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Microsoft powerpoint - farraye & cross-case breakout-infections-print.pptx

Prevention and Treatment of
Opportunistic Infections in IBD
38 year old female pediatric nurse with 7 year
Patients: Case Studies
history of pan colitis doing well on
mesalamine
Francis A. Farraye MD, MSc
In remission for 5 years
Clinical Director, Section of Gastroenterology
Recent fl
are treated with
ith steroid
(20mg/d )
with transient improvement
Boston Medical Center
Worsening symptoms so admitted to her local
Professor of Medicine
community hospital
Boston University School of Medicine
C. diff negative
Started on Solumedrol 20mg q 6h, increased
to 50mg q 6h on day 3
Background
Global increase in the incidence of IBD
Over next week, worsening symptoms with
More patients on combination therapy:
decreasing HCT, albumin and increasing
steroids, anti-metabolites and biologic agents
bloody stools
Immune system suppression predisposes to
Infliximab added 5mg/kg on day 5
opportunistic infections
Developed fever and d
yspnea on day 11
CXR-infiltrates and hypoxia requiring
Increasing reports of Pneumocystis Jiroveci
intubation
Pneumonia (PJP), formerly pneumocystis
Diagnosed with Pneumocystis Jiroveci
carinii (PCP) in IBD patients
Pneumonia (PJP), formerly pneumocystis
No evidence-based guidelines for
carinii (PCP)
prophylaxis
Treated with Bactrim later changed to
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory
bowel diseases. Gastroenterology. 2011 May;140(6):1785-94. Poppers DM, Scherl EJ. Prophylaxis against

Atovaquone
Pneumocystis pneumonia in patients with inflammatory bowel disease: toward a standard of care.
Inflamm Bowel Dis. 2008;14:106-13.

Pneumocystis Jiroveci Pneumonia
Epidemiology of PJP in IBD Patients
Ubiquitous unicellular fungus
Case control study using administrative data from
Develops in patients with defects in T-
IMS Health Inc, LifeLink™ Health Plan Claims
lymphocyte immunity
Database
108,604 patients with IBD matched to four non-IBD patients
Exact incidence in IBD is unknown
IBD patients had a 3.48-fold increased risk of PJP when
Higher mortality in non-HIV patients
compared to non-IBD patients
Absolute risk with biologic agents is debatable
Incidence rate ratio, 4.49 (95% CI, 2.14-9.75) in CD
patients compared to non-IBD patients
Risk increases with number of immune
modulating agents
Incidence rate ratio, 2.40 (95% CI, 1.11-5.10) in UC
patients compared to non-IBD patients
Passive FDA reporting system identified 84 PJP
Incidence rate: 32/100,000 person-years vs.
cases between 1998-2003, 16 cases in IBD
4/100,000 person-years in non-IBD
patients
Kaur N, Mahl TC. Pneumocystis jiroveci (carinii) pneumonia after infliximab therapy: a review of 84 cases. Dig
Long MD, Farraye FA, Okafor PN, et al. Increased risk of PJP among patients with IBD. Inflamm Bowel Dis.
Dis Sci. 2007 Jun;52(6):1481-4.
2012, in-press.
Risk Factors for PJP in IBD
Recognizing PJP
High degree of suspicion
High dose corticosteroid use
Triad of fever, hypoxia, cough
Triple immunosuppressive therapy (steroids, anti-
metabolites, anti-TNF agents)
Chest x-ray may show diffuse or no infiltrates
Immunosuppresion with cyclosporine
Slow progression in HIV, more rapid in non-HIV
cohorts culminating in respiratory failure with 30-
y phopenia (lym
y phocyte count
<600, CD4+ <300)
50% mortality
Low TPMT levels
Histopathological staining of sputum samples
Advanced age
PCR of sputum samples may be more sensitive
Comorbidities, especially COPD
Feasibility of oral washes in combination with PCR
Recent CMV infection
merits additional studies
Beta-D-glucan and KL-6 may have less utility in non-
Okafor PN, Nunes DP, Farraye FA. Pneumocystis Jiroveci Pneumonia in inflammatory bowel disease: When
should prophylaxis be considered? Inflamm Bowel Dis. 2012, in press.

