[PAGID] Puzzling patient with high normal IgG levels but noan tibody responses to vaccines

[Berger, Melvin]

I have never seen an IgG as high as 1000 but I have certainly seen as
high as 400 in patients who turned out to have BTK mutations and less
than or equal to 1% peripheral B-cells. I have alaso seen XLA patients
present with neutropenia and pseudomonas. In fact, if you look back at
Mary Ellen's series in Pediatrics a few years ago, neutropenia is quite
common in XLA- that's why I asked yesterday. 

Mel Berger

-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org
[mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Conley,
Mary-Ellen
Sent: Friday, July 13, 2007 11:49 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [PAGID] Puzzling patient with high normal IgG levels but
noantibody responses to vaccines

Hi Howard,
I also think he might have XLA.  The presentation with Pseudomonas
sepsis, particularly in patients with XLA who come to medical attentiion
at less that 12 months of age, is not all that uncommon.  I think the
babies get a viral infection, get secondary neutropenia, and then get
pseudomonas sepsis.  Sometimes the neutropenia has resolved by the time
the patient presents with sepsis, but often they are still neutropenic
like Ashish's patient.  

I have also seen an IgG as high as 1000 in a patient with a proven
mutation in Btk who had no antibody response to vaccine antigens and had
less than 1% CD19+ cells.  We know that mutations in Btk cause a leaky
defect in B cell development and sometimes there are very few
circulating B cells but there are probably a few B cells in the spleen.
The unexpectedly high IgG, IgM and IgA is more likely to happen in
patients who have an amino acid substitution rather than a premature
stop codon or frameshift mutation in Btk.  Statistically, the patients
with amino acid substitutions have milder disease - which would not fit
with pseudomonas sepsis; but there are a lot of exceptions.
Mary Ellen






Mary Ellen Conley, MD
Department of Immunology
St. Jude Children's Research Hospital
332 N. Lauderdale
Memphis, TN 38105-2794
FAX  901-495-3977
TEL  901-495-2576


-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org
[mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of HOWARD M
LEDERMAN
Sent: Thursday, July 12, 2007 3:00 PM
To: pagid at list.clinimmsoc.org
Cc: 'Torgerson, Troy'; 'Guerrerio, Pamela A'
Subject: Re: [PAGID] Puzzling patient with high normal IgG levels but no
antibody responses to vaccines

Ashish and Troy,

If I understand this correctly, your case is different from ours in that
the IgG level was below normal.  Our case has an IgG level >1000 with NO
antibody.  If only a few B cells slipped through because of a Btk point
mutation, I think I would have expected a low IgG level and perhaps an
oligoclonal gammopathy.

Howard M. Lederman, M.D., Ph.D.
Professor of Pediatrics and Medicine
Division of Pediatric Allergy and Immunology Johns Hopkins Hospital -
CMSC 1102 600 N. Wolfe Street Baltimore, MD 21287-3923
Phone:  410-955-5883
Fax:    410-955-0229
e-mail: Hlederm1 at jhem.jhmi.edu


----- Original Message -----
From: Ashish Kumar <kumar036 at umn.edu>
Date: Thursday, July 12, 2007 2:47 pm
Subject: Re: [PAGID] Puzzling patient with high normal IgG levels but no
antibody responses to vaccines
To: "'Torgerson, Troy'" <troy.torgerson at seattlechildrens.org>,
pagid at list.clinimmsoc.org
Cc: "'Guerrerio, Pamela A'" <pfrisch1 at jhmi.edu>



> The patient Troy mentioned is one that I had discussed on this forum a



> few  weeks ago. This is a 14 mo boy who was perfectly healthy for the 

> first year  of his life and then developed recurrent pneumonia - 3 

> times in 3 months.

>  The 3rd time, it was bilateral and associated with pancytopenia. When



> I saw  him, his total IgG was around 250, with slightly below normal 

> IgA and IgM  (not in the agammaglobulinemia range). He did have 

> protective titers to  Diphtheria and Tetanus. However, his CD19 and 

> CD20 counts were zero.

> We

>  rechecked these on fresh samples and they were still 0. As Troy 

> mentioned,  he has a BTK mutation but it is a mystery how he made 

> antibodies and had  detectable IgG, M and A at the age of 14 months, 

> if he has no B cells. There  is no family history to help us out 

> either. I wonder if he is a mosaic for  the BTK mutation, which would 

> explain this situation - I don't know if this  has been reported 

> before. Another interesting piece in this case is that the  absolute 

> lymphocyte count is low - around 1200, and I have not seen this in  

> any other patient with agammaglobulinemia.

>   

>  Ashish Kumar M.D., Ph. D.

