Transcript 1-2-Isonx

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
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.
Respiratory Viruses in Transplantation
•Case-Based Discussion of Common Respiratory Viral
Infections in Transplantation
o
Influenza
o
Respiratory Syncytial Virus
o
Parainfluenza Virus
Case 1: Should We Vaccinate?
• 34 year old Hispanic Female who underwent an uneventful living
donor kidney transplant 3 months prior
o
Alemtuzumab and steroids for induction
o
Tacrolimus and Mycofenolate mofitil for maintance
o
Valganciclovir (CMV D+/R-) and TMP-SMX for prophylaxis
• Past Medical History
o
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?
Case 1: Should We Vaccinate?
• You recommend:
A. Injectable influenza vaccine for the patient
B. Defer influenza vaccine until 6 months post-
transplant
C. Injectable influenza vaccine for the children
D. A and C
Case 1: Should We Vaccinate?
• You recommend:
A. Injectable influenza vaccine for the patient
B. Defer influenza vaccine until 6 months post-
transplant
C. Injectable influenza vaccine for the children
D. A and C
Prevention of Influenza: Vaccines in SOT
• Concerns
o
o
Early studies showed poor efficacy
Case reports of rejection associated with vaccination
• Influenza vaccine is safe & effective in SOT
o
o
>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. 2011;11:2020-2030.
Prevention of Influenza: Vaccines in SOT
• Limitations of Current Data
o
o
No data in alemtuzumab-induced recipients
Limited data of protective efficacy against culture/PCR-proven influenza
Birdwell et al. Am J Kidney Dis. 2009; 54: 112-121.
Prevention of Influenza: Vaccine Recommendations
Kumar et al. Am J Transplant. 2011;11:2020-2030.
Case 2: Fever in February
• Our same 34 year old Hispanic Female living donor kidney
transplant patient presents in early February with:
o
3 days history of fever and cough
o
No significant sick contacts
o
She was appropriately vaccinated for influenza in October
• What do you do for the patient?
Case 2: Fever in February
You do which of the following for the patient:
A. Obtain a Respiratory Virus PCR nasal swab
B. Initiate oseltamivir 150mg BID until results are available
C. Send a CMV viral load of the blood
D. Send blood and urine cultures
E. Obtain a Chest Radiograph
F. All of the Above
Case 2: Fever in February
You do which of the following for the patient:
A. Obtain a Respiratory Virus PCR nasal swab
B. Initiate oseltamivir 150mg BID until results are available
C. Send a CMV viral load of the blood
D. Send blood and urine cultures
E. Obtain a Chest Radiograph
F. All of the Above
Diagnosis of Respiratory Viral Infections
30
November – April
35
20
15
10
5
0
35 37 39 41 43 45 47 49 51 1
3
5
7
9 11 13 15 17 19 21 23 25 27 29 31 33
2005 Report week 2006
% Influenza
% Parainfluenza
% Respiratory Syncytial Virus
% Adenovirus
Diagnosis of Respiratory Viral Infections
•Serology: Acute & Convalescent
•Culture (Misses 7-50% of PCR+)
o
o
MDCK
R-Mix (Mink Lung, A549)
•Monoclonal Antibody (DFA)
•Rapid Antigen Assays
•PCR
o
Single vs. Multiplex
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)
Treatment of Influenza
• Antiviral Therapy and Outcomes
o
o
o
No prospectively collected data
Most data with NAIs > M2 Inhibitors
Reduced mortality


o
Reduced viral shedding at day 10

o

o
M2 Inhibitors 20% vs. 50%
Lower rate of pneumonia

o
M2 Inhibitors: 60% vs. 70%
NAI: Few deaths reported with use
M2 inhibitors: 11% vs. 21%
NAI: 0-5% vs. 21%
Reduced risk of BOS
Risk of resistance emergence
Ison MG. Antiviral Therapy. 2007; 12:627-638.
Ison MG et al. J Heart Lung Transplant. 2008; 27: 282-288.
Khanna et al. Transpl Infect Dis. 2009; 11:100-105.
Treatment of Influenza: Unanswered Questions
• Optimal Duration of Antiviral Therapy
o
o
o
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
o
o
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
Case 2: Fever in February
• The respiratory virus PCR returns with RSV. What do you do?
A. Stop the oseltamivir
B. Start inhaled ribavirin
C. Start oral ribavirin
D. Give a dose of IgIV 500mg/kg x 1
E. Monitor the patient
F. A and E
Case 2: Fever in February
• The respiratory virus PCR returns with RSV. What do you do?
A. Stop the oseltamivir
B. Start inhaled ribavirin
C. Start oral ribavirin
D. Give a dose of IgIV 500mg/kg x 1
E. Monitor the patient
F. A and E
RSV in Hematopoietic Stem Cell Transplantation
Shah JN, Chemaly RF. Blood. 2011; 117: 2755-2763.
RSV in Lung Transplantation
• 38 pts oral ribavirin compared to 29 pts given “best
supportive care including corticosteroids”
o
o
Ribavirin 15-20 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:
o FEV1 drop from baseline during infection: 20% (IQR 15–32) vs 18%
(IQR 13–30)
o Graft function recovery < 30 d: 84% vs 59% (P=0.02)
o New onset BOS within 6 months: 5% vs 24% (P=0.02)
Fuehner et al. Antiviral Therapy. 16:733, 2011
RSV in Lung Transplantation: New Agents
GS-5806
DeVincenzo et al. N Eng J Med. 2014; 371: 711-722.
Case 2: Fever in February
• The respiratory virus PCR returns with PIV. What do you do?
A. Stop the oseltamivir
B. Start inhaled ribavirin
C. Start oral ribavirin
D. Give a dose of IgIV 500mg/kg x 1
E. Monitor the patient
F. A and E
PIV: New Treatment Options
• DAS181
o Sialidase that cleaves the receptor for the virus off cell surface
o Inhaled or nebulized formulations
Drozd et al. Transplant Infect Dis. 2013; 15: e28-e32.
Are you a registered organ donor?
I am!
Questions?
Michael G. Ison, MD MS
+1-312-695-4186
[email protected]
Prevention of Influenza: Vaccines in HSCT
• No serologic response 0-6 months post-transplant
Transplant Type
Auto-HSCT
Allo-HSCT
Time Post-Tx
A/H1
A/H3
B
0 – 12 mo
30%
32%
38%
> 12 mo
50%
50%
71%
0 – 12 mo
31%
9%
20%
> 12 mo
13%
40%
33%
• 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
Ljungman P, Avetisyan G. BMT. 2008; 42: 637-641.
Ljungman P et al. BMT. 2009;44: 521–526.
Prevention of Influenza: Antiviral Prophylaxis
RT-PCR
Culture
Protective efficacy = 74.9%
Protective efficacy = 88.8%
95% CI for difference: 2.3%, 10.7%
95% CI for difference: 0.7%, 6.6%
Subjects (%)
8.4% (20/238)
3.8% (9/238)
1.7% (4/237)
0.4% (1/237)
No change in IC50 with breakthrough viruses
Ison et al. Antiviral Research. 2012;17(6):955-964.
Molecular Diagnostics: Limitations
Krunic et al. Ann NY Acad Sci. 2011; 1222: 6-13.
Molecular Diagnostics: Limitations
Pabbaraju et al. J Clin Micro. 2011; 49: 1738-1744.
FEV1 Change from Pre-Infection (%)
Treatment of Influenza
Ison et al. J Heart Lung Transplant. 2008; 27: 282-288.
Treatment of Influenza
Kumar et al. Lancet Infect Dis. 2010; 10: 521-526.