[PAGID] Puzzling patient with high normal IgG levels but no antibody responses to vaccines

[HOWARD M LEDERMAN]

Mary Ellen,

Are you interested in testing his blood??

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


----- Original Message -----
From: "Conley, Mary-Ellen" <maryellen.conley at STJUDE.ORG>
Date: Friday, July 13, 2007 11:48 am
Subject: Re: [PAGID] Puzzling patient with high normal IgG levels but no antibody responses to vaccines
To: pagid at list.clinimmsoc.org



> 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

>  [ 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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