>  Assistant Professor

>  Pediatric Hematology/Oncology/Blood and Marrow Transplantation  

> University of Minnesota

>    _____

>  

>  From: Torgerson, Troy [

>  Sent: Thursday, July 12, 2007 1:21 PM

>  To: pagid at list.clinimmsoc.org; Ashish Kumar

>  Cc: Guerrerio, Pamela A

>  Subject: RE: [PAGID] Puzzling patient with high normal IgG levels but



> no  antibody responses to vaccines

>   

>  Ashish Kumar has a patient with a similarly unusual story - I don't 

> know if  he is on the PAGID listserve but I have cc'd this to him so 

> he can hopefully  provide more of the clinical details.  Essentially 

> very low B cell numbers  but normal/near normal IgG levels.  We 

> evaluated Btk and expression was  normal in platelets by flow 

> cytometry.  When we sequenced the gene we found  a previously 

> unreported point mutation in the kinase domain that doesn't  show up 

> in any of the SNP databases.  Btk-base shows several point mutations  

> in residues 4-5 base pairs up and downstream but only a nonsense 

> (stop)  codon mutation at the same location.  We are not yet sure 

> whether this  mutation affects Btk function but this will be a key 

> question.  Since Btk is  expressed, it is theoretically possible that 

> this could generate a  hypomorphic Btk that could allow a few B cells 

> to slip through development  and start churning out antibody in 

> response to activating signals but no  specific Ab responses due to 

> the limited number of clones - or NOT??

> 

>   

>  Best,

>   

>  TT

>   

>  Troy R. Torgerson MD PhD

>  Attending Physician, Pediatric Immunology/Rheumatology  Co-Director 

> Immunodeficiency Molecular Diagnostic Lab

>  307 Westlake Ave. North

>  Suite 300

>  Seattle, WA  98109

>   

>  Tel (206) 987-7450

>  Fax (206) 987-7310

>    _____

>  

>  From: pagid-bounces at list.clinimmsoc.org  [ On Behalf Of HOWARD M 

> LEDERMAN

>  Sent: Thursday, July 12, 2007 10:22 AM

>  To: PAGID LISTSERV

>  Cc: Guerrerio, Pamela A

>  Subject: [PAGID] Puzzling patient with high normal IgG levels but no



> antibody responses to vaccines

>   

>  I have seen pts with low normal IgG levels but poor antibody 

> responses, but  this case seems to be way out of my experience.  Are 

> there any specific  diagnostic tests that I should be considering?

>  --------- ----------- ------------- ------------ -------------- 

> ------------

>  ---------- -------------

>  J.S. is a 10-month-old Caucasian male who had no significant 

> infections  until 8 mos of age when he developed fever (T=104), 

> lethargy and poor  appetite.  A full sepsis workup was conducted and 

> his blood culture grew  Pseudomonas aeruginosa in 24 hrs.  His left 

> tympanic membrane spontaneously  ruptured during his hospitalization

and cultures also grew

> pseudomonas.   A

>  head CT was normal except for bilateral middle ear opacification.  A 

> chest  x-ray was normal.  An abdominal ultrasound was normal.

>   

>  An immunodeficiency workup showed virtually no CD19+ B-cells (0-2%;  

> 11-169/cu mm) with normal numbers of T (90% CD3, 68% CD4 = 4467/cu mm,



> 21%

>  CD8 = 1349) and NK (6% = 368/cu mm) cells. Serum immunoglobulins were



> normal  for age (IgG 446 mg/dL, IgA 30 mg/dL, IgM 35 mg/dL).

>   

>  J.S. had no other history of infections other than intermittent mild 

> viral  upper respiratory tract symptoms.  He has had no skin 

> infections or urinary  tract infections.  His growth has been normal. 

> He had received all routine  childhood vaccines.

>   

>  Subsequent lab tests have shown INCREASING IgG levels (1020 mg/dL) 

> with low  normal IgA (34 mg/dL) and IgM (31 mg/dL). Despite the 

> elevated IgG levels,  he had NO detectable IgG antibody to previously 

> administered standard  vaccines (<0.2 mcg/ml to 14 tested pneumococcal



> serotypes, < 0.11 to HIB  mcg/ml and <0.10 IU/ml to tetanus).  He had 

> NO increase in IgG Ab after  booster doses of Prevnar and Hib 

> conjugate vaccines; tetanus increased only

>  marginally to 0.66 IU/ml.   Repeat T and B cell studies by FACS were

>  essentially the same (CD19 3%; CD20 3.3 %; abs ct 140).  Serum IFE 

> showed no  evidence of a monoclonal gammopathy. PCR tests for EBV and 

> CMV were  negative.

>   

>    I am open to any and all suggestions.

>  

>  

>  Howard

>  Howard M. Lederman, M.D., Ph.D. 

>  Professor of Pediatrics and Medicine  Division of Pediatric Allergy 

> and Immunology  Johns Hopkins Hospital - CMSC 1102  600 N. Wolfe 

> Street  Baltimore, MD 21287-3923

>  Phone:  410-955-5883 

>  Fax:    410-955-0229 

>  e-mail: Hlederm1 at jhem.jhmi.edu

>  

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