Prevention and treatment of opportunistic
infections in IBD: Case studies
Dec 13, 2013
Millie D. Long MD, MPH
Inflammatory Bowel Diseases Center
University of North Carolina-Chapel Hill
Case 1
• 29 year old female with colonic CD
• Hypersensitivity rxn to thiopurines
• Maintained on infliximab monotherapy 10 mg/kg
q 8 weeks
• Previously on MTX, this was d/c due to desire
for pregnancy
• Clinically in remission
• Calls with new onset painful rash on her back
Skin
Herpes Zoster
• Herpes zoster (HZ) is caused by reactivation of
latent varicella zoster virus (VZV)
• 1 million cases annually
• In the US, lifetime risk approaching 1 in 3
• About 10%–18% of persons with HZ develop
post-herpetic neuralgia (PHN)
Leung J, et al. Clin Infect Dis. 2011 Feb;52(3):332-40.
Herpes Zoster in IBD
• Incidence of zoster is higher in IBD
– 20 - 50% increase in UC
– 60 - 90% increase in CD
• Incidence increases with age
• Medications associated with zoster
–
–
–
–
Corticosteroids (adjusted OR 1.5 – 1.7)
Azathioprine/6-mp (adjusted OR 1.9 - 3.1)
Biologic anti-TNF (adjusted OR 1.8)
Combo therapy (adjusted OR 3.3)
Gupta et al. Clin Gastroenterol Hepatol. 2006 Dec;4(12):1483-90.
Long MD et al. Aliment Pharmacol Ther. 2013; 37: 420-9.
Herpes Zoster in IBD
Long MD et al. Aliment Pharmacol Ther. 2013; 37: 420-9.
Herpes Zoster in IBD
Long MD et al. Aliment Pharmacol Ther. 2013; 37: 420-9.
HZ and Anti-TNF
• New users of anti-TNF identified (all indications,
IBD, RA, psoriatic arthritis, etc)
• Compared incidence of HZ after initiation of antiTNF versus standard DMARD (mtx, etc for RA)
• Among anti-TNF users for IBD, incidence
11.3/1000 patient-years
• Adjusted HR for anti-TNF: HR 1.09 (0.88-1.36)
as compared to other DMARDs (aza/6mp)
• 2-fold increased risk with corticosteroids in IBD
(adjusted HR 1.99; 95% CI, 1.12-3.52)
Winthrop KL, et al. JAMA. 2013: 309 (9): 887-95.
Prevention? Zoster Vaccination
• Administered as a single 0.65 mL dose
• No need to ask about history of varicella
(chickenpox) or to have serologic testing as
indicated only in individuals >60
• Zoster vaccination is not recommended for
persons of any age who have received
varicella vaccine
• Live vaccine
– Inactivated vaccine is in development
MMWR, June 6, 2008, Vol 57, #5 Prevention of Herpes Zoster
ACIP Recommendations
• Zoster vaccine is recommended for all persons
aged >60 years who have no contraindications,
including persons who report a previous episode
of zoster or who have chronic medical conditions
• Zoster vaccination is not indicated to treat acute
zoster, or to prevent persons with acute zoster
from developing PHN
MMWR, June 6, 2008, Vol 57, #5 Prevention of Herpes Zoster
ACIP Recommendations
• Those >60 with anticipated immunosuppression
should be vaccinated
• Zoster vaccine should be administered at least
14 days before initiation of immunosuppressive
therapy, although some recommend waiting 1
month after zoster vaccination to begin
immunosuppressive therapy if delay is possible
MMWR, June 6, 2008, Vol 57, #5 Prevention of Herpes Zoster
ACIP Contraindications
• Zoster vaccine should not be administered to
persons with primary or acquired
immunodeficiency including:
– Persons on immunosuppressive therapy, including
high-dose corticosteroids (>20 mg/day of prednisone
or equivalent) lasting two or more weeks.
