[CIS-PAGID] Advice please

[Rohan Ameratunga (ADHB)]

Hi Mikko,

Greatly appreciate your detailed comments.

The DNT cells were gamma-delta.

Normal CD8 count

No necrotic skin lesions

I have submitted a paper on Samter's triad in childhood.  Samter's (diagnosed by graded aspirin challenge) has not been described in children although aspirin sensitive asthma has.  I have not done an aspirin challenge on this child as the case we which hopefully be published was a severe reaction.

Switched and unswitched CD27 cells were slightly low- see my more recent post with a summary of the results.

Normal IgM levels.

Your point about the risks of IVIG/ scIg is well taken.  In this child I was very worried about progress to bronchiectasis.  The treatment seems to changed both subjective and objective parameters.  As indicated I am hoping we can slowly wean him off it.

You may be right that when whole genome analysis becomes a routine test in 5-10yrs we will find mutations of immune deficiency/ inflammatory genes in these children.

Best

Rohan
________________________________________
From: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] On Behalf Of Seppänen Mikko [Mikko.Seppanen at hus.fi]
Sent: Wednesday, May 30, 2012 5:53 PM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS-PAGID] Advice please

Dear Rohan,

...yet bear in mind that IVIG's not just anti-inflammatory, but also stimulates through FcR-DC-SIGN--> IL-4, IL-33, thus it is a Th2 immunostimulant, and the allergies and nasal polyposis point to Th2-hyperinflammation. Thus if asthma develops, it may no longer be safe...? Overproduction of IL-4 is most heavily associated with asthma development (in GWASs).

BTW (someone may have asked these already?), did You check for MHCI-deficiency, since the pt has early-onset nasal polyposis, and emphysema/bronchiectasis may not yet have developed (nor CD8 lymphopenia)? NSAID intolerance? Are TCRalpha/beta+CD8+ counts low? TCRgamma/delta were pending, were they high?

Pneumonias--> MyD88/IRAK4 & specific granule def: for example no necrotic lesions of skin or mucosal surfaces are present, so all seem highly unlikely... MyD88/IRAK4 even more so. Chemotaxis and granulocyte morphology were however probably already checked?

And if DNT were high, were they also TCRalpha/beta+?

And finally, IgM was not high, was it? B-cell-, smB-levels, IgG2/4 -levels? (Thinking of MSH6 def and PMS2 def). We do end up using experimental IVIg from time to time, but it is not w/o risks

mikko

PS. And I strongly agree with Ricardo that there are unexplored, milder  B-cell deficiencies out there, all those phenotypes strike a bell, but for example some "hypogammaglobulinemia with normal immunogolbulins"- patients even with low smBs seem to tolerate IVIg/SCIg very poorly, especially if allergies present. And one must be very cautious in interpreting the response findings as pointing to these milder defects, IF p.o. steroids and inhalants used at higher doses within previous 18 months...

__________________________________________________
Mikko Seppänen, MD, PhD, Docent (Associate professor/Senior Lecturer)
Specialist in Internal Medicine and Infectious Diseases
Senior Consultant, Physician in charge (PIDD)
EM(E)A Expert, PIDDs and Intravenous Immunoglobulin Therapy

Immunodeficiency Unit
Division of Infectious Diseases
Department of Medicine
Helsinki University Central Hospital
Hospital District of Helsinki and Uusimaa
Aurora Hospital, Ward 4-2 and Outpatient Clinic
P.O.Box 348
FI-00029 HUS, Helsinki
FINLAND
phone +358 9 47175923, fax +358 9 47175945
_________________________________________


-----Alkuperäinen viesti-----
Lähettäjä: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] Puolesta Rohan Ameratunga (ADHB)
Lähetetty: 29. toukokuuta 2012 21:40
Vastaanottaja: pagid at list.clinimmsoc.org
Aihe: Re: [CIS-PAGID] Advice please

Hi Mark and others,

I greatly appreciate your help.  Given it is unlikely he has a severe immune defect, we may trial him off treatment in our summer.  Possibly may need to use it during the winter months in the next 1-2 years before weaning him off it completely.  Having looked at the options, IVIG seems to be much safer than MTX, MMF etc as an anti inflammatory treatment.

Thanks again.

Rohan
________________________________________
From: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] On Behalf Of Mark Ballow [markbal.aird at gmail.com]
Sent: Monday, May 28, 2012 3:27 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS-PAGID] Advice please

Rohan,

not sure this is getting thru on the list serve. Good thought by both Drs Wasserman and Sorensen. Our paper you found in the "older" literature does support the use of IVIG in patients such as yours. Back in the  1990's we did not have the same "tools" we have now to evaluate the immune response. We were treating these patients with IVIG more as an anti-inflammatory approach rather than as replacement therapy in a PIDD patient. In many of the patients after 9 months of therapy the IVIG was stopped and they seemed to have continued improvement of their chronic sinusitis. I would recommend a similar course of treatment so as not to comment this patient to life-long IVIG therapy.

Mark Ballow
SUNY Buffalo

On Mon, May 21, 2012 at 2:37 PM, Rohan Ameratunga (ADHB) <RohanA at adhb.govt.nz<mailto:RohanA at adhb.govt.nz>> wrote:
Hi Ricardo,

I appreciate your detailed comments.  Shall review the notes and get back to you.  I struggle with SPAD- the tetanus is a v. strong immunogen, diphtheria is usually poor, HIB measures protein responses and there are a lot of technical issues with the WHO pneumo assay. You are an expert in this area.

