[CIS-PAGID] IVIG reaction

[Seppänen Mikko]

Dear Charles,

I have just one pt with severe SLE + (extra as well) -intestinal Crohn's + RTX+ then developing falling IgG, IgA  --> CVID-like secondary PAD (=genetically predisposed??) and several septic episodes before IRT, Ig production never recovered.

She certainly very much sounds like Yours, tolerated IVIg - after a while - very poorly, but nowadays she tolerates weekly infusions of Subcuvia very well, very few mild infections = presently the least of her many problems...

mikko seppänen
Helsinki, Finland
________________________________
Lähettäjä: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] Puolesta Kirkpatrick, Charles
Lähetetty: 22. helmikuuta 2012 19:10
Vastaanottaja: pagid at list.clinimmsoc.org
Aihe: Re: [CIS-PAGID] IVIG reaction

Here is how I have handled these reactions.  Most patients do well when they are changed to SQ IgG.  However, a have a few patients who are antibody deficient after receiving Rituximab.  Two of them have SLE as the primary disease.

Both did well on IV IgG for over a year and then began to have dyspnea and chest tightness with each IV infusion,  One developed a diffuse erythroderma and the other has extensive urticaria and mild angioedema.  Changing lot numbers and brands of IV IgG did not solve the problem..Changing to SQ IgG worked for a few months then the reactions recurred.

Eventually, we divided the monthly dose of IgG by 30.  Each patient gives herself a small subcutaneous infusion (7 cc in 1 case; 10 cc in the other) each evening.  So far this schedule is working.

As I mentioned, the primary diagnosis is SLE in each patient.  Are these patients more likely to react to IgG in the experience at other centers?

Charles Kirkpatrick



From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Richard Wasserman
Sent: Monday, February 20, 2012 7:49 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS-PAGID] IVIG reaction

Virtually all of the data we have on IgG treatment derives from industry sponsored trials going back more than 30 years. I believe that the development of those protocols is heavily influenced by the regulatory agency guidance. It would certainly be nice if the agencies or a group of immunologists could agree on a standardized description of systemic and local IgG side effects with a scoring system for each. At this time, most studies use some qualitative scale of mild, moderate and severe with no definition of what constitutes a mild, moderate or severe episode of migraine or malaise. The decision is up to each investigator at each site. This is complicated by the subjective nature of these adverse events. Nevertheless, as a community, we are not doing the best for our patients if we can't collect meaningful data.
Richard Wasserman
2012/2/20 Seppänen Mikko <Mikko.Seppanen at hus.fi<mailto:Mikko.Seppanen at hus.fi>>
Dear all

It would be hard to disagree with Richard and Melvyn on conclusions we should draw. However, to come up with WHAT exactly to follow up in the future clinical trials and in registry-generated data, these discussions are helpful, since many facets of what IgGRT might have as side effects (and what potentially causes them) would otherwise go unnoticed and unrecorded systematically!

So much to do, so little time! And especially, so little investigator-driven trials...

m

________________________________
Lähettäjä: 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>] Puolesta Berger, Melvin
Lähetetty: 19. helmikuuta 2012 5:08
Vastaanottaja: pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>
Aihe: Re: [CIS-PAGID] IVIG reaction
I totally agree with Richard's comments and wouldn't change one word.

One other thing I would say about systemic reactions to IVIG is that in several different studies/reports, it is noted that febrile and/or anaphylactoid reactions are more common with naive patients and when switching brands. This is likely for some of the reasons Richard described. I think that aseptic meningitis and severe headaches occurring several days after each infusion are probably of a different pathogenesis.  I have often found that either by shortening the interval between IV infusions and/or by using weekly subcu, and therby avoiding the big shifts in serum IgG (and presumably CSF IgG a couple of days later), the migraine/aseptic meningitis symptoms may be moderated. I notice that the patient in Niraj's original message has an IgG of only 563- is that on monthly IVIG ?  If so, I would suggest bringing the patient up slowly by giving smaller doses more frequntly by either IV or SC route.

Also, I wonder if this patient has an elevated Sed Rate, CRP and/or circulating immune complexes.


Melvin Berger, M.D., Ph.D.
Adjunct Professor of Pediatrics and Pathology
Case Western Reserve University
Cleveland, OH 44106

________________________________
From: pagid-bounces at list.clinimmsoc.org<mailto:pagid-bounces at list.clinimmsoc.org> on behalf of Richard Wasserman
Sent: Fri 2/17/2012 7:16 AM
To: pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>
Subject: Re: [CIS-PAGID] IVIG reaction
I have followed this thread with interest. While it is clear that there are differences in the frequency of both infusion site reactions (ISRs) and systemic side effects among the available gamma globulin products based on the published reports of their pivotal trials, the limitations of those reports preclude meaningful comparison.

