[CIS-PAGID] B12 deficiency, probable granulomatous CVID and partial correction of hypogamma

[Seppänen Mikko]

Dear all,

I was baffled today by a hypoganmmaglobulinemic 50-y old female.

She is active smoker, COPD, specific diffusion capacity 61%, radiologically respiratory bronchiolitis, no bronchiectasis. Strongly now adviced against smoking.

2002 atrophic gastritis of corpus, and severe non-atrophic gastritis of antrum, B12 then normal and pathologist adviced to follow up, not done. Autoimmune hypothyroid disease noted 2005, on replacement therapy.

September 2010 apical pneumonia bilaterally, responded slowly and at first only partially to i.v. and p.o. antibiotics, a.o. TBC not found (extensively studied). Then Feb 2011 clinical second pneumonia, and bilaterally diffuse basal consolidations, responded slowishly to antibiotics. Then developed perihilar lymphadenopathy and in BAL granulomatous inflammation, thought to have sarcoidosis, but IgG 5.6 g/l, IgM 0.39, both low. IgA normal. Remitted to local ID specialist: CVID?

Tetanus and diphtheria titers at protective level. No response to Pneumovax ( 7/7 serotypes, all <2x, low postvaccination titers), thus local ID specialist consulted us. Vitamin A normal, normal thyroid hormone levels, but B12-TC2 (transcobalamin2-associated B12) only 25  = low, and even has complained for 1 year of progressive memory deficit, was started with B12 injections.

She was then revaccinated (always a bit worry about inducing tolerance, but twice before this has worked and vaccine responses bocome normal, neither of those patients had more than mild steroid -induced IgG-hypogamma), absolutely with no response.
However, IgG rose to 7.3 and IgM to normal 0.56 (been described at least twice in literature), granulomatous changes disappeared from lungs (???) leaving only mild respiratory bronchiolitis and somewhat thick septae. Also IL2R, ADA normalized, lysozyme is still a bit high, dU-Ca normal all along. No thymoma. CD4 first a bit low, now normal, CD8 constantly low 0.06-0.12, normal B- and NK-cells. MBL2/MASP2 deficiency, CH100L 0%.

Immunofixation of urine and serum, as well as B-differential and fecal antitrypsin pending (fecal calprotectin and S-Alb however normal).
She also has hepatic alkaline phosphatase above 2SD, MRI, autoantibodies normal, normal liver functions, liver biopsy is pending.
Thus she began with typical "probable granulomatous CVID" phenotype, and once her B12 was corrected
---> she was left with "specific antibody deficiency - even w/o? granulomas",
---> and in follow up just after 1 month her IgG is again below 2SD 6.4 g/l, IgA, IgM normal and IgE not taken (though ordered). Thus now "possible CVID".

Would You treat?
Have You seen anything alike? If yes, what happened to them???

mikko
Helsinki, Finland

________________________________
Lähettäjä: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] Puolesta Javier Chinen
Lähetetty: 10. toukokuuta 2012 14:27
Vastaanottaja: pagid at list.clinimmsoc.org
Aihe: Re: [CIS-PAGID] B-cell subset question and IgE

powerpoint of the presentation. CIS2010.

Thanks

Javier Chinen, MD, PhD


________________________________
From: Mikko.Seppanen at hus.fi
To: pagid at list.clinimmsoc.org
Date: Thu, 10 May 2012 08:14:32 +0300
Subject: Re: [CIS-PAGID] B-cell subset question and IgE


Dear all



Richard, You refer to data on response testing while on therapy that I at least am not aware of, could You please give a reference? I do have tried testing 2-3 months later and found myself struggling with reliability issues (real or unreal), and my patients do yet again wait for 6 months. Thus if any data, I would appreciate it as well. Half life / consumption of IgG can be very variable in patients and is different in healthy vs. agammaglobulinemic?



TBE-vaccines (Encepur, Ticovac) are proteins, just like rabies. Thus a bit problematic if response is + but pt fits CVID phenotype: as You all know, it is not that rare to see (a short lasting but) nice T-B response to strong T-B antigens (tetanus) while e.g. diphtheria (and Pneumovax of course) are missing and the patient is a typical CVIDs pt in all regards otherwise.

Since I give TBE and even rabies (travelers) vaccines  more or less regularly (being an ID doctor) I have not seen nor heard nor read of any real safety issues (occasionally 2.-3. rabies vaccine gives relatively severe local reaction), aside from an occasional MS patient, where the issue of safety with protein antigens remains unsolved but the more recent consensus considers them most likely safe. Polysaccharides are BTW safe, thus no contraindication to test an MS pt with Pneumovax.



There is also a very tolerable Japanese Encephalitis vaccine (Ixiaro) now in the market (in US as well?), the older vaccine had real safety issues… however, early Ixiaro responses can be very variable in normal population (my colleague A Kantele has studied and probably already published on that), thus 2 vaccine shots are needed.



Measuring IgE has helped me, since appr. 90% of CVIDs in our patient material do not produce IgE  (? does anyone have an exact figure in a large material?) and thus if it indeed is immeasurable, adds credence.



And Zachary, I have been through the same for the last 15 years, even more so for the last 5, so if You come to ESID Florence, we might both find a discussion therapeutic! And my hair’s been very gray for >10 years now... so dyeing might not help… but You are not alone! My warmest appreciation for doing what You do!



mikko



BTW Nobody was eager to comment on IgG2D?



