[CIS PIDD] [cis-pidd] HSCT consideration for CID/Variant SCID

Joshi, Avni Y., M.D. Joshi.Avni at mayo.edu
Thu Oct 2 11:22:33 EDT 2014


Thank you all for your input.

Some updates:
Her repeat testing shows:

1)      CD3 T cells: 900( were 1100-1200 at birth and 1 month age)

B cells:86 (34 and 66 at birth and 1 month of age)

2)      Lymphocyte proliferation assay:

Minimally decreased CD45+proliferation to PHA, CD3 is robust and normal now.

3)      CD4 Recent Thymic Emigrant (RTE)@ 3 months age:

51% RA and 47% RO ( was 67%RA and 21%RO @1 month age)



4)      TREC:

1158 copies/106 CD3 T cells ( was 1593 copies /106 CD3 T cells@ 1 month age)



5)      WES is pending.


We are planning on repeating her immune studies in 3 months' time and holding off on the transplant.
Will post her progress on the list serve over time.

Thank you all again for your input.

Sincerely,

Avni

Avni Joshi
Mayo Clinic, Rochester, MN




From: Keller, Michael [mailto:MKeller at childrensnational.org]
Sent: Thursday, September 25, 2014 3:31 PM
To: CIS-PIDD
Subject: RE: [cis-pidd] HSCT consideration for CID/Variant SCID

Were the TRECS absent, or just low?   I wonder how they'd look if you resent them now?

I wonder if you could check markers of T-cell activation (CD69, HLA-DR) with stimulation?

Tough decision but I agree with further testing particularly given the absent B-cells.   Radiation sensitivity testing sounds like a very good move.

Mike


-------------------------

Michael D. Keller MD

Division of Allergy / Immunology

Children's National Health System

111 Michigan Ave NW, Room 1W-314B

Washington, DC 20010

Clinic: 202.476.3016

Office: 202.476.5843

Fax: 202.476.2280

www.childrensnational.org<http://www.childrensnational.org>



________________________________
From: Daniel Conway [dhconway at hotmail.com]
Sent: Thursday, September 25, 2014 3:54 PM
To: CIS-PIDD
Subject: Re: [cis-pidd] HSCT consideration for CID/Variant SCID
I think that the best surrogate markers absent genetic determination or a definitive OI (the avoidance of which is the goal of NBS) for scid are low TREC, T cell lymphopenia, and low proliferations.  And these proliferations are low for this patient.

Spectratyping may not be as strong a surrogate marker of immune defect.

I would suggest transplant.


Sincerely,
Daniel H. Conway, MD
Assistant Professor of Pediatrics
St. Christopher's Hospital for Children
Drexel University College of Medicine

On Sep 25, 2014, at 2:48 PM, Cowan, Mort <mcowan at peds.ucsf.edu<https://urldefense.proofpoint.com/v2/url?u=http-3A__mailto-3Amcowan-40peds.ucsf.edu&d=AAMGaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1CtvFqkSey45L0vbcX0oKI&m=0WbJ6awOFn-5MHDZMcwWDspe_HyDmeX70FrrVH3uTXI&s=Hg41ghdfZSmNICW6qo2eWSfjKEAqD-T5QMk9rnRfAgE&e=>> wrote:
Great idea, Jack.  I'm putting that on our "to-do" list for the PIDTC.  I know Jennifer wants to do this as well.  m

Morton J. Cowan, M.D.
Professor of Pediatrics
Chief, Allergy, Immunology, and Blood and Marrow Transplant Division
UCSF Children's Hospital, Room M659
505 Parnassus Ave
San Francisco, CA 94143-1278

Phone: 415-476-2188
FAX: 415-502-4867

**Confidentiality Notice** This email communication and any attachments may contain confidential and privileged information for the use of the designated recipients named above. Distribution, reproduction or any other use of this transmission by any party other than the intended recipient is prohibited.

From: Bleesing, Jacob [mailto:Jack.Bleesing at cchmc.org]
Sent: Thursday, September 25, 2014 9:55 AM
To: CIS-PIDD
Subject: RE: [cis-pidd] HSCT consideration for CID/Variant SCID

I also agree with Mort.

Looking at our own (first year) experience with NBS, this seems to be (becoming) a recurring theme. The "shock & awe" approach to BMT seems appropriate for some/most, but not all cases picked up NBS

Perhaps the PIDTC (and its participating Centers) can come up with guidelines and practical tools to deal with this. It is easy to list relevant assays, such as TCR spectratyping, radiosensitivity studies, etc., etc.; it would be better if we can establish where this actually is offered (and executed in a timely fashion)

For example, having a handful of Institutions provide:


-          More extended T-cell function panels

-          CDR3 spectratyping

-          Radiosensitivity assays

-          [centralized] exome sequencing (to concentrate interpretative skills/learning curves)

And from a research (R&D of new diagnostic tools) perspective, see link below. The goal of this method is to establish the presence of antigen-specific precursor T-cells within the naïve T-cell compartment. Consider that the TREC/CD45RA-RO and other data places the patient in the [proverbial] grey-zone, establishing the presence of antigen-specific T-cells to several naïve epitopes [in the referenced paper derived from human cancers, HIV, HCV, CMV and influenza)] would be reassuring (at least to me it would).


