[PAGID] Allergy fellow seeking assistancewithIRAK-4 def evaluation

[Otto, Hans F Maj USAF AETC 59 MDOG/MMIA]

Thank you all for your excellent and expert feedback!  I am sorry for
the delay in my response but it has been a busy 48 hours.

In response to Dr Sullivan's thread "Is there a reason you don't think
he has garden variety CVID?"  No, common things being common, this could
be CVID but as it is a diagnosis of exclusion I am trying to pursue
reasonable alternative diagnosis that may explain his somewhat unique
presentation (i.e., GABHS strep pericarditis as 1st presentation of CVID
would be a 1st).  That includes other PID and acquired IDs.  If he has
CVID, then as we monitor his Ig's over time (~6months), we should see
them trend down again as we are not giving further IVIG.

As Dr Fleisher very correctly states, his hypogamm could have been a
"red herring" in the respect that he may have had the extreme bad luck
to develop a primary infection with constrictive pericarditis (CP) that
then resulted in intestinal lymphangectasia (IL) resulting in the well
reported protein-losing enteropathy (PLE), thus the hypoalbuminemia,
hypogammaglobulinemia and lymphopenia for which we were consulted.  If I
had been more astute at the time, I could have checked
alpha-1-antitrypsin levels and clearance in his stool to aid with this
diagnosis but that ship has sailed.  Certainly, IL with PLE all
secondary to CP fits well with the clinical scenario but again, as it
stands now, I believe it remains a diagnosis of exclusion. 

As Dr Blaese suggests, it may be worth checking DTH status now and, if
negative, again in a few months to track his response over time as he
and his colleagues did in one of the earliest descriptions of IL with
PLE secondary to CP(J of Ped 86;548-54, 1975) though the cause of CP was
unclear.  His case had months of acute colicky pain followed by
explosive diarrhea until he was diagnosed with PLE and over a year later
he was finally found to have CP.  Given the pathogen implicated in my
patient (GABHS) his inoculation to presentation was very likely brief
and the role of his 1 day of diarrhea 1 week before presentation as
being the source of loss of his Ig I believe to be less likely.  Was
there a inherent susceptibility to infection that started it all?  As Dr
Fleisher wrote, I don't have the answer either...only seeking the tools
to find the answer.

It has been well cited in the older literature (Am J Med 44;842-50, 1968
and J of Ped 86;548-54, 1975) that some but not all cases of CP can
result in IL and it is not clear why some do and most don't.  As such,
his hypogamm would be expected to be transient (as has been demonstrated
in animal models) and would have resolved with clinical improvement of
his CP if he had not already been given IVIG.  Now, we are monitoring
his Ig's to see if they trend back down but consistent with Dr
Fleisher's and my hypothesis, they may not ever trend low again as his
CP has clinically improved.  
Here are the numbers Dr Fleisher requested.
Date	IgG (mg/L)	IgA (mg/L)	IgM (mg/L)
2/25/08	<100	18	5.0
2/26/08	113	32	41
4/4/08	1708	155	61
5/5/08	1391	108	67
6/23/08	1331	128	77

In response to Dr Conway's thread, in another article by most of the
same authors of the JEM article (Immunol Res 38; 347-352, 2007) they
cite that all invasive infections (septicemia, arthritis, meningitis)
occurred before 14 y/o and all fatal infections before 8 y/o.  Review of
table 1 from the JEM article shows a wide enough distribution of ages
that fits well with this 7 y/o patient.

As Dr Fleisher cites, IRAK-4 def has been reported with S. aureus, S
pneumonia and to a lesser extent other pyogenic/gram negative
infections.  They did not report GABHS but certainly TLR dysfunction
(IRAK-4) would be susceptible to GN pyogenic infection.  Considering the
likelihood based on reported cases of both in the worldwide literature,
it may be more likely for the patient to have IRAK-4 as susceptibility
to pyogenic infection (>28 cases of IRAK-4 def worldwide) than the even
more rare spontaneous GABHS pericarditis (5 cases worldwide).  While
that may be an adulteration of epidemiology, I believe that IRAK-4
should be considered and evaluated.

Treatment options would differ depending on the outcome of evaluation.
IL secondary to CP would require to treatment once the CP has resolved.
In the case of GABHS CP, we would not expect recurrence of the infection
once treated but scarring could persist (apparently not the case in our
patient).  In the case of IRAK-4 def, the authors of Immunol Res
recommend prophylactic IVIG until the age of 10 y/o, prophylactic
antibiotics and an intensive vaccination program.

In response to Dr Casanova's thread, the patient did have a fever
starting 2 days prior to admission, T max of 105F, was acutely ill,
pan-ST depression on EKG in the ER.  He was ultimately intubated later
the night of admission and placed on pressor support when he went into
cardiac tamponade.  Cardiology performed a pericardiocentesis then
placed a drain which was removed a week later.  It was from the initial
purulent tap that infectious diseases identified the gram negative cocci
and confirmed GABHS the following day or so.  He responded to
ampicillin, defervesced in 1-2 days and was extubated after 3-4 days.  

If you think the CD62L shedding could be performed at your lab (Paris?)
or the NIH, I would be happy to initiate coordinate the logistics for
proper collection, funding and shipping on my end if you or Dr Fleisher
have a POC on your ends (fresh blood?, what color top tube?, on ice?,
overnight?, etc).  If this step does not answer the question and we
think there are other paths of the TIR that are worth pursuing, I would
appreciate any assistance/guidance that you may have to offer.

Whew...I think I responded to everyone's notes.  Drs Casanova or
Fleisher: let me know if you would be able to perform and if so the POC
to coordinate the logistics of getting the serum to you I a timely
fashion.

Most 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


-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org
[mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Fleisher, Thomas
(NIH/CC/DLM) [E]
Sent: Wednesday, June 25, 2008 9:09 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [PAGID] Allergy fellow seeking assistancewithIRAK-4
defevaluation

I think that we need clarification regarding the current antibody status
of this patient, what I read is that the Igs are normal at this
juncture. Is this the case?  It is important to remember that the low
Igs were accompanied by low albumin and low lymphocyte numbers, this is
classic for IL (or a secondary IL). Since it appears to have resolved
this would be best explained by secondary IL.

 

Thomas A. Fleisher, M.D.

Chief, Department of Laboratory Medicine

NIH Clinical Center

tel 301 496-5668

fax 301 402-1612

email tfleishe at mail.nih.gov

 

________________________________

From: Daniel Conway [mailto:dhconway at hotmail.com] 
Sent: Wednesday, June 25, 2008 10:04 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [PAGID] Allergy fellow seeking assistance withIRAK-4
defevaluation

 

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 -0400
From: TFleishe at cc.nih.gov
To: pagid at list.clinimmsoc.org
CC: casanova at necker.fr; SHOLLAND at niaid.nih.gov
Subject: 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 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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