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Vaccination Issues in a 24 Year Old w/Crohn's Starting Immunosuppressives

A 24-year-old Patient with Crohn's Disease Starting Immunosuppressive Therapy: Vaccination Issues to Consider

Sharmeel K; Wasan; Paul R. Skolnik; Francis A. Farraye

Clin Gastroenterol Hepatol. 2010;8(12):1016-1016. © 2010 AGA Institute

Clinical Scenario

A 24-year-old preschool teacher with a 3-year history of Crohn's disease (CD) presents to your office for a second opinion regarding the management of 4-week history of worsening abdominal pain and diarrhea. She has lost 8 pounds during this time. On physical examination, she has tenderness in the right lower quadrant. Colonoscopy is performed and reveals progression of her disease, with evidence of severe terminal ileitis and moderate extensive colitis. She notes that she has been compliant with her mesalamine regimen. Her father also has CD, maintained on 6-mercaptopurine (6-MP), and recently developed a severe episode of herpes zoster. After a long discussion, the decision is made to initiate therapy with an anti–tumor necrosis factor (anti-TNF) agent. She is concerned about infections and wants to know what she can do to minimize her risk.

The Problem

Current medical management of CD includes the use of various immunosuppressive therapies, including corticosteroids, immunomodulators (such as 6-MP, azathioprine, and methotrexate), and biologics (infliximab, adalimumab, certolizumab, and natalizumab). Although effective in treating CD, these medications also put patients at risk for various infections. As described in the case above, the patient's father developed herpes zoster while on an immunomodulator. Although the overall incidence of vaccine-preventable illnesses among inflammatory bowel disease (IBD) patients is unknown, case reports of patients developing fatal varicella or fulminant hepatitis while on immunosuppressive therapy have been described in the literature. Despite these severe events, many IBD patients are still not being adequately vaccinated. In a survey study of 108 gastroenterologists, the majority believed that the primary care physician was responsible both for determining which vaccinations to give the IBD patient (65%) and for administering the vaccine (83%). In this same study, gastroenterologist knowledge of the appropriate vaccinations for the IBD patient was also noted to be poor. In addition, there are patient factors that are barriers to vaccinations. In a survey of 169 patients, only 28% had regularly received the influenza vaccine, and only 9% had received the pneumococcal vaccine. Many patients are afraid of the side effects of the vaccine, think that the vaccine will make their IBD worse, or are skeptical as to whether vaccinations are effective at all. Educational programs on vaccinations directed to gastroenterologists who prescribe immunosuppressive agents and to patients receiving these medications are therefore crucial to improving vaccination rates and compliance. Recommendations for vaccinations should then be provided by the gastroenterologist to the patient and the primary care physician for appropriate administration.

Management Strategies and Supporting Evidence
Live Vaccines

The basic management strategy involves avoiding the live, attenuated vaccines in the immunosuppressed patient because of concerns about vaccine-related infections. The measlesmumps-rubella (MMR), varicella, and herpes zoster vaccines are the 3 most commonly administered live, attenuated vaccines. Because of the risk for prolonged viremia with the MMR vaccine, any patient who is anticipating immunosuppressive therapy within the ensuing 6 weeks should avoid MMR vaccination. Similarly, waiting at least 4–12 weeks between administering the varicella or herpes zoster vaccines and initiation of immunosuppressive therapy has also been recommended. In patients without a history of varicella exposure (or vaccination), or who do not have serologic evidence of immunity, who work in environments with a high risk of exposure to primary varicella infection, delaying immunomodulators and anti-TNF agents until a sufficient period has elapsed after vaccination with the live, attenuated vaccine should be considered after weighing the risks and benefits for each particular patient. Because the incidence of herpes zoster is higher in IBD patients than in patients without IBD, the immunosuppressed state must be carefully defined. In regard to the herpes zoster vaccine, the Advisory Committee on Immunization Practices states that patients on short-term corticosteroid therapy (<14 days), low doses of methotrexate (<0.4 mg/kg/week), or low doses of 6-MP (<1.5 mg/kg/day)/azathioprine (<3.0 mg/kg/day) are not sufficiently immunosuppressed to increase the risks associated with a live, attenuated vaccine, and as a result, the herpes zoster vaccine might be administered.

The anthrax, intranasal influenza, oral polio, smallpox, Bacillus Calmette–Guérin, oral typhoid, and yellow fever vaccines are the other live, attenuated vaccines that should be avoided in the immunocompromised IBD patient who might be traveling to endemic areas. Consultation with an infectious diseases travel medicine expert is indicated in these situations to counsel patients as to the advisability of travel or alternative methods of prevention (eg, the inactivated typhoid or influenza vaccines).
Inactivated Vaccines

The inactivated vaccines are considered to be safe for administration, regardless of the state of immunosuppression. Patients should therefore follow the recommended vaccine schedule for adults and receive the tetanus, diphtheria, pertussis, human papillomavirus (HPV), influenza, pneumococcal, hepatitis A, hepatitis B, and meningococcal vaccines as indicated.
Areas of Uncertainty

To understand why there is so much anxiety regarding vaccinating the IBD patient, it is important to briefly review the current data on the immunologic response mounted in this patient population. In studies including IBD patients, immunomodulators and anti-TNF agents are associated with a slightly diminished immune response to the influenza vaccine, but overall, a majority of patients develop protective antibody titers. Similarly, studies evaluating the 23-valent pneumococcal vaccine suggest that patients on combination immunosuppressive therapy with an immunomodulator and biologic agent have an impaired immune response compared with non-immunocompromised patients. Thus, although safe to administer while immunosuppressed, this impaired response suggests that the optimal time to administer the influenza and pneumococcal vaccines is before the initiation of any immunosuppressive therapy to maximize the chances of developing protective antibodies.