http://www.ncbi.nlm.nih.gov/pubmed/20200354<https://urldefense.proofpoint.com/v2/url?u=http-3A__www.ncbi.nlm.nih.gov_pubmed_20200354&d=AAMGaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1CtvFqkSey45L0vbcX0oKI&m=0WbJ6awOFn-5MHDZMcwWDspe_HyDmeX70FrrVH3uTXI&s=RKIAgQSIgVntJO9nGEBUkOnhYkswlg2bTDMGa7LrvkY&e=>



Jack


From: Cowan, Mort [mailto:mcowan at peds.ucsf.edu<https://urldefense.proofpoint.com/v2/url?u=http-3A__mailto-3Amcowan-40peds.ucsf.edu&d=AAMGaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1CtvFqkSey45L0vbcX0oKI&m=0WbJ6awOFn-5MHDZMcwWDspe_HyDmeX70FrrVH3uTXI&s=Hg41ghdfZSmNICW6qo2eWSfjKEAqD-T5QMk9rnRfAgE&e=>]
Sent: Thursday, September 25, 2014 12:51 AM
To: CIS-PIDD
Subject: RE: [cis-pidd] HSCT consideration for CID/Variant SCID

Dear Avni,

I wouldn't jump to transplant for this child at this point in time.  Even though the PHA appears low, the T cell numbers are not that low, the CD45RA expression is not too bad, and I'm concerned that the TCR distribution by spectrotyping is normal.  This may be a CID but at 3 m/o I'm not sure you have enough data to prove it.  We have seen children like this improve over time and in fact, come off IVIG and make specific antibody and thrive w/o a transplant.

I would keep the child on prophylactic antibiotics and IVIG but would take my time and try to identify a gene mutation.  I would repeat the IgM (and T cell studies) over the next few months and see if they are improving.  It would be nice if you could immunize with tetanus a couple of times and then check for proliferation to antigen; not sure if this is possible while the child is on IVIG, however.

I'd like to hear others' comments.

Mort

Morton J. Cowan, M.D.
Professor of Pediatrics
Chief, Allergy, Immunology, and Blood and Marrow Transplant Division
UCSF Children's Hospital, Room M659
505 Parnassus Ave
San Francisco, CA 94143-1278

Phone: 415-476-2188
FAX: 415-502-4867

**Confidentiality Notice** This email communication and any attachments may contain confidential and privileged information for the use of the designated recipients named above. Distribution, reproduction or any other use of this transmission by any party other than the intended recipient is prohibited.

From: Heimall, Jennifer [mailto:heimallj at email.chop.edu<https://urldefense.proofpoint.com/v2/url?u=http-3A__mailto-3Aheimallj-40email.chop.edu&d=AAMGaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1CtvFqkSey45L0vbcX0oKI&m=0WbJ6awOFn-5MHDZMcwWDspe_HyDmeX70FrrVH3uTXI&s=Lrz5clqylB_dI255g3tfX93qJHOfJSjMujb61jOA9Rg&e=>]
Sent: Wednesday, September 24, 2014 9:17 PM
To: CIS-PIDD
Subject: Re: [cis-pidd] HSCT consideration for CID/Variant SCID

Yes, I would. I think you are right that this is consistent with an atypical SCID. You could consider whole exome sequencing as there are few known mutations missed by the gene ex comprehensive panel but I would not wait for that result before transplant with the worsening T cell numbers, low B cells and poor PHA stim.
You might consider also getting a radio sensitivity assay completed before the transplant since this is a t/b negative phenotype.

Hope the patient does well!
Jen


Sent from my iPhone

On Sep 24, 2014, at 10:30 PM, "Joshi, Avni Y., M.D." <Joshi.Avni at mayo.edu<https://urldefense.proofpoint.com/v2/url?u=http-3A__mailto-3AJoshi.Avni-40mayo.edu&d=AAMGaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1CtvFqkSey45L0vbcX0oKI&m=0WbJ6awOFn-5MHDZMcwWDspe_HyDmeX70FrrVH3uTXI&s=vuXUyWGWntSC9hT14zOgaQ84fhDnYkWU5j2CrT7nXWo&e=>> wrote:
Dear Colleagues,
We seeking your input for consideration of HSCT in a 3 month old female infant who was picked up via the NBS for SCID in MN.

She has shown evidence of :
T cell lymphopenia ( CD3 -1100-1200 cells/mcL)
B cell lymphopenia (34 cells/mcL)
NK lymphocytosis ( 1400cells/mcL)
with decreased thymic output(67% express CD45RA)and TREC at 2 wks age.

Sequential T cell measurement has shown declining T cell numbers ( CD3:900cells/mcL) and decreasing CD45RA expression(~50%). Chimerism studies have shown all T cells to be of her own. Her TCR-vb spectratyping has shown gaussian distribution without any oligo-clonality.
B and NK cell counts have been stable.
Immunoglobulins:    IgA =2 mg/dL and IgM =12 mg/dL    IgG was normal .

Lymphocyte proliferation assay has showed very significantly decreased proliferation to PHA (Max proliferation --12% for CD3 and 6.5% for CD45).

She is now 3 months old and we have found a 10/10 matched  unrelated donor.
She is doing well on monthly IVIG, Bactrim and fluconazole prophylaxis. No rash or organomegaly.
Comprehensive SCID panel (Gene Dx) has come back negative.

She fits the picture of variant SCID or CID.

Would you proceed with HSCT?

Thank you for your input,

Sincerely,
Avni


Avni Y Joshi, MD, MSc
Mayo Clinic
Rochester MN







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