Morning Report

Morning Report
November 21 2011
John Nick Gaetano
Discussant: Dr. Rubin
Please Swipe!

MKSAP
A 29-year-old woman is evaluated for a 6-week
history of bright red blood per rectum along with
mucoid stool and tenesmus. She has two or three
bowel movements a day. The patient is otherwise
healthy and takes no medications; her parents and
two siblings are alive and well.

MKSAP
On physical examination, the temperature is 36.8
°C (98.0 °F), the blood pressure is 110/76 mm Hg,
the pulse rate is 76/min, and the respiration rate is
12/min. There is no scleral icterus. The abdomen is
soft and not tender or distended with normal bowel
sounds. Rectal examination reveals red blood in the
rectal vault with normal rectal tone and no palpable
masses.

MKSAP
Laboratory studies, including serum C-reactive
protein and erythrocyte sedimentation rate, are
normal. Ileocolonoscopy shows mild to moderate
erythema from the anal verge to 10 cm; the rest of
the colon and terminal ileum are normal. Biopsy
specimens show mildly active chronic colitis in the
rectum.

MKSAP
Which of the following is the most appropriate
therapy for this patient?
A. Azathioprine
B. Infliximab
C. Mesalamine (topical)
D. Metronidazole
E. Prednisone

Please make your selection...
A. Azathioprine
B. Infliximab
C. Mesalamine (topical)
D. Metronidazole
E. Prednisone
20% 20% 20% 20% 20%
A. B. C. D. E.

MKSAP
Ulcerative colitis can be classified by both extent and
severity of disease, and treatment is guided by both factors.
This patient has mild to moderate ulcerative proctitis, with
disease limited to the distal rectum. Therefore, the best
treatment would be local therapy with suppositories or
enemas. Options include cortisone foam and mesalamine
or corticosteroid suppositories for proctitis and
hydrocortisone or mesalamine enemas for left-sided colitis.
Topical mesalamine is more effective than topical
corticosteroids, and almost half of the dose of topical
corticosteroids may be absorbed systemically, leading to
adverse long-term side effects. Maintenance of remission
can be achieved with topical mesalamine.

HPI
36 M with a h/o AML s/p stem cell transplant 3 weeks ago
presents to the ED with nausea, vomiting and diarrhea.

HPI
36 M with a h/o AML s/p stem cell transplant 3 weeks ago
presents to the ED with nausea, vomiting and diarrhea.
• 10 day of chills, nausea/vomiting, no measured temp
• Not keeping down food or liquids
• 10 watery BM/day last 2 days, progressively worse over last
week, small amount each episode, no blood, no distinct
odor, no fecal incontinence, decreased with decreased PO
• Cramping abd pain lasting ~20 sec, comes and goes,
improved with BM
• Burning substernally with food
• No melena, no hematochezia, no hematemesis
• No urinary sxs
• No rash
• Reports compliance with all meds

History
PMHx
• AML, flt-3+, dx 6 months
ago. Induction Doxarubicin
and Cytarabine, HIDAC
consolidation 5 mo prior
• Matched unrelated donor
stem cell transplant 3
weeks prior, d/c from
hospital 2 days ago
• VRE bacteremia/line
infection during chemo
Medications
• tacrolimus 1mg q12
• valacyclovir 2g q6
• voriconazole 200mg bid
• Bactrim ppx
• Zofran prn
• Vicodin
Social Hx
• Works for Airline, travels to
China frequently, last time
10 months ago.
• No tobacco, no EtOH, no
illicit drug use

Physical Exam
Temp 36.5, HR 142, BP126/77, RR 18, PaO2 99% on RA
Gen: lethargic, responds appropriately to questions, can give
very precise history, oriented x3
HEENT: Anicteric, Dry MM, No oral ulcers, no exudates, no
erythema, no LAD.
Cardiac: Tachy, regular, no murmurs/rubs, flat neck vein
Lungs: CTAB
Abd: Soft, non-tender, no distension, hyperactive BS, no
organomegaly, no succusion, rectal exam deferred.
Ext: warm and dry without erythema, without edema.
Skin: no rashes, no purpura, no peticchiae
Neuro: no deficits

Differential?