Even if one were to ignore the fact that the studies were not controlled and were not contemporaneous, each study protocol prescribed a different system for capturing and evaluating ISRs; so different that it is not possible to compare the results. To my knowledge, there is not a broadly agreed upon system for evaluating either ISRs or systemic side effects in gamma globulin trials.

While interesting, ad hoc collections of anecdotes regarding gamma globulin tolerability are, at the end of the day, also of limited utility. Certainly, each of the products are well tolerated by some patients. Some patients appear to tolerate all products. Some patients have difficulties. In my experience, it is hard to predict which patient/product pairing will work the best; a lot to trial and error is required.

Having said all that, I don't think that, at this time, we can conclude that a particular stabilizer (glycine, proline or even carbohydrate) is responsible for ISRs. Similarly, I don't think a conclusion can be drawn regarding a relationship of IgA content and ISRs. Keep in mind that the insolation/purification methodologies are at least somewhat different for each product, that is why there are differences in IgA content. Although these methodologic differences do not introduce easily detectable, gross changes in IgG molecules, it makes sense that different processing techniques may cause, to different degrees, subtle alterations of the conformation of some of the IgG molecules in a preparation and these subtle changes explain the differences in tolerability.

Currently, there is at least one large scale registry type data collection effort underway in the US. Perhaps, although it is uncontrolled, the shear weight of large numbers of patient experiences will answer some of these questions, at least at the clinical level.

Richard L. Wasserman, MD, PhD
DallasAllergyImmunology
2012/2/17 Seppänen Mikko <Mikko.Seppanen at hus.fi<mailto:Mikko.Seppanen at hus.fi>>
Dear all

Vow, very interesting! Especially so, since I just a 4 weeks ago met a “possible CVID” (SPAD with IgG2 def, excess of transitionals in B diff, recurrent pneumonias, nodular lymphoid hyperplasia of lungs, sicca, psoriasis and autoimmune hypothyroidism) patient (w/o known migraine) who had her IgGRT started with IVIg (to reach plateau fast and easily), tolerated i.v. Privigen (with proline) well w/o headache, but once Octagam’s s.c. Gammanorm 16.5% (with glycine, I suppose it ) was started, got massive headaches lasting 2 days each after 2 infusions. Baffled, I switched her from 3. infusion on to s.c. Hizentra 20% (again with proline, same monthly dose in all) and headache disappeared completely! Just phoned her to check this actually was so. So it is NOT always about the peak and how fast one gets there…   And “the amino acid which in some patients causes headache individually differs”… ??

I cannot comment yet on Vivaglobin---> Hizentra switch, since we only got Hizentra from 1. Feb this year, and it remains to be seen whether I’ll get to see more headaches... My general impression on SCIg preparations (we also have Baxter’s Subcuvia) is that those with low IgA content might have less and milder local reactions, does anyone agree?

Jason, maybe we should publish these?

As to the migraine vs. infusion-related headache, I do have the same impression, but  it should probably be addressed more formally in some upcoming study?

__________________________________________________
Mikko Seppänen, MD, PhD
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
_________________________________________

Lähettäjä: 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>] Puolesta Hare, Nathaniel D
Lähetetty: 16. helmikuuta 2012 16:49
Vastaanottaja: pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>
Aihe: Re: [CIS-PAGID] IVIG reaction

Jason,

That is interesting.  I have discussed this with our neurologist.  The only reference I could find about this issue was:

http://www.ncbi.nlm.nih.gov/pubmed/8037406,

which concludes that aseptic meningitis is more likely to develop in patients with a history of migraine.  Not sure if that is true, but interesting to think about none the less.  My patient too has a history of migraines, and her migraines worsened after her first episode of aseptic meningitis.

Thank you for your comments.

Nathan


Nathaniel D. Hare MD
Allergy & Immunology
CMC - Dartmouth Hitchcock Keene
Keene, NH  03431

ph  (603) 354-5496
fax (603) 354-5498
________________________________
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 Jason Raasch, MD
Sent: Thursday, February 16, 2012 8:51 AM
To: pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>
Subject: Re: [CIS-PAGID] IVIG reaction

All,

A few observations:

I have found that quite predictably patients who have a history of migraine headaches  (before ever having IVIG) have difficulty with post-infusions headaches, often severe.  In these instances no amount/type of pre-medications, fluids, etc has been particularly helpful.  Are these episodes migraine or are they asceptic meningitis?  Are migraines a predictive factor for asceptic meningitis?

