[CIS PIDD] [cis-pidd] CVID, hyper-eosinophilia, lymphadenopathy

[Routes, John]

Zach
Agree with James===we now have biopsy results on 15 or so patients and are in the process of submitting a paper on this—-granuloma are present in nearly all cased (one case w/o) BUT it depends on how many sections you look at and the experience of the pulmonary pathologist. Although it sounds like you are describing follicular bronchiolitis (present in every patient we saw) can’t be sure—anyway, I believe this is very likely  GLILD-=if yo want a second opinion  suggest you contact/send block to Dr. Arjun Rao at MCW, the pulmonary pathologist who reads our open lung biopsies —-=since it is T cell predominant as you describe it, I think it would be a mistake to just treat with rituximab—-we have had excellent responses to RTX/AZA with clearing  or near clearing of the infiltrates in many cases—-we substitute MMF if TPMT deficiency is present (we genotype prior to starting)—-guess I am less concerned with eosinophilia as it is not that high—
Jack


John M. Routes, MD
Chief, Section of Allergy and Clinical Immunology
Co-Director, Clinical and Translational Science Institute of Southeast Wisconsin
Professor of Pediatrics, Medicine, Microbiology and Molecular Genetics
Department of Pediatrics
Children's Hospital of Wisconsin
Medical College of Wisconsin
9000 W. Wisconsin Ave.
Milwaukee, WI  53226-4874
Phone: Office 414-266-6840
Fax: 414-456-6487 (Clinical)
Fax: 414-456-6323 (Laboratory)
Email: jroutes at mcw.edu<mailto:jroutes at mcw.edu>





On Dec 12, 2013, at 7:53 AM, Zachary D. Jacobs, MD <zjacobs.md at gmail.com<mailto:zjacobs.md at gmail.com>> wrote:

Thanks to everyone so far for the very helpful information.  The hyper-eosinophilia along with a relatively stable follicular bronchiolitis has been present for the past seven years or so.  I have only been following him for the past two years, and my work-up has been hampered by the fact that getting him to agree to any study is like pulling teeth.  He felt well so didn't want to do anything about it. It has only been the past several months where I have been able to start to piecemeal together on him a more complete work-up and everything has accelerated in the past weeks with the development of the pulmonary hypertension.  I have not tested for sIL2R.  Where would I go for sequencing of PIK3CD?

Thanks,

Zach


On Thu, Dec 12, 2013 at 12:50 AM, Klaus Warnatz <klaus.warnatz at uniklinik-freiburg.de<mailto:klaus.warnatz at uniklinik-freiburg.de>> wrote:
HI,

I agree with what has been stated before. granulomatous disease may not be evident on biopsy and possibly also not present in ILD in your patient.
Do you have a follow up of sIL2R ? did I understand correctly that the eosinophilia developed two years ago? If you are replanning bronchoscopy anyway I would check again for pathogens and for eosinophils in the BAL.
Given the increased CD21low cells I would consider RTX because we find these cells often in the BAL of these patients (obviously not knowing whether these cells are part of the pathophysiology). Steroids I would also use.
Have you considered PI3K def in the patient?
I also think that this patient runs a higher risk for lymphoma.

best regards (could you give us an update on the further course, please?)

klaus
Prof. Dr. med. Klaus Warnatz

UNIVERSITÄTSKLINIKUM FREIBURG
University Medical Center Freiburg
Center for Chronic Immunodeficiency
Division of Rheumatology and Clinical Immunology

Tel: +49-761-270-77640<tel:%2B49-761-270-77640> / FAX -71000 / Pager: 12-7100

Breisacher Str. 117, 79106 Freiburg, Germany
klaus.warnatz at uniklinik-freiburg.de<mailto:klaus.warnatz at uniklinik-freiburg.de>
http://www.uniklinik-freiburg.de/cci

Am 11.12.2013 um 21:55 schrieb Verbsky, James:

Zach

I think you are dealing with GLILD (sarcoid like lung disease in CVID).  Follicular bronchiolitis, lymphocytic interstitial pneumonia, and granulomatous disease can all be seen in this.  Actually Charlotte Cunningham-Rundles last series looking at lung pathology in CVID did not show granulomas.  My guess is there is some sampling error or clinical variability, but I would not let the lack of granuloma skew away from this diagnosis.  Treatment is controversial.  Jack Routes has a small series on Rituxan/Imuran.  Charlottes paper had a case of rituxan.  Others have used cellcept.  I would argue this person needs more than steroids.
Best

James


James W. Verbsky M.D./Ph.D.
Associate Professor of Pediatrics and Microbiology
Medical College of Wisconsin
Milwaukee, WI
414-266-6701<tel:414-266-6701>



From: Zachary D. Jacobs, MD [mailto:zjacobs.md at gmail.com<mailto:zjacobs.md at gmail.com>]
Sent: Wednesday, December 11, 2013 10:29 AM
To: CIS-PIDD
Subject: [cis-pidd] CVID, hyper-eosinophilia, lymphadenopathy