The data examining the serologic response to the hepatitis B vaccine demonstrate suboptimal titers in the IBD patient on long-term corticosteroids, immunomodulators, and/or anti-TNF agents. Checking post-vaccine titers is encouraged to determine whether the patient should be revaccinated with either twice the standard dose of hepatitis B or with the combined hepatitis A and B vaccine (as a result of the adjuvant-like effect of the hepatitis A vaccine).

Review of the literature concerning other immunocompromised populations, such as the transplant patient or those with systemic lupus erythematosus or rheumatoid arthritis, also suggests there might be a diminished response to vaccines, depending on the immunosuppressive medication regimen that is used. Although the response might be abrogated, a majority of patients are able to mount an immune response that might be diminished in magnitude; checking titers after vaccination in these instances to ensure a protective effect might be important. It is significant to note that in all these studies, the clinical activity of IBD was not worsened after vaccination. Larger studies are needed to further evaluate the immune response among IBD patients, assess the need for confirmatory titers after vaccinations are administered, determine the duration of the immune response to each vaccination, and establish whether subsequent booster doses are required. We suggest that the optimal time to vaccinate the IBD patient is during the initial office visit, which would often allow for sufficient time for safe administration of live, attenuated vaccines before the initiation of immunosuppressive therapy.

Published Guidelines

Guidelines for vaccinating the IBD patient were first published in 2004. On the basis of a review of the routine immunization schedules as well as the data on vaccinating other immunocompromised populations, the authors recommended adhering to the routine immunization schedules for the general population, with the exception of the schedule for the live, attenuated vaccinations. Subsequent literature has supported these recommendations and has also made note of the suboptimal serologic response to the inactivated vaccines, depending on the medications that the patient is taking. Thus, the expert consensus is to immunize the IBD patient with the inactivated vaccines (tetanus, diphtheria, pertussis, HPV [female patients 9–26 years old], influenza, 23-valent pneumococcal, hepatitis A, hepatitis B, meningococcal [at-risk individuals]), to consider immunization with the live, attenuated vaccines (MMR, varicella, herpes zoster [age >60]) before initiation of immunosuppressive therapy, and to consider checking postvaccine titers for immunizations such as hepatitis B to determine whether revaccination is indicated.

Recommendations for this Patient

Our approach for this patient would be to take a thorough vaccination history during her first office visit, as depicted in Figure 1. She notes that she was vaccinated against MMR, varicella, and hepatitis B. Because she is certain about her MMR history, no further testing would be needed with regard to this live, attenuated vaccine. If her MMR status was unknown, serologic testing should be performed to assess her immune status.
Her profession as a school teacher puts her at risk for exposure to varicella. Titers for varicella and hepatitis B were checked before starting her job, and she was found to be immune to varicella but not to hepatitis B. Thus, administration of the live, attenuated vaccines (MMR and varicella) before initiation of immunosuppressive therapy is not an issue. If she had not been immune and if she was not acutely ill, her high risk for exposure would make it reasonable to vaccinate her against varicella and postpone anti-TNF therapy for at least 4 weeks, although some experts would suggest waiting 12 weeks. In this scenario, however, the patient has active CD with evidence of weight loss, suggesting a more urgent need to begin immunosuppressive therapy. Thus, a thoughtful discussion with the patient should review her risks of acquiring varicella against the risks of worsening CD if therapy were to be delayed. In this particular patient, we would not recommend a delay in initiating effective treatment for her CD. She should also be made aware that if she were to be exposed to active varicella, post-exposure prophylaxis with varicella zoster immunoglobulin is recommended.

Herpes zoster vaccine would not be indicated in a 23-yearold patient because this vaccine is recommended for patients 60 and older; however, herpes zoster vaccine should have been administered ideally before initiation of 6-MP in her 64-year-old father. As per the 2008 Centers for Disease Control and Prevention guidelines on herpes zoster, given his low dose of 6-MP (<1.5 mg/kg/day), he is also a candidate to receive the vaccination while taking this medication. Clinical trials have indicated that the patient's father should have been treated with acyclovir, famciclovir, or valacyclovir when he developed the rash because these agents decrease the severity and duration of the pain from herpes zoster and reduce the risk for development of post-herpetic neuralgia. His daughter, who is susceptible to varicella infection, should avoid close exposure to her father. If she had been exposed to her father's open lesions, prophylaxis with varicella zoster immunoglobulin would be recommended.

