[CIS-PAGID] IVIG reaction

[Richard Wasserman]

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>


> **

> 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] *Puolesta *Berger, Melvin

> *Lähetetty:* 19. helmikuuta 2012 5:08

> *Vastaanottaja:* 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

> anaphylact*oid* 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 on behalf of Richard Wasserman

> *Sent:* Fri 2/17/2012 7:16 AM

> *To:* 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>

>

>>  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-à 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****

>>

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>>

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>>

>> FINLAND****

>>

>> phone +358 9 47175923, fax +358 9 47175945****

>>

>> _________________________________________****

>>

>> ****

>>

>> *Lähettäjä:* 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

>> *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] *On Behalf Of *Jason Raasch, MD

>> *Sent:* Thursday, February 16, 2012 8:51 AM

>> *To:* 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****

>>

>> ****

>>

>> ****

>>  ------------------------------

>>

>> ****

>>

>> *This electronic message may contain information that is confidential

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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

>




-- 
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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