– Zoster vaccination should be deferred for at least 1
month after discontinuation of such therapy
MMWR, June 6, 2008, Vol 57, #5 Prevention of Herpes Zoster
ACIP Allowed Immunosuppression
• Short-term corticosteroid therapy (<14 days); low-tomoderate dose (<20 mg/day of prednisone or equivalent)
• Therapy with low-doses of methotrexate (<0.4
mg/Kg/week), azathioprine (<3.0 mg/Kg/day), or 6mercaptopurine (<1.5 mg/Kg/day) for treatment of
autoimmune conditions are also not considered
sufficiently immunosuppressive to create vaccine safety
concerns and are not contraindications
• Contraindication with anti-TNF medications
MMWR, June 6, 2008, Vol 57, #5 Prevention of Herpes Zoster
Vaccination and anti-TNF use
• Retrospective cohort, Medicare claims, age 60+
with immune-mediated dz (RA, IBD, etc), 2 yrs
• 4.0% of patients received HZ vaccine
– Overall incidence of zoster 7.8 cases per 1000
person-years (95% CI, 3.7-16.5)
– Rate among the unvaccinated was 11.6 cases per
1000 person-years (95% CI, 11.4-11.9)
• 633 patients on biologics – no HZ cases
• HZ vaccination HR 0.61 (95% CI, 0.52-0.71) for
HZ risk after 42 days
Zhang J, et al. JAMA. 2012 Jul 4;308(1):43-9.
Clinical Questions
•
•
•
•
•
How do you treat her?
Do you alter her infliximab?
Do you consider prophylaxis?
Do you vaccinate?
Have you seen zoster in your practice?
– What risk factors have you noted?
• How do you use HZ vaccination in your
practice?
Back to the case
• Treatment with valacyclovir, gabapentin for pain
• Infliximab held acutely until blisters scabbed
over
• Infliximab restarted at prior dose
• No treatment with acyclovir or valacyclovir
prophylaxis for now, will follow her clinically to
see if evidence of recurrence
Case 2
Case 2
• 44 year old AA female with long-standing history
of colonic CD with peri-anal pyoderma that has
been medically refractory, has diverting
colostomy
• Prior failed treatment regimens have included:
–
–
–
–
–
Anti-TNF medications
MTX, Aza/6mp (including combination therapy)
Corticosteroids
Cyclosporine
Natalizumab
Case 2
• Currently maintained on anti-TNF
and q2 weekly intralesional
kenalog injections into pyoderma
• Calls with increasing fatigue
and SOB, in clinic O2 sat is
90% on room air, lungs with
decreased breath sounds
bilaterally at bases
Case 2 : CXR
Opacification at
bases bilaterally
Bronch/BAL
confirms diagnosis
PCP (PJP)
• Case reports have described cases of
Pneumocystis jiroveci pneumonia (formerly known
as Pneumocystis carinii or PCP) in IBD
associated with immunosuppression
–
–
–
–
–
Azathioprine
Corticosteroids
Cyclosporine
Anti-TNF
Combinations
Khatchatourian M, Seaton TL. Am J Gastroenterol. 1997;92:1558–1560.
Takenaka R, et al. J Gastroenterol. 2004;39:1114–1115.
PCP (PJP)
• PCP is an atypical unicellular fungus that
produces alveolar infiltrates and local
inflammatory reactions, which widen the
alveolar–arterial oxygen gradient.
• PCP is associated with high rates of morbidity
and mortality given its profound effects on gas
exchange
Poppers DM, Scherl EJ. Inflamm Bowel Dis. 2008;14:106–113.
Jones JL, et al. MMWR CDC Surveill Summ. 1999;48: 1–22.
Incidence of PCP in IBD and non-IBD Populations
Annual PCP Incidence
per 100,000
20
15
13
11
10
5
8
3
3
3
CD
UC
IBD
0
Long MD, et al. Inflamm Bowel Dis. 2013 Apr;19(5):1018-24
Non-IBD
CD or UC
Medications and PCP in IBD
• 20 (53%) were on
steroids alone or in
combination with
other medications
• A total of 19
individuals (50%) had
a hospitalization in
the 60 days before
PCP diagnosis
• More comorbidities
Adalimumab/infliximab
PCP and Prophylaxis: ECCO consensus
* All were infectious
disease specialists
PCP and prophylaxis: considerations
• Patients on high-dose corticosteroids
• Patients on triple immunosuppression with
corticosteroids, anti-metabolites, and anti-TNF or
calcineurin inhibitor
• Lymphopenia (absolute lymphocyte count <600,
CD4+ lymphocyte count less than 300)
• Patients w/ multiple comorbidities (COPD)
• Patients older than 55 years
• Prophylaxis rates on combination therapy are
low: 11% from one provider survey
Okafor PN, et al. Inflamm Bowel Dis. 2013 Jul;19(8):1764-71.
Okafor PN, et al. Inflamm Bowel Dis. 2013;19:812–817
Clinical Questions
• Who has had a case of PJP (PCP)? Has this
case impacted your prescribing patterns of
prophylaxis?