HIV PJP due to smaller disease burden
Thomas CF, Limper AH. Pneumocystis pneumonia. N Engl J Med. Jun 10 2004;350(24):2487-2498. Catherinot E,
Lanternier F, Bougnoux ME, et al. Pneumocystis jirovecii Pneumonia. Infect Dis Clin North Am. 2010
Mar;24(1):107-38.
.

PJP Prophylaxis
PJP Prophylaxis
Primary PJP prophylaxis is cost effective in
Most cited reason for lack of prescribing prophylaxis
Wegener's granulomatosis when annual
was the lack of data or evidence-based guidelines to
direct practice
incidence is as low as 0.2%
In an internet survey of US gastroenterology
iders, onl
prescribe PJP
prophylaxis
Prior experience with PJP and practice in an
academic medical center were associated
with PJP prophylaxis
Okafor P, Wasan, SK, Farraye FA, Pneumocystis Jiroveci pneumonia in inflammatory bowel disease patients: A survey of
prophylaxis patterns among gastroenterology providers. Inflamm Bowel Dis 2012, in press.

Okafor P, Wasan, SK, Farraye FA, Pneumocystis Jiroveci pneumonia in inflammatory bowel disease patients: A survey
of prophylaxis patterns among gastroenterology providers. Inflamm Bowel Dis 2012, in press.

ECCO Guidelines
PJP Prophylaxis and Treatment
ECCO guidelines (2009) based on expert
Trimethoprim-sulfamethoxazole (Bactrim) most
commonly used because of cost, efficacy and side
No vaccines for PJP
effect profile
Recommend monitoring of cell counts
Other options include dapsone, atovaquone,
pentamidine
Primary prophylaxis with Bactrim for patients on
triple therapy
including
including biologic
Treatment may
be i npatient
inpatient o
or outpatient
epending
depending
calcineurin inhibitors
on severity
No consensus for dual therapy
Corticosteroids indicated if PaO2 <70 mmhg, A-a
gradient >35mmhg
Prophylaxis for steroid monotherapy debatable
Involve infectious disease specialist early
No guidelines for primary PJP prophylaxis
by US GI societies
Okafor PN, Nunes DP, Farraye FA. Pneumocystis Jiroveci Pneumonia in inflammatory bowel disease: When should
prophylaxis be considered? Inflamm Bowel Dis. 2012, in press.

Rahier, JF, Ben-Horin S, Chowers Y, et al., European evidence-based Consensus on the prevention, diagnosis
and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis, 2009. 3(2): 47-
91. Viget N, Vernier-Massouille G, Salmon-Ceron D, et al. Opportunistic infections in patients with
inflammatory bowel disease: prevention and diagnosis. Gut. Apr 2008;57(4):549-558.

