[PAGID] Allergy fellow seeking assistance with IRAK-4 def evaluation

[Steven Holland]

Interesting case, very well thought out and synthesized. It seems like an
odd presentation for IRAK4 to be that late and that severe. We can do the
testing for TLR response for you if you are interested. The fever and
overall wellness make me somewhat skeptical that this is the right tree up
which to bark.

Steve


On 6/25/08 9:34 AM, "Fleisher, Thomas (NIH/CC/DLM) [E]"
<TFleishe at cc.nih.gov> wrote:


> The low Igs, albumin and lymphocyte number are strongly suggestive that the

> pericardial effusion was acting very similar to an acquired like intestinal

> lymphangiectasia associated with constrictive pericarditis (J Peds 86:548-554,

> 1975). Since his Igs, lymphocytes and albumin are now normal post treatment of

> the pericarditis (as noted in the narrative), it seems to me that he cannot be

> classified as having a primary antibody defect (he also had protective

> antibody levels to standard immunogens). This leaves the fundamental question

> whether the GABHS pericarditis was a ³bad² luck unusual infection or tied to

> an underlying defect in innate immunity, a question for which I do not have

> the answer. If the latter, IRAK 4 should be ruled out however, the recent

> review in the JEM (204:2407-22, 2007) of 28 patients with IRAK4 deficiency

> revealed that the predominant infectious agents were S pneumoniae (22/28) and

> S aureus (14/28) with a lower incidence of serious gram negative infections

> (7/28). Further there was not a case of pericarditis among this group but of

> course there can always be a first time. I should point out that the NIH

> patient from many years ago with IRAK4 deficiency developed a very unusual

> (atypical) infection that ultimately necessitated a limb disarticulation (J

> Immunol 158:3959-3964, 1997 and JEM 198:521-531, 2003). I have cc¹d Jean

> Laurent Casanova and Steve Holland for their input.

>  

> 

> Thomas A. Fleisher, M.D.

> Chief, Department of Laboratory Medicine

> Chief, Immunology Service, DLM

> NIH Clinical Center

> tel 301 496-5668

> fax 301 402-1612

> email tfleishe at mail.nih.gov

>  

> 

> 

> From: Kathleen E. Sullivan [mailto:sullivak at mail.med.upenn.edu]

> Sent: Wednesday, June 25, 2008 6:53 AM

> To: pagid at list.clinimmsoc.org

> Subject: Re: [PAGID] Allergy fellow seeking assistance with IRAK-4

> defevaluation

>  

> Is there a reason you don't think he has garden variety CVID?

> 

> Kate

> 

> Kathleen E. Sullivan MD PhD

> 

> Chief, Division of Allergy and Immunology

> 

> Professor of Pediatrics

> 

> The Children's Hospital of Philadelphia

> 

> (p) 215-590-1697

> 

> (f) 267-426-0363

> 

> 

> 

>  

> 

> On Jun 24, 2008, at 5:24 PM, Otto, Hans F Maj USAF AETC 59 MDOG/MMIA wrote:

> 

> 

> Dear Colleagues,

> 

>  

> 

> I am a 1st year fellow at Wilford Hall Medical Center¹s Allergy/Immunology

> training program and I would appreciate your assistance with a question.  I

> queried the Immune deficiency foundation and they recommended I post my

> question on this list-serve for discussion.

> 

>  

> 

> Case:

