Infections due to immunomodulators
and biologics: identification, prevention
and treatment
Corey A. Siegel, MD, MS
Geisel School of Medicine at Dartmouth
Dartmouth-Hitchcock Medical Center
2013 Advances in Inflammatory Bowel Disease, CCFA research conference
December 14, 2013
Disclosures
Consultant/Advisory Board
Abbvie, BiolineRX, Given Imaging, Janssen, Salix, Millenium,
Prometheus, Takeda, UCB
Speaker for CME activities
Abbvie, Janssen, Merck
Grant support
CCFA, NIH (K23DK078678), AHRQ (1R01HS021747-01)
Abbvie, Janssen, Salix, Warner-Chilcott
Slides available from me:
corey.siegel@dartmouth.edu
Infections in patients with IBD
1. How often and with what meds?
2. Does combination therapy make it worse?
3. Testing for TB…what to do if positive?
4. PML
5. Vaccinations, dead or alive! (NEW recs here)
6. Preventing and treating varicella zoster
3
How often do infections occur on our meds?
COMMIT
Infections
SONIC
Serious
infections
Pediatrics
Serious
infections
MTX
MTX + infliximab
58.7%
61.9%
AZA
Infliximab
AZA + IFX
5%
2.5%
3.4%
Anti-TNF
IMs
Steroids
3.5%
3.3%
7.3%
Feagan et al. Digestive Disease Week, San Diego, CA 2008. Sandborn, WJ et al. ACG 2008. Dulai PS, et al. Inflamm Bowel Dis 2013.
How often do life threatening infections occur on
anti-TNF therapy?
Reference
Study Design
# Deaths from sepsis thought
attributable to infliximab
# of
Patients
Ljung et al. Gut 2004
Population
Based Cohort
1
191
Seiderer et al.
Digestion 2004
Single-Center
Cohort
0
92
Colombel et al.
Gastroenterology 2004
Single-Center
Cohort
5
500
Sands et al. NEJM
2004
Randomized
Controlled
Trial
2
282
Hanauer et al.
Lancet 2002
Randomized
Controlled
Trial
1
573
Rutgeerts et al.
Gastroenterology 1999
Randomized
Controlled
Trial
0
73
Risk of death from sepsis = 4/1000 pt-yrs
Siegel et al. Clin Gastroenterol Hepatol. 2006;4:1017-1024.
Who is at the most risk for dying from sepsis
related to anti-TNF?
»Older
› Average age = 63 (systematic review); 67 (Mayo)
»Multiple co-morbidities
»Concomitant medications
»Long-standing disease
Young “healthy” patients are not in the
clear, but probably less at risk
Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006
Are opportunistic infections more common if
taking more than 1 medication?
»Opportunistic infections
Prednisone, 6MP/AZA,
Infliximab
Odds Ratio
(95% CI)
1 medication
2.9 (1.5–5.3)
2 or 3 medications
14.5 (4.9–43)
Lichtenstein CGH 2006; Toruner, Gastro 2008
Closer look at the Mayo experience with
opportunistic infections
Herpes zoster
Candida albicans
Herpes Simplex
CMV
EBV
Histoplasmosis
Blastomycosis
Streptococcus
E. Coli
Mycobacterium marinum
Mycobacterium fortuitum
Cryptococcus
Mycobacterium gordonae
28
26
18
12
8
2
1
1
1
1
1
1
1
Toruner et al. Gastro 2008;134:929
Closer look at the Mayo experience with
opportunistic infections
Number of meds
0
1
2 or 3
Specific combinations
Corticosteroids alone
6MP/AZA alone
IFX alone
AZA/6MP + steroids
AZA/6MP + IFX
AZA/6MP + IFX + steroids
Cases
38
38
24
16
20
3
16
1
5
Controls
129
59
12
27
31
2
6
5
0
OR
1.0 (ref)
2.9 (1.5-5.3)
14.5 (4.9-43)
2.2 (1.0-4.9)
3.4 (1.5-7.5)
11.1 (0.8-148)
17.5 (4.5-68)
1.6 (0.1-19)
1.1 (1.0-1.2)
Toruner et al. Gastro 2008;134:929
Quality Measures for IBD
»Both AGA and CCFA quality measures
› HBV testing before initiating anti-TNF
› Testing for latent tuberculosis before starting antiTNF (which method)
› Influenza and pneumococcal vaccinations
Siegel CA, Allen JI, Melmed GY. Clin Gastroenterol Hepatol 2013.
