[CIS PIDD] [cis-pidd] treatment for IL12Rb1 deficiency

Fri May 16 11:00:24 EDT 2014

Thanks Dr. Morales Vasconcelos,

It is very helpful to know that you have been able to treat BCGitis to the point of no relapse.  We wanted to be more aggressive with his antimicrobial treatment but we are getting some resistance from his parents.  I think your experience will encourage them to do so.

He is not having diarrhea and his mesenteric LN have remained stable, on the small side (decreased in size since starting therapy February last year).

Thanks.
Elena
On May 16, 2014, at 5:00, Dewton Vasconcelos <dmvascon at usp.br> wrote:

> Dear Elena, good morning
> 
> Patients presenting IL-12Rb1 deficiency usually respond well to normal doses (50 mcg/m2/3 times a week), as signaling through IFN-g receptor is normal. 
> Moreover, despite IL-12 is the main inducer of IFN-g, there are other cytokines that can induce the production of IFN-g, such as IL-18, IFN-a etc. Therefore IL-12b (p40) or IL-12Rb1 deficient patients present a milder form of MSMD than IFN-gR deficient patients (even double-negative AD IFN-g deficiency).
> Your idea of testing the phosphorylation of STAT1 and STAT4 is interesting, as you can get a functional evaluation of IL-12, IFN-g and also IFN-alpha signaling.
> As the levels of antimycobacterial drugs are low, it's possible to think that if the doses are correct for his weight the patient is losing the drugs through the gut. 
> Does he present diarrhea? How are the mesenteric lymphnodes?
> It is possible to increase the doses of the antibiotic scheme and add ethambutol to increase the efficacy of the therapy.
> Our patients received long lasting anti-mycobacterial therapy (approximately 3 years); the drugs were withdraw without any further relapse of BCGitis.
> 
> Hope it helps.
> 
> Best regards,
> 
> Dewton
> Dewton de Moraes Vasconcelos, MD, PhD
> Primary Immunodeficiencies Outpatient Unit ADEE3003
> Lab. of Medical Investigation Unit 56
> University of São Paulo School of Medicine
> Elena Hsieh wrote:
>> Hi everybody,
>> 
>> We would like to ask your opinion for treatment approaches for BCGosis for a patient with IL12Rb1 chain deficiency.
>> 
>> This is a 3.5yr-old with a compound heterozygous IL-12 receptor beta1 chain deficiency complicated by BCGosis involving mainly pelvic and inguinal LN. His BCGosis has been treated with a combination of INH, rifampin, levofloxacin, clarithromycin for antimicrobial therapy. He also received interferon gamma 50 mcg/M2 3 times a week subcutaneously between February 2012 and April 2013. We saw him in July 2013 and performed antimicrobial serum drug levels sent to National Jewish, which were all somewhat low.  He also reinitiated IFN-gamma at that point at the above dose, and is currently still on it.  Recently, his MRI demonstrated slight increase in size of the R pelvic side LN, and his other para-aortic and mesenteric LNs are stable.  He’s clinically doing reasonably well, growing and developing appropriately. We plan to send blood to Wisconsin for flow cytometry analysis of any residual IL12R surface expression and function (STAT1, STAT4).
>> 
>> Here are our questions:
>> 
>> -        Has anyone been able to definitively treat BCGosis in the setting of Th1 immune defects using the combo of antimicrobials plus interferon-gamma?
>> 
>> -        If so, what dose and duration of IFN-gamma was used?
>> 
>> -        Are there alternative approaches we might consider other than HCT or gene therapy?
>> 
>> -        Paper from Dr. Cassonava’s group (Alangari et al., Clinical and Developmental Immunology, 2010) suggested that for IL12b1 deficiency patients, 200ug/M2 dose is effective and not at lower doses.  If anyone has used these higher doses, what are the toxicities we should monitor? (currently renal and liver function intact)
>> 
>> We appreciate your input.
>> 
>> Thanks.
>> 
>> Elena Hsieh, MD
>> 
>> Allergy and Immunology Fellow
>> 
>> Stanford University
>> 
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