I was recently consulted by our ER for the evaluation of a 6 year old girl, who presented with 1 week of tactile fevers, abdominal/back pain, scleral icterus, fatigue and malaise. Her physical exam was notable for scleral icterus and a firm liver, palpable 4cm below her right costal margin, an enlarged spleen palpable 3-4 cm below left costal margin, and no ascites. While obtaining her history, we learned that at 16 months of age,she had been diagnosed with Immune Thrombocytopenic Purpura (ITP), which initially responded to treatment with steroids and IVIG. She "relapsed" and at age 4 years, she required 4 doses of Rituximab over one month, which induced remission. In the ER, she had high liver function tests, a high GGT and bilirubin.
We began an extensive evalaution for the cause of her liver disease, incluing tesitng for viral hepatitis, anatomic abnromalities (using an abdominal ultrasound)and testing for alpha-1-antitryspin deficiency. All of these were negative. In the process of evaluating her for auotimmune hepatitis, we noted than her total immunoglobulin, which is usally high in autoimmune hepatitis, was quite different than expected. Her immunoglobulins were: IgA < 8 ml/dl (↓) , IgG- 71 mg/dl (↓), IgM- 3500 mg/dl (↑).
We subsequently diagnosed her with HyperIgM syndrome. Therapy with steroids was initiated at 1 mg/kg, with normalization of her liver symptoms and AST/ALT. HSe also started treatmetn with every 2 week IVIG. Her immunology work -up thus far has revealed normal absolute B cell numbers, ↓ switched memory B cells, normal expression of CD40 and CD40 ligand, and normal sequencing of AICDA gene. Unforutnately, further genetic testing has been denied by her health insurance company.
Currrently, the ongoing controversy in her care remains if she actually has a Rituximab induced hypogammaglobulinemia with increased IgM versus a a true HyperIgMGM variant.
Here are some greatrefernces that pertain to this disease:
1. Davies, E.G. et al. Br J Haematol. 149(2): p. 167-80.
2. Durandy, A.,et al.,Immunol Rev, 2005. 203: p. 67-79.
3. Goddard, E.A., et al., J Pediatr Gastroenterol Nutr, 2000. 31(3): p. 317-20.
Thank you for putting this case up; I find this fascinating and it's great to see the clinical representation of the diseases we learn in class. I wonder: did they not already look at her immunoglobulin levels when she was admitted or is that something that occurs secondary to the suspicion? Both diseases ITP and HyperIgM both exhibit the low levels of platelets which could help explain why they were confused. The time periods between admissions also seem very long (to me at least), I do also wonder why that was...
ReplyDeleteAgain, thanks for posting the case.
Wow! This is so amazing to me as well. How symptoms could look like one diagnosis and then be determined to be another after further negative testing. I wonder, how would you even go about differentiating between Rituximab induced hypogammaglobulinemia with increased IgM against a HyperIgMGM variant. Are there more tests that can be conducted in order to differentiate between the two diagnoses the patient is exhibiting? I am interested because I had a cousin who had Retuximab induced hypogammaglobulinemia and have always been curious what was involved in this diagnosis. Also, what is the lifelong prognosis and treatment for someone with these disorders? How disruptive is it to a normal, healthy lifestyle and what life changes must be taken? Thank you so much for sharing this clinical take on immunology, as it really helps me to relate real-life experiences to classroom discussions.
ReplyDeleteAlso, I found a really interesting article dealing with Rituximab and its use in reduction of a Th17 mediated cell response. I thought this was interesting in relating to your post, as this lack of Th1 or 17 class switching ability would leave a vast majority of IgM production. The hyperlink is below.
http://onlinelibrary.wiley.com/doi/10.1002/art.30314/pdf
Rituximab is a chimeric monoclonal antibody against CD20, a B-cell specific marker. So it is odd to find it used, and effective, in conditions which are pretty well established as T cell-mediated (rheumatoid arthritis, multiple sclerosis). No one is quite sure why it works! But there is a growing feeling that at least some B cells are "regulatory" like Tregs, and make immunomodulating cytokines. Of course, they can also present antigens to the T cells.
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