Baseline testing prior to immune suppression
»Testing for latent tuberculosis Quantiferon vs TST
40
35
%
positive
30
25
20
15
10
5
0
No IS (IBD)
IS (IBD)
» QuantiFERON Gold is
consistent despite
immunosuppression or BCG
status
» Lower false positive
» Single office visit
» Cost effective
» Recommended by CDC!
TST (skin test)
QuantiFERON Gold
Disease activity may play a big role in
indeterminate results of Quant-Gold
Schoepfer, Am J Gastroenterol 2008; Diel, Chest 2007; Hradsky O et al. J Pediatri Gastroentenrol Nutr 2013. Epub ahead of print.
If Tuberculosis Screening Test is Positive…
» Quant Gold positive or skin test ≥ 5mm
» Chest X-Ray
» Work with ID experts
» Before initiating anti-TNF, ideally treat for 6 months with
INH, but not always practical – 2 months acceptable
(sometimes concurrent needed with close follow)
› INH 300mg PO qd x 6 months
› INH + Rifampicin x 3 months (higher hepatitis risk)
› +/- pyridoxine 50mg PO qd
ECCO guidelines 2009; British Thoracic Society Standards of Care Committee. Thorax 2005;60:800. http://www.cdc.gov/tb/pubs/PDF/1376.pdf
Natalizumab and PML Risk Based on anti-JC
Virus Antibody Status
Anti-JCV Antibody
Status
Negative
< 0.11/1000
Positive (and prior
IS use)
0-2 years
2/1000 (1 in 500)
2+ years
11/1000
(≈1 in 100)
To ORDER anti-JC Virus antibody test:
Quest Labs test # 90257, JC Virus Antibody with Reflex Inhibition Assay
About 50% of Crohn’s patients will be positive
Bloomgren, et al. NEJM 2012;366.20.
General vaccination recommendations for
immunosuppressed IBD patients
»Annual influenza vaccination in IBD patients
»Pneumococcal vaccination in IBD patients, repeat
5 years later
»Consider vaccinating ALL susceptible IBD patients
at diagnosis before immunosuppressed
»NEW recommendations about LIVE vaccines
The pneumonia vaccination(s)
» Consider using “Combination therapy”
» PPSV23 vaccine (polysaccharide) should be given to ALL
patients (high, low or planned immune suppression) and
once 5 years later
» PCV13 (conjugated – super booster) vaccine should be give
to all patients with current or planned immune suppression
› at least 8 weeks before or at least 1 year after PPSV23
vaccine)
Vila-Corcoles A, Ochoa-Gondar O. Drugs Aging 2013; Rubin, LG, et al. Clinical Infectious Diseases, December 2013
Will the vaccinations work in
immunosuppressed IBD patients?