Acute Diarrhea - Differential
Infectious (~90%) Non- Infectious
Viral Infection
• Rotavirus
• Norwalk
• Adenovirus
• HSV
• CMV
Bacterial Infection
• Shigella
• Salmonella
• Camplobacter
• E. Coli
• C. difficile
• Staph Aureus
• MAI
Protozoa
• Giardia
• Cryptosporidium
• Microsporidium
Medications
• Antibiotics
• Antiarrhythmics
• Anti-depressants
• NSAIDS
• Laxatives
Ischemic Colitis
Diverticulitis
Ingestions / Withdrawal
Graft Versus Host Disease
Acute Episode / Presentation IBD

Diarrhea – an Acute Approach

Initial Labs?

Initial Labs
8.1
1.2 68
76N 4L 14M ANC 920
6.5 4.0
0.3 0.3
38 63
284
133
3.2
AG 12
99
22
24
1.0
91
INR 1.2
UA normal, trace ketones
8.7
4.5
1.4
CXR unremarkable
EKG sinus tach, otherwise nl

Management, further workup?
Acute Diarrhea Work up*
• If yes to any: Severe dehydration, duration > 5 days,
mucus/pus/blood in BM, abd pain, recent travel, recent abx
o Check fecal leuks, FOBT, C.diff
• Neg fecal leuks, neg FOBT
o Stool O&P x 3
Pos O&P: parasitic infection
Neg O&P: Med-induced (abx associated), viral,
enterotoxic bacteria
• Pos fecal leuks or pos FOBT
o Stool Cx +/- colonscopy/flex sig
Pos Cx: Cytoxic or invasive bacteria
Neg Cx and positive endoscopic findings/bx: IBD,
radiation, ischemia, GVHD
• Pos C.diff: pseudomembranous colitis
*Gastroenterology 1999; 116:1461-63

More labs, studies
HR improves with IVF, now 70's
EBV IgG 1:640, IgM

Diarrhea
+ Abd pain, > 5 days
• Neg fecal leuks, neg FOBT
o Stool O&P x 3
Pos O&P: parasitic infection
Neg O&P: Med-induced (abx associated), viral,
enterotoxic bacteria
• Pos fecal leuks or pos FOBT
o Stool Cx +/- colonscopy/flex sig
Pos Cx: Cytoxic or invasive bacteria
Neg Cx: correlate with endoscopic findings/bx: IBD,
radiation, ischemia, GVHD
• Pos C.diff: pseudomembranous colitis

More labs, studies
Colonoscopy
Terminal ileum appeared normal. A patchy area of mildly
congested, erythematous and eroded mucosa was found from
sigmoid to cecum. The rectum was involved with these
changes, but less so.
Impression: Non-specific colitis, but likely represented GVHD

Graft Versus Host Disease -
Presentation
• Acute GVHD defined as onset of sxs w/n 100 days of SCT
• Classic presentation is abd cramps, diarrhea, rising bilirubin
and maculopapular rash
• Rash is most common initial sign, can range from sunburnt
only on the neck to bullous lesions covering the entire body
• Liver is the next most common site of involvement,
manifesting as abnormal LFT's, with bili and alk phos rising
first. Reflection of damage to bili canuliculi leading to
cholestasis.

Graft Versus Host Disease -
Presentation
Intestinal manifestations
• Cramping abd pain with diarrhea.
• Severity determined by volume of diarrhea, which can
exceed 10 liters per day
• Frequently begins as watery diarrhea, can become bloody.
Not unusual to require transfusions.
• Ileus can become problematic if narcotic
Upper GI manifestation
• One study characterized GVHD in the upper GI as anorexia.
dyspepsia, food intolerance, nausea and vomiting (biopsy+)
• Upper GI sxs are more responsive to immunotherapy than
lower GI sxs

Graft Versus Host Disease - Diagnosis
• Can be made clinically if common presenting sxs are
present
• Histology is helpful if confirmation is needed
o Typically, GVHD shows intracryptal apoptosis in 90% of
biopsies. Most reliable indicator on path.
• Biomarkers including IL-2, IL-8, TNF receptor-1 can aid in dx
at the onset of sxs and provide prognostic information
independent of severity
• Graded 1-4, 1 being mild, and 4 being life threatening.
Shidom et al. 2003 BMC Gastro enterol;3;5

Pathology

Hill GR, Ferrara JLM. The primacy of the gastrointestinal tract as a
target organ of acute graft-versus-host disease: rationale for the use of
cytokine shields in allogeneic bone marrow transplantation. Blood
2000;95:2754–2759.