Further we do not routinely use the rapid waning of in vivo antibody responses as an indication to use IVIG.

Once more thanks for your comments and will get back to you once I have assembled the information.

Best

Rohan


________________________________________
From: pagid-bounces at list.clinimmsoc.org<mailto:pagid-bounces at list.clinimmsoc.org> [pagid-bounces at list.clinimmsoc.org<mailto:pagid-bounces at list.clinimmsoc.org>] On Behalf Of Sorensen, Ricardo [RSoren at lsuhsc.edu<mailto:RSoren at lsuhsc.edu>]
Sent: Tuesday, May 22, 2012 2:12 AM
To: pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>
Subject: Re: [CIS-PAGID] Advice please

Rohan,

You have demonstrated that your patient has recurrent respiratory
infections that improve on gammaglobulin replacement therapy. There may
be no immune defect detectable by common evaluation methods. But you
have not ruled out several possible defects:

Poor serological memory after immunization with pneumococcal vacccines,
as mentioned by Richard Wqsserman.

IgG subclass deficiencies with normal anti-penumococcal antibodies. They
are rare, but do exist beyond any doubt in my experience.

Different SAD (specific antibody deficiency phenotypes) phenotypes.
These have not been appropriately published yet, but there are several
that can not be diagnosed if you do not provide an exact immunization
history with dates, and the date of evaluation plus the specific values
and method of measuring pneumococcal antibodies. This phenotypes
include unresponsiveness to conjugate polusaccharides that may be
obscured by a subsequent normal response to the polysaccharide vaccine,
unresponsiveness to pure polysaccharides (the commonly known one, less
frequent in children that the firs one) , poor memory, and also possible
real functional deficiencies that are hard to document because trustble
opsonbpophagocytic assays are not easily available. These later
deficiencies are common in the elderly and can  be indirectly suspected
when low class switched memory B cells are present. An IgE level is also
essential and a documentation of how you diagnosed his allergies.

I will be glad to continue this discussion of you provide this
information.

Best regards,

Ricardo Sorensen

-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org<mailto:pagid-bounces at list.clinimmsoc.org>
[mailto:pagid-bounces at list.clinimmsoc.org<mailto:pagid-bounces at list.clinimmsoc.org>] On Behalf Of Rohan Ameratunga
(ADHB)
Sent: Friday, May 18, 2012 2:23 PM
To: pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>
Subject: [CIS-PAGID] Advice please

Dear Colleagues,
I would be most grateful for your opinions on this patient.

Case history

7 year old boy. Developed asthma early infancy. Good response to asthma
prophylaxis.
Developed chronic sinus disease aged 5 including polyps.
Multiple and continuous upper and lower respiratory infections.
Atopic (dust mites, grasses etc) desensitised.- partial improvement.
Adenotonsillectomy- partial improvement
Placed on prophylactic antibiotics (Co-trimoxazole) - but continued to
have breakthrough bacterial infections at least 1x per month. Usually
H.influenzae in spite of vaccination and antibodies.

Investigations

CT sinuses pansinusitis/ nasal polyps
Normal Immunoglobulins 7 g/L (nr >7) and good response to HIB, dip-tet
and pneumovax vaccines
Noted to have 8% double negative T cells (CD3+CD4-CD8-) Gamma-delta
cells awaited.  No other features of ALPS.
Normal in vitro lymphocyte responses to lectins and antigens
(diphtheria, tetanus, Candida)
Primary ciliary dyskinesia unlikely - normal ultrastructure and normal
NO.
Normal sweat test.

Management

Underwent functional endoscopic sinus surgery- rapid recurrence of upper
respiratory tract infections. Subsequently has balloon dilatation of
nasal passages.  Regular sinus lavages.
Continued to have breakthrough upper and lower respiratory tract
infections in spite of above.
Repeat CT sinuses- worsening sinusitis
I was concerned he was at high risk of bronchiectasis.  He had a chronic
moist cough in spite of prophylactic antibiotics.

He was given a trial of subcutaneous immunoglobulin at the beginning of
2011.
There was a dramatic response to this.  His sinus disease settled, he no
longer needs prophylactic antibiotics and has 1-2 bacterial infections
per year while on subcut Ig.  His chest is clear.
Major improvement in QOL- was attending school/ daycare 50%- has only
missed three weeks in the last year after starting Ig.  Can participate
in soccer, watersports, gymnastics etc. Essentially normal busy life.
Previous weight gain 1.5 kg/y- has gained 4kg in 15 months since
starting Ig.
CT sinuses not repeated as he is so well.

Questions

Has anyone had a similar experience?  Presumably this is an
anti-inflammatory response rather than treating an undefined immune
defect.
Interestingly, there is support for this approach in the literature.  A
trial of IVIG seems to have shown objective markers of improvement in
similar patients.
Any comments from any of the authors?  Not sure if Dr Ballow is on the
list serve.
The question is how long to continue the scIg given the dramatic
response.  One option is to stop in our summer (Nov) and review.  Any
comments?

Ramesh S, Brodsky L, Afshani E, Pizzuto M, Ishman M, Helm J, Ballow M.
Open trial of intravenous immune serum globulin for chronic sinusitis in
children. Ann Allergy Asthma Immunol. 1997 Aug;79(2):119-24.

Thanks in advance

Rohan Ameratunga
Adult and paediatric immunologist
Auckland
New Zealand



--
Mark Ballow,MD
Allergy & Immunology Division
Women & Children's Hospital of Buffalo
SUNY Buffalo,School of Medicine
219 Bryant St
Buffalo, NY 14222
716-878-7105