» IBD patients receiving pneumovax, tetanus, influenza
and HIB on azathioprine/6MP monotherapy had a
normal response to vaccinations
» Adult IBD patients receiving pneumococcal vaccine
had poor response if on combination anti-TNF +
immunomodulator therapy
» Pediatric IBD patients receiving influenza vaccine had
a poor response if on combination anti-TNF +
immunomodulator therapy
» In patients with juvenile systemic lupus, main predictor
of LACK of response was a higher disease activity
(not immune suppression)
Dotan, Gastroenterology 2007;132(4):A-51. Lu, Am J Gastroenterol 2009. Melmed, DDW 2008. Mamula CGH 2007;5(7):851. Campos LM, et al. Arthritis Care
Res 2013
Risk of Herpes Zoster (“shingles”) is
increased in IBD
»Case control study, GPRD 1988-1997
› 7823 (Crohn’s), 11,930 (UC), and 79,563 (control)
»Incidence of HZV is about 1.5x higher in IBD
»Risk increases with immunosuppression
› Corticosteroids OR 1.5 (1.1 – 2.2)
› AZA/6MP OR 3.1 (1.7 – 5.6)
Gupta, Lautenbach, and Lewis. Gastroenterology 2006
Zoster in IBD increases with Age
Long et al. Alim Pharm Ther 2013
Varicella and Zoster vaccines in immune
suppressed patients
» Varicella vaccination safe and effective in children with HIV
» Pediatric IBD patients from Boston Children’s  varicella
vaccination in immunosuppressed kids was safe and
effective
» 463,541 Medicare beneficiaries with various inflammatory
disorders (subgroup on biologics)
› No cases of HZV infection in biologic-treated patients who received
Zoster vaccine
› Zoster Vaccine was protective HR 0.61 (95% CI, 0.52-0.71)
Taweesith W. et al. Pediatr Infect Dis J 2011; Lu Y, Bousvaros A. J Pediatr Gastroenterol Nutr 2010; Zhang et al. JAMA 2012
2013 Infectious Disease Practice Guidelines
HOT off the press (12/4/13)
» Differentiate “low-level” from “high-level” immune
suppression
› Low-level = prednisone ≤ 20mg/kg/day, AZA ≤ 3.0mg/kg, 6MP ≤
1.5mg/kg, MTX ≤ 0.4mg/kg/wk
› High-level = prednisone > 20mg, higher doses azathioprine, 6MP,
MTX or ANY biologic
» Varicella vaccine (if not immune)
› NO for high-level
› Maybe for low-level (CDC disagrees)
» Zoster vaccine
› NO for high-level
› YES for low-level if > 50 years old (or younger if history of varicella)
Rubin, LG, et al. Clinical Infectious Diseases, December 2013
Other pearls from the IDSA Guidelines
»How long do you have to wait to start immune
suppression after a live virus vaccine?
› At least 4 weeks
»NEVER give live influenza*, MMR or yellow fever if
immune suppressed
»Household contacts
› CAN receive: MMR, rotavirus for infants, Varicella/Zoster
(but watch for lesions) , yellow fever, oral typhoid
› CANNOT receive: live influenza, live polio
Rubin, LG, et al. Clinical Infectious Diseases, December 2013
What if your patient gets it?
Shingles is very different than disseminated varicella
22
Treating Varicella in Immunosuppressed Patients
» Zoster (Shingles)
› Treat within 1 week of onset (or before full crusting of
lesions)
› Localized disease  valacyclovir, acyclovir,
famcyclovir
› Disseminated zoster (or severely immunosuppressed)
 IV acyclovir
» Chickenpox
› Oral or IV antiviral treatment
Ahmed, Herpes 2007;14(2):32. CDC recommendations, Available at: http://www.cdc.gov/vaccines/vpd-vac/varicella/dis-faqs-gentreatment.htm
Post-Exposure Prophylaxis
-Varicella (chickenpox & shingles)» What constitutes exposure?
› Chickenpox  Close indoor contact, face-to-face contact
› Shingles  Contact with open lesions
» Are they susceptible?
› Negative history of disease, no vaccination, negative titers
» If not immunosuppressed
› Vaccination within 3-5 days of exposure
» If immunosuppressed
› Within 96 hrs  Varicella zoster immune globulin (VariZIG)
› Later than 96 hrs  Consider IVIg
› Limited data on acyclovir
Centers for Disease Control and Prevention (CDC). Available at: http://www.cdc.gov/vaccines/vpd-vac/varicella/vac-faqs-clinic-highrisk.htm. Centers for
Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep 2006; 55(8): 209–10. Asano, Pediatrics 1993; 92(2): 219–22.
Summary
» We are never going to prevent all infections
» But, we have an opportunity to prevent serious infectious
complications by thoughtful patient selection and vaccination
» We still have more to learn about vaccinations (particularly
live vaccinations and anti-TNF)
» Critical to have early recognition and treatment of infections
in immunosuppressed patients (lower threshold for
intervention)
Slides available from me:
corey.siegel@dartmouth.edu