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

[Fleisher, Thomas (NIH/CC/DLM) [E]]

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 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 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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