Treating the Inpatient with Severe
Crohn’s Disease: Case Studies
Peter D.R. Higgins, MD, PhD, MSc
University of Michigan
Hans H. Herfarth, MD, PhD, FACG, AGAF
University of North Carolina
Today’s Cases
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Difficult inpatients with Crohn’s disease
The kind that are NOT eligible for clinical trials
Limited, if any, RCT data available
There are frequently NO right answers
Management through general principles, art,
analogy, and the limited science available
CASE 1
COMPLICATED CROHN’S DISEASE
Crohn’s Disease
• 49 year old female with CD x 5 years (2009)
– Initial Sx intractable nausea and wt loss
• Gastric, duodenal, jejunal and and ileal disease
• Failed 5-ASA x 6m, did well on Aza x 3 years
• 2013 seizure, R burning facial pain, HA
– MRI – leptomeningeal lesion, Bx: cerebral vasculitis
• Rx with 80 prednisone qd, pain and seizures
continue
– Progression on MRI, pain 8/10, Keppra no effect
• Neurologist wants to start Cytoxan Jan 2014.
Options
• Continue Aza (controlling CD) with Cytoxan?
• Stop Aza during Cyclophosphamide, then
resume Aza?
• Stop Aza during Cyclophosphamide, then new
Rx?
– Options for new Rx?
Case Continued
• Cytoxan with some benefit (5 cycles)
– Off Aza, covered with entocort 9 mg po daily
– Fewer seizures, continued R facial pain/numbness
• August admitted to hospital
– Periumbilical and RUQ/RLQ pain, 10 loose BM qd
– Rising WBC (20K), CRP 82 mg/L, fatigue and fever
– Alk Phos 487, AST 82, ALT 58, Tbil 2.3
– Worsening edema in arms and legs (albumin 1.6)
– Neurology – no more Cytoxan
Evaluation?
• Labs?
• Scopes?
• Scan?
Workup
• CTE – inflammation in stomach, D, J, I, and
rectosigmoid
• Upper – ulcerations of antrum and D2 with
granulomas
• FS – acute colitis, suggestive of EHEC
• MRCP – PSC with hilar stricture – ERCP dil.
– Pip/tazo for cholangitis/ ? EHEC
Chronic IBD/Vasculitis Therapy?
• Short term (post Abx)
– Prednisone (lots of side effects)
– Dual BUdesonide?
• Maintenance Options?
– Aza (but onset of Vasculitis through Aza)
– Anti-TNF?
– Vedo (what about vasculitis?)
– Mycophenolate and/or MTX?
– Natalizumab? (treat both??)
Latest update
• Prednisone taper, IFX/Aza (2 infusions)
– CD Sx returning, Alb 2.7
• New LE weakness, continued R facial pain
– Trileptal and Keppra combo not helping
Case 2
Severe Indeterminate Colitis
Hans Herfarth, MD, PhD
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Case
• 32 year old female, dx of indeterminate Colitis (based on
mild non-specific histologic inflammation in TI) 5 years ago.
• HPI: 20 bloody bm’s/day, oral steroids for 10 days, no
improvement, hospitalization, steroid iv.
• Course of the disease: Initially 5 years ago steroid
dependent disease course. Start of azathioprine with long
term remission. Patient self-discontinued azathioprine 2
years ago while feeling well.
• Labs: WBC 3.4 (diff: lymphocytes 500), HGB 8.1,
CRP 3. C. diff. negative.
• Physical exam: Tender abdomen, fever 39.1°C
Case
• Endoscopy: Severe colitis to transverse colon (more compatible
with UC) and normal terminal ileum and ascending colon.
• Histology: severe colitis (H&E), no granuloma.
Suspicion of CMV colitis
CMV Colitis– Clinical and Laboratory Features
Ulcerative colitis >> Crohn’s disease
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Diarrhea
Bloody Diarrhea
Fever
Toxic Megacolon
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Leukopenia
Lymphopenia
LFT’s
What test do you perform to diagnose CMV colitis?
• Immunohistochemistry for CMV
• CMV – serologies (IgG and IgM)
• CMV –PCR using colonic biopsies
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Qualitative
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Quantitative
• CMV PCR plasma
Tests, Costs and Problems in the Detection
of CMV Infection
Test
Sensitivity
Specificity
Cost Problem
Histology (H&E)
10-87%
92-100%
$
Sampling error
Histology (IHC)
78-93%
92-100%
$$
Sampling error
CMV culture
45-78%
89-100%
$$
1-3 week incubation
CMV -DNA
65-100%
40-92%
$$$
CMV IgM
100%
99%
$$
May be not present in
immunocompromised patients
CMV IgG
98-100%
96-99%
$$
4x increase between two separate
titers
CMV antigen
60-100%
83-100%
$
Blood & cerbrospinal fluid,
semiquantitative
Kandiel and Lashner 2006
Predictive Model for CMV Disease in IBD
Predictive
variable
OR
95% CI
p value Score
component
Refractory
disease*
4.24
2.21-8.11
<.001
14
Risk category for
CMV
IM exposure
1.95
1.05-3.62
<0.34
7
• ≥24 high risk
Age 31-53y
2.26
1.02-5.03
<0.35
8
Age ≥ 54y
2.69
1.20-6.02
• Moderate risk ≥
14<24
CS exposure
2.05
0.94-4.48
Fever
2.02
0.84-4.87
Endoscopic
ulcer UC
1.37
0.73-2.59
10
• Low risk < 14
Sensitivity and
specificity >85%
*Refractory disease required minimal or no improvement in symptoms after 14 days of oral CS, 7 days of
intravenous CS, 2 induction doses of a TNF antagonist, or after escalated dosing of a TNF antagonist.