• For whom do you offer prophylaxis in your
practice?
• What do you commonly use for prophylaxis?
• What downsides do you see to prophylaxis?
Back to the case…
•
•
•
•
Hospitalized in ICU
Required intubation, bronch/BAL
Treated with SMP/TMX and corticosteroids
Eventually with improved oxygenation and full
recovery after prolonged hospital course
• Pyoderma unchanged
Case 3
Case 3
• 31 year old male with ileocolonic CD failed
multiple therapies including mesalamine,
antibiotics, budesonide, immunomodulators and
several anti-TNF-a medications.
• May 2008, started on natalizumab (NZB) with a
rapid and sustained response. A baseline MRI
was normal.
• In March 2011, 35th infusion of NZB.
• Two weeks later (day 0), difficulty with
concentration and visual field defects
Case
• On day 6, a brain MRI demonstrated increased
T2 and FLAIR signal in the left parieto-occiptal
lobe
PML
• Within 24 hours, he underwent a lumbar
puncture. CSF PCR for JC virus had 2.9 million
copies, confirming PML. Plasma exchange
(PLEX) was initiated to remove circulating NZB.
• Mirtazapine 15mg daily was started on day 8
due to in vitro evidence for inhibition of JC virus.
• He underwent five PLEX sessions (1.5 plasma
volumes, albumin replacement) over ten days.
PML
• On Day 17, worsening expressive aphasia and
visual symptoms.
• Methylprednisolone 1 gram/day followed by a
prednisone taper was started for suspected
immune reconstitution inflammatory syndrome
(IRIS).
• By Day 49, he had receptive aphasia and rightsided sensory and motor loss. Brain MRI
showed progression of PML lesions
•
PML
• Mirtazapine was increased to 60mg daily, and
mefloquine 250mg daily for three days, followed
by 250mg weekly for three weeks, was started
due to in vitro activity against JC virus.
• By Day 76, he reached a nadir of neurologic
function, with receptive aphasia, one word
sentences and minimal right-sided motor or
sensory function. Slow recovery followed.
• By Day 113, he tapered off corticosteroids. Most
recent brain MRI showed left cerebral involution.
MRI Series
A
B
C
A: Initial PML diagnosis (day 6). B: Extention of PML (day 53).
C: Last follow-up MRI with cerebral involution (day 167).
PML
• Progressive multifocal leukoencephalopathy
(PML) is a rare neurologic disorder caused by a
common human virus (JC virus) that infects
oligodendrocytes, resulting in demyelination or
destruction of the cells in the brain and usually
death within months
• PML is typically seen in immunosuppressed
patients with cancer, those who have undergone
organ transplant, or AIDS patients with
depressed T cell function
Keeley KA, et al. Ann Pharmacother. 2005 Nov;39(11):1833-43.
PML and Natalizumab
• As of 2012, 212 confirmed cases of PML among
99,571 MS patients on natalizumab (2.1 /1000)
• All 54 patients with PML for whom samples were
available were positive for anti-JC virus Ab
• Risk among those JC virus negative: 0.09 cases
or less/1000 patients (95% CI 0 to 0.48)
• Factors associated with increased risk:
– JC virus positive
– Prior immunosuppression
– 25-48 months of therapy (longer duration)
Bloomgren G, et al. N Engl J Med. 2012 May 17;366(20):1870-80
PML Prevention?
• The risk of PML should be stratified into high,
medium and low risk groups according to
presence or absence of anti-JC virus antibodies,
prior immunosuppressive therapy, and treatment
duration.
• Anti JC virus (Anti-JCV) Ab testing is now widely
available
• Anti-JCV Ab prevalence in a large, diverse,
multi-national multiple sclerosis (MS) cohort was
57.6%.
Olsson T, et al. Mult Scler. 2013 Oct;19(11):1533-8
Clinical Questions
• Do you use natalizumab in your practice?
– TOUCH program
• Do you test for anti-JCV Ab?
• Do you have a protocol for testing once on
therapy?
– Note: false-negative rate of 2.7% (95% CI, 0.9–6.2).
• Do you pull patients off of natalizumab who turn
anti-JCV Ab positive?
Bozic C, et al. Ann Neurol. 2011 Nov;70(5):742-50.
Back to the case…
• At last follow-up, he has persistent expressive
aphasia limiting the fluency of speech but he is
able to follow commands
• He has 4/5 strength and mildly decreased
sensation to light touch on the right side
• He is disabled