She also notes that she was recently immunized against hepatitis A before traveling abroad. Because she has no detectable antibodies to hepatitis B, despite recently having received the hepatitis B vaccine series, we would recommend that she receive another series of hepatitis B vaccination with twice the routine amount of antigen. If she had not been immune to hepatitis A, instead of administering hepatitis B vaccine with twice the antigen concentration, we would have recommended proceeding with the combination A/B vaccine (Twinrix; Glaxo-SmithKline Biologicals, Rixensart, Belgium).

Her age and gender suggest that she should receive the HPV vaccine, particularly because of some data suggesting an increased risk for cervical dysplasia in women treated with immunosuppressive therapy. She notes that she has not yet received the influenza vaccine or the H1N1 influenza vaccine and notes that she has never taken the pneumococcal vaccine. All should be administered by using the inactivated seasonal and H1N1 influenza vaccines and not the live intranasal influenza vaccines.


* Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, 2010. Ann Intern Med 2010;152:36–39.
* Harpaz R, Ortega-Sanchez IR, Seward JF, et al. Prevention of herpes zoster recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2008;57:1–30.
* Lu Y, Jacobson DL, Ashworth LA, et al. Immune response to influenza vaccine in children with inflammatory bowel disease. Am J Gastroenterol 2009;104:444–453.
* Mamula P, Markowitz JE, Piccoli DA, et al. Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2007;5:851–856.
* Melmed GY. Vaccination strategies for patients with inflammatory bowel disease on immunomodulators and biologics. Inflamm Bowel Dis 2009;15:1410–1416.
* Melmed GY, Ippoliti AF, Papadakis KA, et al. Patients with inflammatory bowel disease are at risk for vaccine-preventable illnesses. Am J Gastroenterol 2006;101:1834–1840.
* Melmed GY, Agarwal N, Frenck RW, et al. Immunosuppression impairs response to pneumococcal polysaccharide vaccination in patients with inflammatory bowel disease. Am J Gastroenterol 2010;105:148–154.
* Sands BE, Cuffari C, Katz J, et al. Guidelines for immunizations in patients with inflammatory bowel disease. Inflamm Bowel Dis 2004;10:677–692.
* Viget N, Vernier-Massouille G, Salmon-Ceron D, et al. Opportunistic infections in patients with inflammatory bowel disease: prevention and diagnosis. Gut 2008;57:549–558.
* Wasan SK, Baker SE, Skolnik PR, et al. A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol 2010;105:1231–1238.
* Wasan SK, Coukos J, Farraye FA. Gastroenterologist knowledge and behavior in vaccinating the inflammatory bowel disease patient. Gastroenterology 2010;138(Suppl 1):S-534.
Something my rheumatologist is thankfully on top of. :) I had to get a flu shot when I entered his care, and will be required to get a pneumonia shot if put on a TNF inhibitor (which is very likely). I'm otherwise up to date on vaccinations, though will have to have another TB test among other things before I can start a biologic.
Thanks, David. Very informative post. It seems there's always something that I hadn't realized I need to be aware of with the Crohn's.



Super Moderator
Thanks for posting David. It's good to know the kids GI has all bases covered, phew!

Dusty. :)
What a very informative post and quite a coincidence. I am in the uk and now on azathioprine and prednisolone and will be when I eventually get back to work. I work in healthcare and will be exposed all the time to shingles and chicken pox and all other infectious disease which I will not be able to avoid. So I decided to be proactive and find out what I should do and what my risk was/how to reduce risk - do I need to wear a mask, can I still get infected if had previous infection as I am immununosupressed etc etc.

Gastro and gp didn't know so I rang occupational heath at local hospital ...who didn't know and advised I ring the Health Protection agency (in the uk they run all the infectious disease surveillance/ flu pandemic programmes etc and have virologists etc in the team).

They said they would get back to me with some answers....after 5 days they rang me yesterday...they are very sorry they can't tell me how much at risk I am and what I should do - they've not been asked this before- why don't you ask your clinician !! but I have!!....I guess I'll just have to see what happens!
I found this very helpful because I've just started a new job as a police cadet and my employer wanted to check my hep B titer levels. I came back as being negative (meaning I have no immunity) so now they'd like to vaccinate me.

I'm a pretty interesting case though because I take Humira weekly and 250mg of Imuran a day. This study suggested to me to go ahead and try the Hep B series even though I could not respond because of my degree of immunosuppression.

I just get so nervous about vaccines... sigh.
I get nervous too because there is no research in how an autoimmune person will react to vaccines. Vaccines have never been studies in the autoimmune population, and they contain adjuvents which are designed to create a hyper immune response to the antigen. There are many studies and cases where vaccines are actually linked to autoimmunity.

Here is a list of studies, and meta analysis' if you are interested.

http://www.greenmedinfo.com/search/node/vaccines autoimmune
I never comment in these threads but I do read them and I appreciate that you post them, so I thought I should say that.
I just wanted to follow up here. I asked my GI nurse about getting the Hep B vaccine and she seemed surprised that I had already had the series and my Hep B titers still came back with negative immunity. She said there's a small percentage of the population who can not become immune to it and I may be one of them. She suggested I get a booster and pull my titers again, and if they aren't positive then I probably can't do much about it.