McCurdy et al. 2014
Detection of CMV-DNA in Stool and Colon Biopsy and
Plasma – Quantitative PCR
1000000
CMV [Copies/ml]
100000
10000
Biopsy
1000
Stool
Plasma
100
10
1
0
1
2
3
4
Patient No.
5
6
Patient No. 1, 2 CMV DNA plasma, stool <500 copies, No. 4 stool test solidified, No. 5
Plasma test not done.
Herfarth et al. 2010
Relationship Between Cytomegalovirus (CMV) DNA Load in
Inflamed Colonic Tissue and Therapeutic Outcome
Cutoff
250 copies/mg of tissue
Roblin et al. 2011
CMV DNA Copies in Colonic Biopsies and Risk of
Colectomy in the Following 6 Months
p<0.03
p<0.04
100.0%
100%
87.5%
80%
60%
40%
50.0%
36.4%
20%
0%
n=7
n=4
n=6
All IBD<2000 All IBD >2000 UC <2000
copies/ml
copies/ml
copies/ml
n=4
UC >2000
copies/ml
Onyah et al. DDW 2014
Case
• CMV DNA PCR mucosal biopsy positive.
CMV DNA PCR plasma: positive.
H&E and immunohistochemistry (IHC) for CMV negative.
What now?
CMV-Colitis Therapy in IBD
Ganciclovir 5 mg/kg intravenously every 12 h
after 3–5 days, switch to oral valganciclovir for a total of 2to 3-wk.
Review in Am J Gastroenterol by Kandiel and Lashner 2006
Literature is equivocal about need for therapy, Meta-analysis does
not show effect. (Kopylov et al. 2014)
Problems:
No prospective studies.
Do we treat the reason of the exacerbation or only a
“innocent” bystander
Case
• Start valganciclovir 900 mg bid + steroid taper,
valganciclovir stop after 10 days due to leukopenia (1.6)
• 4 months later, clinical remission, but surveillance
colonoscopy shows still active inflammation and low grade
dysplasia on biopsy.
• Patient decides for colectomy and 2 stage IPAA.
Diagnostic and Therapeutic Algorithm for CMVColitis at UNC
IBD not responding to
steroids after 2-3 days Suspicion of CMV colitis
? Therapy if
• only biopsy CMV PCR+
• only plasma CMV + but low
replication
Flexible sigmoidoscopy
with biopsies
Therapy if
• H&E and/or IHC +
• CMV-DNA PCR biopsy and
plasma +
H&E, IHC, CMV-DNA PCR
biopsy qualitative,
+plasma CMV DNA PCR
qualitative and
quantitative
CASE 3
PENETRATING CROHN’S DISEASE
Penetrating CD
• 22 year old female with CD since 2010
• Presented with Abd pain, bloody stool
– Dx severe UC, colectomy/J pouch 2011
• 2012 first labial abscess (of several)
– Ileal biopsies with chronic ulcerating inflammation
– Extends >30 cm proximal to pouch
• Started IFX monotherapy
– Breakthrough Sx (bloody diarrhea) 7th wk between
infusions in June 2013
– Low trough -> To q 6 week Rx
2014 - Losing Response
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Fatigue, increasing diarrhea
CDTOX negative, CRP 2.8
Active ulceration on scope, CMV negative
Esoterix IFX level/Ab:
– IFX 36 mcg/mL
– Anti-IFX Ab 56 ng/mL
(REF <0.4)
(REF <22)
Options?
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Increase or decrease IFX dose?
Decrease IFX interval?
Add an immunomodulator?
Switch TNF inhibitor?
Change drug class?
Switched to ADA 160/80,
40 mg q week
Added Aza
Worsening fistulas
• 2 weeks later: recurrent Sx, 4T MR: V-shaped
tract extending from the inferior aspect of the
internal anal sphincter anteriorly to the skin of
both labia.
• How to treat fistulas?
– Short term?
– Longer term
Fistula Options?
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Change anti-inflammatory meds?
Antibiotics?
Setons?
Local Rx (doxycycline, APC)?
Diversion?