_________________________________________________

Mikko Seppänen, MD, PhD, Docent (Associate professor/Senior Lecturer)

Specialist in Internal Medicine and Infectious Diseases

Senior Consultant, Physician in charge (PIDD)

EM(E)A Expert, PIDDs and Intravenous Immunoglobulin Therapy



Immunodeficiency Unit

Division of Infectious Diseases

Department of Medicine

Helsinki University Central Hospital

Hospital District of Helsinki and Uusimaa

Aurora Hospital, Ward 4-2 and Outpatient Clinic

P.O.Box 348

FI-00029 HUS, Helsinki

FINLAND

phone +358 9 47175923, fax +358 9 47175945

_________________________________________



Lähettäjä: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] Puolesta Richard Wasserman
Lähetetty: 9. toukokuuta 2012 17:18
Vastaanottaja: pagid at list.clinimmsoc.org
Aihe: Re: [CIS-PAGID] B-cell subset question



Given the half life of IgG and the recent data suggesting that you can evaluate pneumococcal polysaccharide response while on therapy, there is no need to keep them off for six months. I would get new baseline studies two months after the last IGIV treatment and vaccine at that time. It may be more palatable.
Richard Wasserman

On Wed, May 9, 2012 at 9:13 AM, Zachary D. Jacobs, MD <zjacobs.md at gmail.com<mailto:zjacobs.md at gmail.com>> wrote:

Thanks for the replies.  It is a challenging situation for me.  I inherited a large group of his patients he had on IgGRT that fit this general profile, probably around fifty.  The ones who didn’t think they ever needed to be on it were easy to trial off.  However, the majority of these patients have been on therapy for several years and are reluctant to come off.  They were told that without IVIG / SCIG they could die from an infection by someone who had been practicing for fifty years, and then they hear from me, just out of training, that they may not need it and so they can become skeptical.  Generally, I have tried to establish a rapport with the patients and a good doctor / patient relationship before broaching the subject of trialing off.  I have found that if I order B-cell subsets, even with the lack of published clinical utility for the test, if the memory B-cells are normal in number then the patient has something to grasp and feels better about trialing off therapy.  I then perform repeat antibody studies when they have been off for six months.



Any advice on how to better deal with the situation would be much appreciated.



Zach



On Tue, May 8, 2012 at 5:50 PM, Cunningham-Rundles, Charlotte <charlotte.cunningham-rundles at mssm.edu<mailto:charlotte.cunningham-rundles at mssm.edu>> wrote:

In my view the memory B cell phenotype can't be used in substitution of a complete antibody workup ( off Ig of course) .
 I would not use the CD38+IgM or any other combination to assess antibody production either .

Nice if we had a way around that but this is not it.


Charlotte

Charlotte Cunningham-Rundles, MD, PhD
Departments of Medicine and Pediatrics
The David S Gottesman Professor
The Immunology Institute
Mount Sinai School of Medicine
1425 Madison Avenue
New York, NY 10029
Phone: 212 659 9268
Fax: 212 987 5593
Email: Charlotte.Cunningham-Rundles at mssm.edu




________________________________

From: "Zachary D. Jacobs, MD" <zjacobs.md at gmail.com<http://gmail.com>>
Reply-To: PAGID <pagid at list.clinimmsoc.org<http://list.clinimmsoc.org>>
Date: Tue, 8 May 2012 16:10:17 -0500
To: PAGID <pagid at list.clinimmsoc.org<http://list.clinimmsoc.org>>

Subject: [CIS-PAGID] B-cell subset question

Hello all,


I have been seeing a 52 year-old woman who was started on IVIG about 18 months ago by a now retired immunologist.  She had been having recurrent sinusitis and had frequent courses of antibiotics but she had no imaging performed during this time, did not have history of sinus surgery and did not have much in the way of lower respiratory tract infections.  Her quantitative immunoglobulins were normal, except that IgM was consistently high in the 450 mg/dl range. SPEP was normal.  Vaccine testing at the time showed suboptimal response to PPV-23 with pre-immunization specific antibody panel showing 5 of 12 serotypes > 1.3 ug/ml and post-immunization it rose to 7/12 serotypes with protective levels.  Therefore, she was started on IVIG by him and she has clinically improved with fewer infections.


I have been evaluating her and would like to trial her off of IVIG.  What I have been doing of late is obtaining B-cell subsets on patients, and if their memory B-cell counts and frequencies are normal I encourage them to go off IVIG to see how it goes.  For this patient, the frequencies of the memory B-cells were normal, as were the counts of the switched and unswitched memory B-cells, but the count of the IgM-only memory B-cell was elevated at 16 cells/mcl (0-12), and her total IgM(+) B-cell count was elevated at 395 cells/mcl (37-327) with 87% of CD19 cells being IgM(+).  I thought this was interesting given her historically high IgM counts.


Does anyone have experience in dealing with this particular immunophenotype and how she would fair off IgG replacement?  Should any further work-up be undertaken?


As an aside and while I’m here writing, this same retired immunologist had several patients on IVIG with at times soft indications.  Since I have been doing B-cell subsets on these patients I have found several that have normal memory B-cell counts (switched and unswitched) but had low numbers of plasmablasts (CD38+ IgM -/+).  These patients often have a history of chronic bronchitis or sinusitis with a mildly low IgG in the mid-400 to mid-500 mg/dl range, normal IgA and IgM, and mild to moderately impaired specific antibody responses to PPV-23. What is the clinical significance of low plasmablasts potentially causing hypogammaglobulinemia, especially in regards to infectious complications and need for IgG replacement?


Thanks as always,


Zach

--
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

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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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Richard L. Wasserman, MD, PhD
DallasAllergyImmunology
7777 Forest Lane, Suite B-332
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Office (972) 566-7788
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