Conclusions (1)
Conclusions (2)
PJP in IBD patients is a growing concern
Bactrim prophylaxis for patients on triple
Fever is the principal and often the only initial
therapy as recommended by ECCO
manifestation of a serious infection
Consider regular monitoring of lymphocyte
Low incidence rates preclude feasibility of
counts for patients on dual agent or high
dose steroid monotherapy
More case-control studies are needed
Consider prophylaxis in high risk patients on
Predictive models to identify patients at
triple immunosuppression OR monitor total
highest risk of PJP will be useful
lymphocyte and/or CD4+ counts closely
A case-by-case approach to identify at-risk
Early recognition and treatment is essential
groups that may benefit from prophylaxis is
recommended
Vesicular Rash in a CD Patient on
Herpes Zoster Epidemiology
55 year old female calls complaining of a rash
At least 1 million people a year in the United
on her neck that began 24 hours earlier
States get shingles
She thinks it is shingles because her father had
Rash usually lasts from 2 to 4 weeks
similar rash several years ago
Main symptom is pain, which can be quite
Diagnosed with Crohn's Disease 12 years ago
Limited ileocecal resection 8 years ago
Very rarely, shi
es nfecti
tion can lead t
pneumonia, hearing problems, blindness,
On 6MP for 8 years with surveillance
encephalitis or death
colonoscopy showing few aphthous erosions
in the neoterminal ileum
Approximately 20% of patients can develop
post-herpetic neuralgia
Rash typical of shingles
http://www.cdc.gov/vaccines/vpd-vac/shingles/vacc-need-know.htm
Herpes Zoster in IBD Patients
Herpes Zoster in IBD Patients
Retrospective cohort study/nested case-control
In the cohort study, the incidence of zoster was
study using 1988-1997 data from the General
higher in patients with CD and UC compared with
Practice Research Database
controls
7823 CD and 11,930 UC patients were matched
UC incidence rate ratio, 1.21; 95% CI, 1.05-1.40
on age, sex, and primary care practice to 79,563
CD incidence rate ratio, 1.61; 95% CI, 1.35-1.92
randomly selected controls without CD or UC
In the nested case-control study, corticosteroids
In the nested case-control study, 185 CD
(adjusted odds ratio, 1.5; 95% CI, 1.1-2.2) or
patients with zoster and 266 UC patients with
azathioprine/6-mercaptopurine (adjusted odds
zoster were matched on sex and year of birth to
ratio, 3.1; 95% CI, 1.7-5.6) were both associated
1787 IBD patients without zoster
with zoster
IBD patients, especially those on
immunosuppressive medications, are at higher
risk for herpes zoster compared with the general
Gupta G, Lautenbach E, Lewis JD. incidence and risk factors for herpes zoster among patients with inflammatory
population
bowel disease. Clin Gastroenterol Hepatol. 2006;4: 1483–1490.
Gupta G, Lautenbach E, Lewis JD. incidence and risk factors for herpes zoster among patients with inflammatory
bowel disease. Clin Gastroenterol Hepatol. 2006;4: 1483–1490.

