[PAGID] Allergy fellow seeking assistancewithIRAK-4 def evaluation

[Jordan Orange]

Greetings,

That is a very thoughtful response and I have enjoyed reading it -  
thank you.

As an aside, TLR ligand-induced cytokine responses from PBMCs can also  
be performed as a screening test for IRAK-4 and related deficiencies.
Although it is a more cumbersome test, it is commercially available  
and is offered by ARUP laboratories in Utah.
http://www.aruplab.com/guides/ug/tests/0051589.jsp

The turnaround time is rather short and they will accept as little as  
3ml of blood from pediatric patients.

Very best,

Jordan

Jordan Orange MD/PhD
University of Pennsylvania School of Medicine
Children's Hospital of Philadelphia, Division of Immunology
3615 Civic Center Blvd,  ARC-1016H
Philadelphia, PA 19104
(Voice) 267-426-5622
(Fax) 267-426-5727
www.orangelab.org

On Jun 26, 2008, at 4:58 PM, Otto, Hans F Maj USAF AETC 59 MDOG/MMIA  
wrote:


> 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

>


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