriately vaccinated for influenza in October
What do you do for the patient?

11. Case 2: Fever in February
You do which of the following for the patient:
Obtain a Respiratory Virus PCR nasal swab
Initiate oseltamivir 150mg BID until results are available
Send a CMV viral load of the blood
Send blood and urine cultures
Obtain a Chest Radiograph
All of the Above

12. Case 2: Fever in February
You do which of the following for the patient:
Obtain a Respiratory Virus PCR nasal swab
Initiate oseltamivir 150mg BID until results are available
Send a CMV viral load of the blood
Send blood and urine cultures
Obtain a Chest Radiograph
All of the Above

13. Diagnosis of Respiratory Viral Infections30 35 20 15 10 5 35 37 39 41 43 45 47 49 51 3 1 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33
November – April
2005 Report week 2006
% Influenza
% Respiratory Syncytial Virus
% Parainfluenza
% Adenovirus

14. Diagnosis of Respiratory Viral Infections
Serology: Acute & Convalescent
Culture (Misses 7-50% of PCR+)
MDCK
R-Mix (Mink Lung, A549)
Monoclonal Antibody (DFA)
Rapid Antigen Assays
PCR
Single vs. Multiplex

15. Challenges of Respiratory Virus PCR Assays
There is variability in the quality of collection of specimens
There is variability of the sensitivity and specificity of the various assays
There is a disconnect between the upper and lower respiratory tract
Disseminated infection may not present primarily in the respiratory tract (especially with adenovirus)

16. Treatment of Influenza
Antiviral Therapy and Outcomes
No prospectively collected data
Most data with NAIs > M2 Inhibitors
Reduced mortality
M2 Inhibitors: 60% vs. 70%
NAI: Few deaths reported with use
Reduced viral shedding at day 10
M2 Inhibitors 20% vs. 50%
Lower rate of pneumonia
M2 inhibitors: 11% vs. 21%
NAI: 0-5% vs. 21%
Reduced risk of BOS
Risk of resistance emergence
Ison MG. Antiviral Therapy. 2007; 12:
Ison MG et al. J Heart Lung Transplant ; 27:
Khanna et al. Transpl Infect Dis. 2009; 11:

17. Treatment of Influenza: Unanswered Questions
Optimal Duration of Antiviral Therapy
Patients have prolonged shedding
Premature interruption of therapy could result in resistance and clinical decline
Many experts recommend a duration > 5 days
Many recommend that duration is guided by duration of shedding
Optimal Dose of Therapy
Studies have failed to document improved outcome with high dose oseltamivir
2 of the 3 studies demonstrated a lower rate of resistance with the higher dose
Role of IV Therapy, Antibodies and Combination
Management of Resistant Influenza

18. Case 2: Fever in February
The respiratory virus PCR returns with RSV. What do you do?
Stop the oseltamivir
Start inhaled ribavirin
Start oral ribavirin
Give a dose of IgIV 500mg/kg x 1
Monitor the patient
A and E

19. Case 2: Fever in February
The respiratory virus PCR returns with RSV. What do you do?
Stop the oseltamivir
Start inhaled ribavirin
Start oral ribavirin
Give a dose of IgIV 500mg/kg x 1
Monitor the patient
A and E

20. RSV in Hematopoietic Stem Cell Transplantation
Shah JN, Chemaly RF. Blood ; 117:

21. RSV in Lung Transplantation
38 pts oral ribavirin compared to 29 pts given “best supportive care including corticosteroids”
Ribavirin mg/kg/d in 2 divided doses X 14 d
RSV 64.2%, PIV 28.4%, HuMPV 7.5%; infiltrates 10%
Ribavirin vs non-ribavirin group:
FEV1 drop from baseline during infection: 20% (IQR 15–32) vs 18% (IQR 13–30)
Graft function recovery < 30 d: 84% vs 59% (P=0.02)
New onset BOS within 6 months: 5% vs 24% (P=0.02)
Fuehner et al. Antiviral Therapy. 16:733, 2011

22. RSV in Lung Transplantation: New Agents
GS-5806
DeVincenzo et al. N Eng J Med ; 371:

23. Case 2: Fever in February
The respiratory virus PCR returns with PIV. What do you do?
Stop the oseltamivir
Start inhaled ribavirin
Start oral ribavirin
Give a dose of IgIV 500mg/kg x 1
Monitor the patient
A and E

24. PIV: New Treatment Options
DAS181
Sialidase that cleaves the receptor for the virus off cell surface
Inhaled or nebulized formulations
Drozd et al. Transplant Infect Dis ; 15: e28-e32.

25. Michael G. Ison, MD MS +1-312-695-4186 mgison@northwestern.edu
Are you a registered organ donor?
I am!
Questions?
Michael G. Ison, MD MS

26. Prevention of Influenza: Vaccines in HSCT
No serologic response 0-6 months post-transplant
Reduced in vitro B-cell responses by ELISPOT vs. healthy controls
Some studies have demonstrated robust T-cell responses to influenza vaccine despite no serologic response
80% efficacy against virologically confirmed influenza
GVHD may be associated with reduced responses
Pre-treatment with rituximab may be associated with reduced response for at least 6 months post-treatment
Transplant Type
Time Post-Tx
A/H1
A/H3 B
Auto-HSCT
0 – 12 mo
30%
32%
38%
> 12 mo
50%
71%
Allo-HSCT
31% 9%
20%
13%
40%
33%
Ljungman P, Avetisyan G. BMT ; 42:
Ljungman P et al. BMT. 2009;44: 521–526.

27. Prevention of Influenza: Antiviral Prophylaxis
RT-PCR
Protective efficacy = 74.9%
95% CI for difference: 2.3%, 10.7%
Culture
Protective efficacy = 88.8%
95% CI for difference: 0.7%, 6.6%
Subjects (%)
No change in IC50 with breakthrough viruses
Ison et al. Antiviral Research. 2012;17(6):

28. Molecular Diagnostics: Limitations
Krunic et al. Ann NY Acad Sci ; 1222: 6-13.

29. Molecular Diagnostics: Limitations
Pabbaraju et al. J Clin Micro ; 49:

30. Treatment of Influenza
Ison et al. J Heart Lung Transplant ; 27:

31. Treatment of Influenza
Kumar et al. Lancet Infect Dis ; 10: