[PAGID] complications in XLA patient

[Conley, Mary-Ellen]

Hello Ashish,
Your patient may have more than one process going on.  The history of slowly progressive leg ulcers starting after 10 years of age has been seen in several XLA patients.  I have seen two patients and several have been reported.  It is caused by a "flexispira-like or Helicobacter-like" organism that is very difficult to culture (J Clin Micro 37:2439, 1999; Clin Inf Dis, 2001 ).  The culures take 4-6 weeks to grow, if they grow.  We had a patient who had this infection and our lab was not able to get the bacteria to grow.  The infection is indolent but very difficult to eradicate.  The people at the NIH (Steve Holland) recommend IV merepenem for a year as well as leviquin and azithromycin. One of our patients had a relapse in blood cultures after being taken off IV antibiotics after 6 months of therapy.  I am pretty confident that that's what was going on intially in your patient.  The immunosuppression may have supressed the symptomatic inflammation without getting rid of the organism.

I don't know of patients who have had liver involvement with these organisms.  That doesn't mean it can't happen.  Alternatively, there may be a component of autoimmune disease following infection.  I think the inflammatory bowel disease seen in some patients with XLA is secondary to a GI infection that is not well controlled and elicits an overactive T cell response.  B cells in the gut produce IL-10, a valuable anti-inflammatory cytokine.
Mary Ellen





Mary Ellen Conley, MD
Department of Immunology/ Mail Stop 351
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, TN 38105-3678
FAX  901-595-3977
TEL  901-595-2576


-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Ashish Kumar
Sent: Thursday, February 12, 2009 9:46 PM
To: Pagid
Subject: [PAGID] complications in XLA patient

I need help with a very complex patient. It's a long story so please bear with me.

- 24 year old Vietnamese male with X-linked agammaglobulinemia
- was on monthly plasma infusions in Vietnam until 2003 when he came to the US and was switched to IVIG (BTK mutation was confirmed as well)
- developed ulcers on legs at age 14  that spread (ulcer spanned ankle to knee on right leg) and became chronic
- after multiple biopsies and cultures, chronic non-healing ulcers diagnosed as pyoderma gangrenosum; immune suppression initiated 4 years ago with prednisone+MMF with gradual but dramatic response; at one point ulcers were completely healed
- one episode of ascites 3 years ago, with no clear etiology; fluid drained and did not recur
- recently traveled to Vietnam for a month (large dose of IVIG prior to
departure)
- upon return, leg ulcers noted to have regressed to original state of 2003, along with significant ascites
- evaluation including paracentesis, liver biopsy, viral PCRs reveal no etiology; ascites fluid noted to be transudate, liver biopsy showed neutrophil infiltration with regenerative nodular hyperplasia
- prednisone resumed for PG with mild improvement in leg ulcers; MMF not restarted because he was noted to have low WBC and platelets (30k)
- 2 weeks later developed fever, recurrence of massive ascites followed by profuse watery bloody diarrhea; 4 litres of bloody watery stool in a one day
- GI endoscopy showed duodenum heavily infiltrated with lymphocytes, mucosa of duodenum completely denuded with significant apoptotic bodies
- pathology consistent with grade III-IV GVHD; also noted to have several esophageal varisces on endoscopy although none actively bleeding
- after ascitis fluid was drained, massive splenomegaly was palpable, confirmed by abdominal CT, which showed multiple splenic infarcts
- underwent splenectomy with normalization of platelet count; spleen pathology just showed multiple infarcts

The ascites and splenic infarcts can be explained by portal hypertension caused by regenerative nodular hyperplasia of liver. But what caused that - the same dysregulated T-cells that caused the GVHD-like gut pathology? We cannot find any infectious agents anywhere, so do we initiate immune suppression? If so, with what - he developed watery diarrhea 2 weeks after Prednisone was initiated (1.5 mg/Kg). In the BMT world, steroid resistant GVHD would be treated with ATG or sometimes Infliximab/Remicaid. The symptoms began 2-3 weeks after he returned from Vietnam, so a tropical infection is less likely since the incubation period would be too long. He has puzzled all the specialists - GI, tropical medicine, pathology. Any ideas?

Thanks!

Ashish Kumar

--
Ashish Kumar, MD, PhD
Assistant Professor
Pediatric Hematology/Oncology/Blood and Marrow Transplantation University of Minnesota 420 Delaware St. SE Minneapolis, MN 55455
Ph: 612-626-2778
Fax: 612-626-4842


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