Case 4
Pain in Crohn’s Disease
Hans Herfarth, MD, PhD
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Case
40 yo female patient
• Diagnosis of Crohn‘s disease (CD) at age 24
Intermittent treatment with steroids and 5-ASA for 10 years
• CD flares up with severe colitis, steroid refractory. Initiation of
infliximab and 6-MP. Remission after 2nd infusion of infliximab.
• 3 months later diagnosis of fibromyalgia. No effects of pregabalin,
start of pain management by outside pain clinic.
Case 2 (cont'd)
• Now admission with increased diarrhea (8-10 BMs daily), nonbloody and severe abdominal pain (10 out of 10).
• Previous medication before admission:
- For CD: Infliximab q 8 weeks, last infusion 4 weeks ago and 6MP (1.2 mg/kg bodyweight).
- For fibromyalgia: Fentanyl patch 25 mcg/hr and
oxycodone/acetaminophen 7.5 mg/325 mg 3-4 tablets daily as
needed.
• Physical exam: No fever, abdomen soft, diffusely tender on deep
palpation, no rebound tenderness.
• After admission: Patient is on hydromorphone 4 mg iv q 4 hours
Possible Reasons for Recurrent IBD Symptoms
(Pain, Diarrhea)
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Flare
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Stricture, Abscess
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Infection (e.g. C. diff, CMV)
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Bacterial overgrowth
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Narcotic Bowel Syndrome
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IBS
Case 2 (cont'd)
Workup
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Laboratory: CBC, CRP, calprotectin normal
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CT-abdomen with oral contrast: Normal, no dilated loops,
no abscess
• Upper-GI endoscopy and colonoscopy:
Possible Reasons for Recurrent IBD Symptoms
(Pain, Diarrhea)
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Flare
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Stricture, Abscess
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Infection (e.g. C. diff, CMV)
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Bacterial overgrowth
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Narcotic Bowel Syndrome
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IBS
Use of Narcotics in Hospitalizations for IBD
117 patients with IBD (exclusion of postoperative pat. (up to 1 month) and
pat. with abscesses.
• 70. 1% receiving pain medications at admission ( median 12 mg in first
24 hours, median daily later on 7.5 mg/day.
• 7.7 % PCA pump
Risk Factors for Inpatient Narcotic Use
Odds ration
95% confidence
interval [CI]
Narcotics prior to admission
5.4
1.5 – 19.0
Smoking
4.3
1.2 – 15.6
Psychiatric diagnosis
2.2
0.4 – 11.6
Long et al. 2012
Diagnostic Criteria for Narcotic Bowel Syndrome
Chronic or frequently recurring abdominal pain that is
treated with acute high-dose or chronic narcotics and all of
the following:
• Pain worsens or incompletely resolves with continued or
escalating dosages of narcotics.
• Marked worsening of pain when the narcotic dose wanes and
improvement when narcotics are re-instituted (soar and crash).
• Progression of the frequency, duration, and intensity of pain
episodes.
• Nature and intensity of the pain not explained by a current or
previous GI diagnosis.
Grunkemeier et al. 2007
Detoxification Protocol
for Narcotic Bowel Syndrome (1)
Reduction of morphine dose
Treatment of anxiety
Treatment of withdrawal symptoms
Start of medications for long term control of abdominal pain
Physician – Patient Relationship
Days 1
2
3
4
5
6
7
8
9
10………..
Grunkemeier et al. 2007
Detoxification Protocol for Narcotic Bowel Syndrome (2)
Effective communication with the patient is essential.
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Explanation of rationale/benefit of stopping the narcotics
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Explanation of the withdrawal program.
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Affirmation of the patient’s pain and an explanation of the
underlying pathophysiology of NBS (i.e. altered motility and/or
visceral hypersensitivity).
• Total narcotic daily dose should be converted to morphine equivalents
and total drug dose be reduced by 10-33% q 24 hours.
• In inpatients setting administration of morphine as continuous
infusion (not PRN).
Grunkemeier et al. 2007
Detoxification Protocol for Narcotic Bowel Syndrome (3)
• Start of TCA (25-150 mg/qhs) or SNRI (30-90 mg. qd) for immediate and
long terms pain control and to help manage psychological
comorbidities.
• Mirtazepine (15-30 mg. qhs) can be considered instead of or in addition
to a TCA or SNRI if nausea is a prominent feature.
• For withdrawal symptoms clonidine (start with 0.1 mg bid)
• For anxiety benzodiazepine (1 mg q 6 hours)
• For constipation e.g. PEG 3350 17 g bid
Grunkemeier et al. 2007
Outcome after Discontinuation of Narcotics in IBD
Medically adherent
Surgically adherent
Mod/severe pain
None/mild clinical
symptoms
Narcotics
discontinued
n=22
100 %
Narcotics
continued
n=17
53 %
100 %
27 %
94 %
82 %
80 %
24 %
Hanson et al. 2009