[CIS-PAGID] Rituximab and Chronic ITP PATIENT NUMBER 2

[Seppänen Mikko]

Dear all,

I completely agree with points raised by Drs Vasconcelos and Routes (for example one naturally has to think of other forms of PAD than CVID), though I would test only after >>12 months after rituximab. Best data on vaccine responses and rituximab in my opinion comes from Pescovitz MD et al JACI 2011;128:1295-302, does anyone know additional good data...?

OWN CASE:
I actually have my own very similar patient as well presently in our unit, just 10 minutes ago I was consulted on him. I personally met him in September.

Patient is male, 22-year old:
His story does make one think of CVID, but disconcertingly, he IS still able to produce IgE (18 IU/l) as well as specific anti-horse-IgE (RAST positive). This would, in genuine CVID, be rare indeed? Also has very few clinical infections to date and is also chronically eosinophilic since at least Oct 2008 (0.65-0.77-1.02-0.86 x 10to9th/appr 10%). No parasites found, is asthmatic... no nasal polyposis, no Samter's triad.

Bronchial asthma since adolescence, ITP since April 2007, difficult to reach remission in ITP, p.o. Prednisolone + IVIg w/o response, then dexamethasone pulse steroids + prednisolone p.o., 2009 again twice dexamethasone pulse steroids and finally rituximab x4 (1-2/2010). 

Since 2/10 in remission, NO immunomodulatory therapies in 21 months now.

Since Jan 11 IgG+IgA-hypogamma noted (no previous levels known), IgA 0.44-0.40-0.44 g/l, IgG 3.4-4.4-4.0 g/l, IgM 0.69-1.08 (normal and still increasing).

B-Ly normal since March 2011, in 4-9/11: 1.75-1.77 x 10 to 9th, Ly diff 4/11-9/11:

CD3+       CD19      CD4         CD8        NK (CD16+56+) 
0.71       0.08      0.346       0.36       0.19
1.00       0.11      0.488       0.50       0.27

thus basically normal, CD4s normalized in appr. 19 months after immunomodulation stopped

Very recent EUROClass: B+smB-21normTr norm, 
The exact B-cell FACS results:
B-cell Ags         %         T-cell Ags % 
__________________________________________________________  
CD19                 8       CD3          71   
CD19&CD21*           84      CD4&CD3      34   
CD19&CD27*           3       CD8&CD3      35   
CD19&CD27&IgD+IgM+*  2,4                       
CD19&CD27&IgD-IgM-*  0,5     Other        
CD19&CD38lowCD21low* 13,4    Ags       
CD19&CD38++IgM++*    6,3     CD3-&CD16/56 20   
__________________________________________________________
activated CD38lo21lo B cells 3.4% of all B cells, thus high.

Before testing of vaccine responses, a.o.t. vitamin A, B12-TC2 normal, S-prot normal, fecal antitrypsin as well, no proteinuria. 

Tetanus (strong T-B-recall Ag) 0.26-0.20, DEcreases after vaccine, diphtheria (weak T-B-recall Ag) NO change 0.03-0.02, thus insufficient. Cf. the article I mention above. Should be able to produce by now....?
Pneumovax: very low 0-titers, no increases after vaccine in 7/7 serotypes. 

He has almost no infections, seems to recover even from flus normally, but still HRCT shows thick-walled bronchi, centrilobular ground-glass nodularity, pronounced interlobular septae, especially in upper lung fields, and I am concerned that if I wait too long bronchiectasis may develop.

Scientifically, I agree that CVID dg is not certain, more so since we still in my opinion know a little too little about rituximab (Somehow the situation is analogous to cases where - after treated nHL - one develops CVID-phenotype, often extremely typical and might even had recurrent rep infections for years before nHL dg, and we cannot be certain if it is secondary when comparing with CVID who only after CVID dg develops nHL though both look the same..). 

I would be quite certain of the dg IF IgE was below detection limit, regardless of clinical infections...? But this young man still produces IgE, even specific anti-horse-IgE (he also has clinical allergy against horse, allergic rhinitis, conjunctivitis).

Thinking analogously of the typical pediatric recurrent ITP--> Evans ---> CVID: earlier we did not use rituximab, but have given number of diagnoses of CVID after other life-saving immunomodulatory treatments. These ITP/Evans + rituximab -patients likely will come more and more common in the future.... This is not the first I have seen (met 2-3 previous patients, all others have had no IgE-production and all have then developed full blown CVID).

I would value Your opinions!!! 

I personally think he is in the process of developing CVID, "almost there"?? We will start SCIg, but will measure IgA and IgE periodically and if necessary (if these raise and not decrease as one would expect), reassess later...
Have You seen patients like this, what happened to them in the follow up?? Any other suggestions as to the hypogamma diagnosis?

Yours

mikko

__________________________________________________
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
_________________________________________


-----Alkuperäinen viesti-----
Lähettäjä: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] Puolesta Dewton Vasconcelos
Lähetetty: 7. joulukuuta 2011 15:11
Vastaanottaja: pagid at list.clinimmsoc.org
Aihe: Re: [CIS-PAGID] Rituximab and Chronic ITP

Dear Rafael

I think that despite low IgG it is not possible to ascertain that your 
patient has CVID.
Other diseases can present low IgG and autoimmunity, for example the 
hyper IgM syndromes.
Among these, CD40 and CD40L deficiencies are more related to cellular 
defects and some of them present CNS infections such as JC or 
enteroviral infections, and neutropenia is common in these patients.
Think in the possibility of CVID, some of these patients present a ALPS 
phenotype with hematological autoimmune manifestations.
In the context of Rituximab, nowadays is not useful to look for B cell 
subpopulations, but if the patient improves we can test him later.
Low CD4s and NK cells can be associated to the primary disease (a PID?) 
or to the severe infection (it is common to see this feature in patients 
presenting disseminated tuberculosis or cryptococcosis).

All the best,

Dewton Vasconcelos
University of São Paulo

Rafael Firszt wrote:

> I am seeing a 14 yo boy with a history of chronic ITP and neutropenia who got Rituximab in March of this year.  He was just admitted to hospital with encephalitis of unknown cause. Before Rituximab was given he had an IgG of 478.  Since being admitted he got a dose of IVIG but no functional studies have ever been done on him.  He has no history of other infections.

>

> His Enumeration drawn last week shows:

> CD4:CD8 Ratio:   ratio  * 1.05

> % CD19:  %  * 12

> % Natural Killer Cells:    * 3 L

> % CD3:  * 84

> % CD2:  %   86

> Absolute CD4   * 373 L

> CD4+CD45RO+ cells   * 249

> Absolute CD45RA   * 112 L

> Absolute CD8   * 356

> Absolute CD19   * 105

> Absolute Natural Killer Cells   * 30 L

> Absolute CD3  * 747

>

> Therefore he has low NK cells, low CD4 and low CD45RA.  It is interesting that his B cell count is normal.

>

> He has ongoing work-up for his encephalitis but ID feels it is most likely virally-induced.

>

> I can't test him for function because of recent IVIG.

>

> With history of ITP, neutropenia, initial low IgG and now encephalitis he likely has a form of CVID (I think).

> Based on this history I several questions:

>

> 1) Any other investigations?  (I have mitogen studies pending)

> 2) Would you continue IVIG monthly assuming he has CVID or would you stop and re-evaluate his function after several months to confirm the possible CVID

> 3) In CVID or after rituximab, have any of you seen low NK cells and low CD4 and low CD45RA in either of these situations?

>

> Thanks for any help

>

> Rafael Firszt

> University of Utah

>

>