VZV Exposure History and
VZV Exposure History and
Immunity
Immunity
History of VZV-related illness was accessed by
The calculated positive and negative predictive
epidemiological questionnaire, and serological
values for the reported history of VZV exposure
testing for VZV-IgG was performed
were 93% and 0%
121 IBD (86% CD, mean age 37 ± 12.8) patients
Negative history of VZV exposure is a poor
were studied
predictor of seronegativity
87% of th
tients were
on mmunomodulator
History-positive patients may still be seronegative
therapy (anti-TNFs- 71%)
and exposed to VZV infection
Previous exposure to VZV was reported by 104
Suggest serological testing of all IBD patients with
patients, and 97/104 (93%) were VZV-IgG
subsequent immunization of the seronegative
seropositive
patients before initiation of immunosuppressive
Seventeen patients, all seropositive, reported
negative exposure history
Kopylov U, Levin A, Mendelson E, et al. Prior varicella zoster virus exposure in IBD patients treated by
anti-TNFs and other immunomodulators: implications for serological testing and vaccination guidelines.
Kopylov U, Levin A, Mendelson E, et al. Prior varicella zoster virus exposure in IBD patients treated by
Aliment Pharmacol Ther. 2012 Jul;36(2):145-50.
anti-TNFs and other immunomodulators: implications for serological testing and vaccination guidelines.
Aliment Pharmacol Ther. 2012 Jul;36(2):145-50.
VZV Vaccine
VZV Vaccine
Herpes Zoster vaccine first licensed in 2006
One-time vaccination
Lyophilized preparation of a live, attenuated
No maximum age for getting the shingles vaccine
strain of varicella zoster virus (VZV)
Anyone 60 years of age or older should get the
Herpes Zoster vaccine reduced the risk of
shingles vaccine, regardless of whether they recall
shingles by 51% and the risk of post-herpetic
having had chickenpox or not
neuralgia b
cans ages 0
40 and older
CDC recommends Herpes Zoster vaccine for use
have had chickenpox, even if they don’t remember
in people 60 years old and older to prevent
having the disease
shingles
Patients with previous episode of shingles can
The CDC does not have a recommendation for
receive Herpes Zoster vaccine
routine use of shingles vaccine in persons 50-59
years old but the vaccine is approved by FDA for
people in this age group
http://www.cdc.gov/vaccines/vpd-vac/shingles/vacc-need-
know.htm
http://www.cdc.gov/vaccines/vpd-vac/shingles/vacc-need-
know.htm
Vaccinating IBD Patients on
Vaccinating IBD Patients on
Immunomodulators with Zoster Vaccine
Immunomodulators with Zoster Vaccine
In 2008, the CDC determined that patients receiving low
Of the 21 patients enrolled thus far, 9 are on immunomodulator
dose immunomodulators are not sufficiently
immunosuppressed to create vaccine safety concerns
None of the patients developed a varicella-like rash
and can receive VZV
Methotrexate (≤0.4mg/kg/week), azathioprine (≤
None of the patients noted an increase in IBD activity after
3.0mg/kg/day), 6-mercaptopurine (≤1.5mg/kg/day)
administration of VZV
Study Design
Patients on
immunosuppressiv
immunosuppressiv therapy
increase
On-going prospective open-label study
specific antibody levels compared to the response noted in the
immunocompetent group (p=0.13 vs p=0.01)
Subjects
Patients ages 50 and older with IBD
Baseline antibody levels were not different between the two
Group A: Currently on low dose immunomodulator
therapy, age 64 (51-76)
Although immunosuppressed patients were able to mount a
Group B: On 5-ASA therapy or no therapy, age 50
statistically significant cytokine response following vaccination it
was reduced compared to the immunocompetent group (p=0.04)
Wasan SK, Berg AM, Liang YM, Ganley-Leal L, Farraye FA. Immune response and safety of herpes zoster
Wasan SK, Berg AM, Liang YM, Ganley-Leal L, Farraye FA. Immune response and safety of herpes zoster
vaccine in IBD patients on methotrexate and thiopurines. Am J Gastroenterol. 2012;107:S668
vaccine in IBD patients on methotrexate and thiopurines. Am J Gastroenterol. 2012;107:S668
Vaccinating IBD Patients on
Conclusions: VZV in IBD Patients
Immunomodulators with Zoster Vaccine
Immunocompetent patients with IBD who were
Risk of VZV is increased in immunosuppressed
vaccinated with VZV were able to increase their
IBD patients
antibody response to the vaccine antigens
Up to 50% of adults born in tropical areas of the
world have no history of primary infection
Immunosuppressed patients with IBD who were
vaccinated with VZV had much lower antibody
Number of reports of severe, disseminated, and
responses to
antigens
rarely fatal v
aricella
varicella infection i n
immunosuppressed IBD patients
Additional studies are needed to determine the
clinical significance of this blunted response and
The risk of VZV infection is increased with all
whether the immunological response is protective
immunosuppressants, but corticosteroids and
or requires an altered vaccination regimen
combination immunosuppression appear to be a
particular risk
Wasan SK, Berg AM, Liang YM, Ganley-Leal L, Farraye FA. Immune response and safety of herpes zoster
Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflamm
vaccine in IBD patients on methotrexate and thiopurines. Am J Gastroenterol. 2012;107:S668
Bowel Dis. 2012 Mar 20. doi: 10.1002/ibd.22950. [Epub ahead of print]
Conclusions: VZV in IBD Patients
Cases Followup
Healthcare providers need to be aware of the
38 year old woman with PJP
various manifestations of primary and secondary
Intubated in ICU for 4 weeks
VZV infection in immunosuppressed IBD patients
Survived and sent to rehab
Patients should be screened for VZV immunity and
Steroids tapered, PJP prophylaxis continued with
vaccinated prior to commencing
atovaquone
immunosuppression
Patient refused to take 6MP
UC flared with steroid taper and underwent colectomy
55 year old woman with Zoster
6MP held and antiviral therapy (famciclovir) started
Rash resolved after one week
No post herpetic neuralgia
Received Herpes Zoster vaccine
Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflamm
Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflamm
Bowel Dis. 2012 Mar 20. doi: 10.1002/ibd.22950. [Epub ahead of print]
Bowel Dis. 2012 Mar 20. doi: 10.1002/ibd.22950. [Epub ahead of print]

Source: http://www.advancesinibd.com/assets/Slides/clinical/Farraye%20&%20Cross-case%20breakout-infections-print.pdf

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