I have also had these same patients experience headache, "flu-like" symptoms (fatigue, nausea, myalgia) after Hizentra.  None of them ever has had an LP to see if consistent with asceptic meningitis.  No hospitalizations from ScIg.

 I have found that a fair number of patients who do not tolerate Privigen  (migraine history or not)  cannot tolerate Hizentra.  Proline intolerance?

When I started using Hizentra, I was quite dubious when patients would report adverse effects (as noted above) as most tolerated Vivaglobin without incident.  On 3 occasions with Hizentra, I switched patients back to Viva (when it was still available), had their symtpoms resolve, switched them BACK to Hizentra and their symptoms recurred.  These three have successfully transitioned to subcutaneous Gammagard Liquid and tolerating it without difficulty.

In patients who have not tolerated Hizentra (and again I find this more frequently than when we were using Vivaglobin) we have transitioned patients to subcutaneous GGL, Gamunex-C and even a few on subcu Flebogamma.

So Niraj, if this patient does benefit from IgG replacement (and for the sake of argument presuming it is indicated) I think consideration/discussion of product is important and in the case of ScIg (as Hans' points out) consideration of product, dose, frequency and method (pump versus push) of ScIg may be important.

It is interesting that we as a community typically oppose third-party mandates of what IVIG/ScIg product to use (freedom of choice) but in our academic discussions (particularly at meetings) we rarely discuss product-specific experiences.

-J


Jason Raasch, MD

Midwest Immunology Clinic
15700 37th Ave N
Ste 110
Plymouth, MN 55446

Phone: (763) 577-0008
FAX:     (763) 577-0192



On Feb 15, 2012, at 14:22 PM, Patel, Niraj C wrote:

Dear Colleagues,

I saw this patient for the first time this week, and she has extreme difficulty tolerating IVIG infusions.
45 yo female with lupus since 1994, history of pericarditis, antiphospholipid syndrome, oral ulcers and peripheral neuropathy. She received epratuzumab (antiCD22) for lupus in June 2008 (IgG level prior was 610).  She was started on IVIG in March 2009 for low IgG 530 (normal IgA, IgM) and chronic sinusitis despite. No antibody to vaccines was done.  She initially tolerated IVIG (400mg/kg) for several months (IgG levels in 700-800), until she began developing headaches, vomiting, fever.  No laryngeal swelling, wheezing, or hives.  Despite premedication with 50mg Benadryl, changing IVIG formulations, 20mg demamethasone the night prior and 20mg the morning of infusion, decadron (unknown dose) prior to infusion, and rate slowed to 70cc/hr (15 hour-long infusion), her symptoms worsened. She had aseptic meningitis in May 2011 and Nov 30 2011 thought due to IVIG, although the latter episode occurred 6 days after infusion and no lumbar puncture done either time. Symptoms included fever, neck pain, vomiting, photophobia and was hospitalized for 1 week each time and treated with high-dose steroids.

During the almost 2 years on IVIG, she noted remarkable improvement in sinus symptoms and had just 1 sinusitis during this time period (compared to chronic nasal symptoms and antibiotics at least once monthly prior to IVIG).  She stopped her IVIG after Nov 30 2011 due to adverse reaction and her chronic nasal symptoms returned after 4-6 weeks.  CT of sinus this week was negative except scant sphenoid fluid and endoscopy of nasal passages was normal (she was on levoquin at that time).  Most recent labs on 1/26/12:

IgG 563 (791-1643)
IgA 89 (66-436)
IgM 75 (43-279)
WBC 9,100
ALC 1,065
CD19B 53 (90-660)
CD3T 809 (690-2,540)
CD4T 405 (410-1,590)
CD8T 362 (195-1,140)
CD56/16 181 (90-590)

1) Would you restart Ig replacement? Try subQ in a monitored setting?
2) Hold on Ig replacement therapy until more definitive evidence of a chronic infectious process?
3) Could an autoantibody to Ig be present in this setting?  If so, offer rituximab?

Thank you in advance for your help.

Niraj

Niraj Patel, MD MS

Department of Pediatrics
Infectious Diseases and Immunology
 Levine Children's Hospital
Carolinas Medical Center
PO Box 32861
Charlotte, NC 28232-2861

Tel:   (704) 381-6803
Fax:  (704) 381-6841
Appt: (704) 381-8840

Email: niraj.patel at carolinashealthcare.org<mailto:niraj.patel at carolinashealthcare.org>


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Richard L. Wasserman, MD, PhD
DallasAllergyImmunology
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--
Richard L. Wasserman, MD, PhD
DallasAllergyImmunology
7777 Forest Lane, Suite B-332
Dallas, Texas 75230
Office (972) 566-7788
Fax (972) 566-8837
Cell (214) 697-7211
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