[PAGID] Allergy fellow seeking assistance with IRAK-4 defevaluation

[Daniel Conway]

I get the sense that IRAK-4 deficient individuals routinely present much earlier than than this.  The JEM paper quoted describes about 75% of all affected individuals having first infection before 2 years of age, with nearly all by about 3 years of age.  
 
Additionally, the reports seem to have hypogammaglobulinemia as an infrequent and poorly described element of this disease.  IgG's are unusual to be so low in the individuals with IRAK-4 and hypogamm.
 
Additionally, the other feature is that IRAK-4 is described as "Better" or unlikely to present with such profound life-threatening problems at this age.  Or so the story goes.  
 
I'd focus on reasons for antibody deficiency-CVID as a prominent choice.  Sincerely, Daniel H. Conway, MD Asst. Professor of Pediatrics St. Christopher's Hospital for Children Drexel University College of Medicine  


Date: Wed, 25 Jun 2008 09:34:02 -0400From: TFleishe at cc.nih.govTo: pagid at list.clinimmsoc.orgCC: casanova at necker.fr; SHOLLAND at niaid.nih.govSubject: Re: [PAGID] Allergy fellow seeking assistance with IRAK-4 defevaluation








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 “bad” 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 cc’d 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 AMTo: pagid at list.clinimmsoc.orgSubject: 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 Center’s 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 “cart before the horse”.  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 pericarditis…all 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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