> 

> I have a previously healthy 7 y/o male who was admitted to our hospital back

> in Feb08 for chest pain and fever of 104F.  He was found to have a pericardial

> effusion which was ultimately tapped and a drain placed after he developed

> cardiac tamponade. His gram stain and culture showed group A beta-hemolytic

> strep (GABHS) and antibiotics were started.  As GABHS pericarditis is very

> rare screening ID labs were checked on HD#2 on the recommendation of

> Infectious diseases consult.  The labs showed a hypogammaglobulinemia (IgG

> <100, IgA 18 and IgM 5) as well as hypoalbuminemia and a lymphopenia which

> both later resolved.  We were then consulted by infectious disease.  Flow

> cytometry was normal.  Specific antibodies were drawn and tetanus and

> diphtheria were at protective levels and several S. pneumo serotypes were

> elevated (>1.3mcg/ml) but we still cannot find his immunization

> hx/documentation.  HIV was negative with negative risk factors but will be

> re-checked again in several months.  He was given IVIG (24g IV on 2

> consecutive days) as an inpatient and his Ig levels increased.  His Ig levels

> have since remained in the normal range.  We are continuing to follow him as

> an outpatient.  He has no chronic medical problems, no consanguinity, no

> delayed cord separation, no travel and normal exam including LN and was well

> until 1 week prior.  One week prior to presentation he and his brother both

> developed a 24 hour acute gastroenteritis-type illness with vomiting x2 and

> some loose BM, all of which resolved after 24 hours without further complaints

> until day prior to ER visit.  He has been remarkably healthy and has never had

> any AOM, sinus infections or other significant childhood infections.  He has

> developed normally and is a straight A student.  He did not have any protein

> in his urine, normal chemistry other than hypoalbuminemia which improved after

> starting TPN; stool was not checked for alpha-1 antitrypsin (not considered at

> the time) and no pleural effusions existed on presentation but did develop

> later in the course (HD#5).  CBC was otherwise normal, CT scans are normal and

> no sign of malignancy.

> 

>  

> 

> DDx:

> 

> Consideration of the differential diagnosis of hypogammaglobulinemia does not

> support drug, genetic, chromosomal nor malignancy.  Given the rarity of GABHS

> pericarditis (5 cases in the world literature), especially in the setting of a

> very healthy young male, we are working under the premise that he has some yet

> unrecognized immunodeficiency (admittedly A/I bias).  Infectious agents seem

> unlikely though we have considered a transient severe protein-losing

> enteropathy which could cause hypogamm then open the window for GABHS

> pericarditis but GABHS is not a common source of infection in CVID nor does

> his acute gastroenteritis seem to have been severe enough to be the source of

> protein-losing enteropathy(mild and <24 hrs).  Constrictive pericarditis can

> cause chylothorax which may cause hypogamm but that would be placing the ³cart

> before the horse².  If this is the case, then he truly would have a rare

> infection with acquired/transient hypogamm and his future risk of infections

> would be low.  If he has a PID, then recommendations would change depending on

> the PID.  He has been well since discharge in early Mar08 with the exception

> of scarring of his pericardial sac causing some degree of constrictive

> pericarditis which is improving.  Our current plan is to continue to monitor

> his quantatative Ig levels over time to see if they drop, re-check HIV in

> Aug-Sept and try to obtain his immunizations history.  He is on no

> prophylactic antibiotics or other treatment at this time.

> 

>  

> 

> In continuing to consider/research some primary immunodeficiency that may have

> predisposed this patient to GABHS strep pericarditis +/- hypogamm, I have come

> to consider IRAK-4 deficiency given the pyogenic infection/pericarditis.  His

> presentation could be consistent with this being the original PID with

> hypogamm being a later finding secondary to the constrictive pericarditis.  I

> have presented this case, updates and research findings to our department on

> several occasions and we continue to find it an interesting/unique case.

> Surely it is possible that he had a rare pyogenic infection with secondary

> hypogamm (chylous loss vs. sepsis vs. other) vs. IRAK-4/UNG-93B w/ secondary

> hypogamm vs. hypogamm/CVID with no other cause whose 1st presentation was

> GABHS pericarditisŠall would be rare.  Now, however, I need help in figuring

> how to next proceed with appropriate evaluation as we believe there are still

> some unanswered questions.  Our department discussions led to the

> recommendation to write to you for assistance.

> 

>  

> 

> Question:

> 

> I am trying to figure out how to order the test described by von Bernuth H, et

> al. A fast procedure for the detection of defects in TLR signaling. Pediatrics

> 2006; 118:2498-2503.  The article describes a procedure for incubating fresh

> serum sample then inducing with anti-human CD62L antibody and then analyzing

> by flow cytometry.  IRAK-4 and UNG-93B (or MyD88) deficiency would show

> impaired CD62L shedding on granulocytes and profoundly impaired IL-6

> production after activation by LPS.  I cannot figure out where I could get

> this test done in the USA or who I would contact for the logistics on their

> end.  I can find gene testing at http://bioinf.uta.fi/IDdiagnostics but that

> does not seem to be an ideal 1st/screening test but maybe I am incorrect and

> should just order the genetics.

> 

>  

> 

> Can you please assist in guidance on how to order this test for our patient?

> Additionally, I am open to any other suggestions for evaluation that you may

> have to add.

> 

>  

> 

> Thanks for your help in advance!  Sincerely,

> 

> Hans

> 

> //signed//

> 

> Hans F Otto, MC, Maj, USAF

> 

> Allergy/Immunology Fellow

> 

> Provider Code 012R58

> 

> 59 MTG/SGMVDA

> 

> Lackland AFB, Texas 78236-9908

> 

> Comm: 210-292-5042/5723

> 

> Fax: 210-292-5016

> 

>  

> 

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> 

>  

> 

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