Hello all,

I am hoping for some help in a case.  He is a man with CVID who I have been following for the last couple of years.  Here is the rundown:

•         Currently he is a 39 year-old man with CVID, diagnosed at the age of 15.  He was  having recurrent sinopulmonary infections at the time and responded well to IVIG when started.  Currently receives he 55 grams IV every four weeks with troughs in the 800 – 900 mg/dl range.  He has undetectable IgA with normal IgM in the 100-150 mg/dl range.
•         Age 26, developed AIHA.  Treated with splenectomy and corticosteroids.  Was also noted to have persistent lymphadenopathy at that time.  Biopsy of LN showed polymorphous lymphoid aggregrates as well as atypical follicular hyperplasia.  There was no concern for a malignant process based upon flow cytometry and immunohistochemistry
•         Age 32, developed ITP which was treated successfully with corticosteroids.
•         Age 34, developed progressive dyspnea and respiratory complaints with pulmonary lesions.  He underwent a lung biopsy via VATS at that time and a biopsy of a nodule showed bronchiolitis with organizing pneumonia. Biopsy of a pulmonary lymph node showed a polymorphous population of lymphocytes, mostly T-cells mature T-cells with a normal ratio.  The histological architecture was normal and the final diagnosis was a reactive lymphoid hyperplasia without features of a lymphoproliferative disorder.
•         His PFTs have remained within normal limits and until recently q 6 months CT scans were stable.
•         Nearly concurrent with his diagnosis of follicular bronchiolitis he developed hypereosinophilia.   His absolute eosinophil count since then has waxed waned since then but it is never less than a 1,000 cells per microliter and upon review of his record since then it has gone as high as 4000 cells per microliter on one occasion.  His average AEC is about 2500.
o   Hypereosinophilia is moderately steroid sensitive when they are used short term (takes AEC down to about 800).  Hydroxycholoroquine has no effect and he has been resistant to undergo treatment with other agents such as azathioprine.
o   Echo obtained ~ 6 months ago was normal.
o   Bone marrow biopsy obtained about six months ago showed no molecular defects associated with hyper-eosinophilia syndrome.
•         Limited CT scan of sinuses show near complete opacification of sinuses with nasal polyposis.
•         B-cell subset analysis shows low switched memory-B cell counts and low CD21 expression.  CD4, CD8 and NK cell numbers were normal with normal relative frequencies.
•         Bronchoscopy with BAL in August 2012 as well as last month showed negative cytology, no eos, and negative cultures.
•         About six weeks ago he had increased shortness of air and fatigue.  He went to the ER where an echo showed hyperdynamic left ventricle function and right ventricular dilatation with moderately reduced systolic function.  He was found to have severe pulmonary hypertension with PA pressure 90/54.  Remodulin was started.
•         CT scans showed interval development of multiple discreet large pulmonary nodules bilaterally predominately in the lower lobes.  He also had interval development of mediastinal hilar lymphadenopathy.  Abdominal scan showed stable retroperitoneal and peritoneal adenopathy.
•         PET scan showed extensive mediastinal axillary, peritoneal and inguinal hypermetablic lymphadenopathy.  He had a dominant right lower lob infiltrate with increased uptake.  Multifocal pulmonary nodules also had increased FDG intake.  Nuclear med bone marrow scan showed no evidence of extramedullary hematopoiesis.  SPECT imaging showed no evidence of abnormal accumulation in any of the pulmonary modules.
•         Flow cytometry of peripheral blood and axillary lymph nodes showed no evidence of monoclonality or increased blasts.
•         The biggest problem right now is an open lung biopsy cannot be performed because of his pulmonary hypertension.  He is scheduled for another bronchoscopy next week, at which point a transbronchial biopsy can be obtained.

Any thoughts on these findings, especially in the context of his longstanding hyper-eosinophilia, would be much appreciated.  Further approaches to his diagnosis and treatment would also be great.  Sarcoid-like disease associated with CVID would otherwise be high on my differential because it can theoretically be associated with eosinophilia, but prior biopsies have failed to show any granulomatous inflammation.  ACE level, for what it’s worth, was very mildly elevated at 69 (reference range 12 – 68 U/L).

Thanks, as always, for the help.

Zach

--
Zachary D. Jacobs, M.D.
The Center for Allergy & Immunology
Saint Luke’s Physician Partners
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--
Zachary D. Jacobs, M.D.
The Center for Allergy & Immunology
Saint Luke’s Physician Partners
Medical Plaza II
4330 Wornall, Suite 40
Kansas City, MO 64111

Ph: 816.531.0930
Fax: 816.753.2671

CONFIDENTIALITY NOTICE. This e-mail and attachments (if any) may contain information that is confidential, proprietary, privileged or otherwise prohibited by law from disclosure or re-disclosure. This information is intended solely for the individual(s) or entity(ies) to whom this e-mail or attachments are addressed. If you have received this e-mail in error, you are prohibited from using, copying, saving or disclosing this information to anyone else. Please destroy the message and any attachments immediately and notify the sender by return e-mail. Thank you.

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