Prevention and treatment of opportunistic infections in IBD: Case studies

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.


Long MD et al. Aliment Pharmacol Ther. 2013; 37: 420-9.


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 anti-TNF 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


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


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


ACIP Allowed Immunosuppression

• Short-term corticosteroid therapy (<14 days); low-to-moderate 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 6-mercaptopurine (<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


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.

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Incidence of PCP in IBD and non-IBD Populations

Long MD, et al. Inflamm Bowel Dis. 2013 Apr;19(5):1018-24

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 comorbiditiesAdalimumab/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- 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 right-sided 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: Initial PML diagnosis (day 6). B: Extention of PML (day 53). C: Last follow-up MRI with cerebral involution (day 167).

A B C

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

Documents

Prevention and treatment of opportunistic infections in IBD: Case studies