GVHD - Treatment
• Steroids are used to treat acute clinical GVHD
• T-cell Immunosuppressives
o Cyclosporine - inhibits IL-2, renal toxicity
o Tacrolimus inhibits IL-2, renal toxicity, neurotoxicity, target
trough for GVHD is 10-30
o Sirolimus - inhibits IL-2 transcription, more GI side effects
than tacro
o Mycophenolate - inhibits purine synthesis, key for T-cell
activation, GI toxcity, marrow suppression, black box:
progressive multifocal leukoencephalopathy.
• Anti-thymocyte thyroglobulin
• IVIg
• Hydroxychloroquine - chronic GVHD, eye side effects
• TNF-a inhibitors show 70% reduction of acute GVHD in
animal models

Our patient
Supportive treatment
Steroid burst
Diarrhea improved with steroids and therapeutic tacrolimus
levels
However...
2 years later presents with persistent non-bloody, diarrhea for 2
weeks, bloating and abdominal pain with bowel movements.

Our patient
Supportive treatment
Steroid burst
Diarrhea improved with steroids and therapeutic tacrolimus levels
However...
2 years later presents with persistant non-bloody, diarrhea for 2 weeks,
bloating and abdominal pain with bowel movements.
Had been weaned from all medications 1 year prior. Last episode of
neutropenia 1 year ago.
Laboratory work-up unrevealing. No evidence of immunosuppression.

Repeat Colonoscopy
Diffuse moderately erythematous, eroded and vascular-pattern-
decreased mucosa was found from rectum to cecum.
Biopsies:
Terminal ileum - Mod active chronic ileitis, will ill-formed
intramucosal granulomas
R Colon, L Colon - Mod active colitis with epithelioid
granulomas
Recto-sigmoid - Mild to mod active colitis
Comment: Findings likely represent inflammatory bowel dz
(favor Crohn's), although a prolonged infectious enterocolitis
should be ruled out.

Crohn's colitis after stem cell transplant
vs. chronic GVHD?
Auto-immune diseases have potential to be treated with SCT,
but is the stem cell transplanted population at greater risk of
acquiring auto-immune disease?
• Late complications well-documented, although acquisition
of auto-immune disease not among them.
• Chronic GVHD is common, reported incidence between 40-
70%*
• Among patients with small bowel and colonic disease,
chronic diarrhea, malabsorption, fibrosis of the submucosa,
and sclerosis of the intestine may be observed.
• Unclear if granuloma formation without overt apoptosis
could be seen with chronic GVHD. Not typical.
*Blood. 2010 Oct 28;116(17):3129-39

Crohn's colitis after stem cell transplant
vs. chronic GVHD?
Our patient responded well to mesalamine. Patient was no
longer on tacrolimus or any other medication.
All symptoms completely resolved within a week of starting
treatment.
Seen 7 months after starting treatment. Had 2 episodes of
diarrhea, cramping and bloating, occurred two days after
running out of mesalamine each time, and resolved
completely upon restarting.

Crohn's colitis after stem cell transplant
vs. chronic GVHD?
Patient received non-myeloablative allogenic stem cell
transplantation for Hodgkin’s
Developed colitis, no infectious cause identified, pathology
consistent with Crohn’s
Responded to hydrocortisone and mesalazine
Donor had NOD2/CARD15 polymorphism

Take Home Points
• Understand the differential in diarrhea in the
immunocompromised
• Tailor your work-up of acute diarrhea based on symptoms
and clinical signs.
• Recognize the signs and symptoms of GVHD
• Understand the pathogenesis of GVHD and the associated
treatments

Chronic Diarrhea - Differential
Inflammatory (fever, hematochezia,
abd pain)
• Infectious
• IBD
• Radiation enteritis
• Ischemic colitis
• GVHD
Osmotic (decrease w fasting)
• stool osm gap > 50
• Medications (antacids, lactulose,
sorbitol + many more)
• Antibiotic associated (decrease
fermentation of CHO to organic
acids by normal flora, net decrease
H20 absorption)
• Lactose intolerance
Secretory (no change with fasting, normal
stool osm gap)
• Hormonal (neuroendocrine tumors,
thyroid dx, Addison's, hyperPTH, DM)
• Laxative abuse/stimulants
• Colitis (diverticulitis, collagenous, IBD)
Malassimalation (inc. fecal fat, gap>50)
• celiac, tropical sprue
• whipple's dz
• panc insufficiency
• Bacterial overgrowth
• Short bowel syndrome
Motility/Functional
• IBS
• Rheumatologic (scleraderma)