[CIS PIDD] [MARKETING]Re: [cis-pidd] Refractory thrombocytopaenia, splenomegaly and high IgM
CIS-PIDD
cis-pidd at lists.clinimmsoc.org
Tue Mar 1 05:34:09 EST 2016
Is the IgM clonal or polyclonal?
Richard Wasserman
Dallas
On Mon, Feb 29, 2016 at 7:25 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
wrote:
> Karl,
>
> We have an indirect test for IgM binding to platelets in our lab at Quest
> in San Juan Capistrano, CA.
>
> The indirect test of platelet binding IgM in serum:
>
> Test code 91806-Platelet Antibody, Indirect (IgM)
> Laboratory Developed Test (As of 07/24/2013)
> ASR Class 1
> **This test is not available for New York patient testing**
>
> --------------------------------------------------------------------------------
> ALIASES : Platelet Associated Antibody * Platelet Bound Antibody *
> Platelet-bound Platelet Antibody
> CONTACT : CLS at 24341 in Special Hematology
> CPT CODES : 86022
> PREFERRED SPECIMEN
> SPECIMEN : Serum
> VOLUME : Standard: 2 mL - Minimum: 1 mL **
> CONTAINER: SST (red-top) (preferred)
> Red-top (no gel)
> SHIP.TEMP: Ship room temperature / Okay to thaw
> STABILITY: Room temperature: 7 Days
> Refrigerated: 14 Days
> Frozen: 30 Days
> Note: No alternate specimen but specimen condition data-choose ST
> option
> REJECT CRIT: Hemolysis; Lipemia; Icterus
> INSTRUCTION: ** This test is not available for New York patient testing. **
> Collect 5 mL whole blood in a serum separator tube (red-top)
> and
> separate serum before submitting
> METHOD : Flow Cytometry
> SCHEDULE : SETUP DAY/TIME*** REPORT DAY/TIME***
> Tue E Wed E
> Sat E Mon E
> Report available: 2-5 days
> *** A=6am-12pm, P=12pm-6pm, E=6pm-12am, N(next day)=12am-6am Pacific Time
> ADDTL TEMP : Shipping refrigerated acceptable; Shipping frozen acceptable
> USE : The identification of circulating platelet antibodies is
> useful
> in order to identify immune-mediated platelet destruction.
> Disorders associated with immune platelet destruction include
> isoimmune neonatal thrombocytopenia, drug induced
> thrombocytopenia, drug sensitivities, allergies and post
> transfusion purpura. The destruction is either congenital,
> ie.,
> autoimmune where a malfunction in the immune response results
> in
> the production of antibodies directed against "self" platelet
> specific antigens; or else platelet destruction occurs when
> the
> patient received platelet-specific antibodies from an outside
> source such as a non-compatible blood transfusion or maternal
> transfusion or maternal transfer across the placental
> barrier. In
> either of the above situations, the detection of platelet
> antibodies is useful in order to determine if an immune basis
> is
> responsible for the thrombocytopenia observed clinically.
> GEN INSTR : 10/28/13-New test (September 2013 Update)
>
>
> We do not have a direct test for IgM on patient platelet.
>
> Sincerely,
>
> Stan
>
> Stanley J. Naides, M.D., F.A.C.P., F.A.C.R.
> Medical Director, Immunology R&D | Interim Scientific Director, Immunology
> R&D
> Quest Diagnostics | Action from Insight | 33608 Ortega Highway| San Juan
> Capistrano, CA 92675| phone: 949-728-4578| fax: 949-728-7852
> stanley.j.naides at QuestDiagnostics.com
>
>
>
> -----Original Message-----
> From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
> Sent: Monday, February 29, 2016 2:32 AM
> To: CIS-PIDD
> Cc: michael.o'sullivan at health.wa.gov.au
> Subject: RE: [MARKETING]Re: [cis-pidd] Refractory thrombocytopaenia,
> splenomegaly and high IgM
>
>
> Dr. O'Sullivan:
>
> Thank you for sharing your case with the listserve. It is rather
> interesting.
>
> I leave it to others to comment on what genetic causes might be to blame
> (the senior immunologists certainly know more about this than I do).
>
> My "outsider"'s point of view -- with the grossly elevated IgM at 2180
> mg/dL, I see the case as one of three possibilities -- either an infection
> causing a cross-reacting IgM autoantibody that is your principal causative
> agent for the thrombocytopenia, or the patient having an autoimmune
> predisposition causing a pathogenic IgM autoantibody, or the high IgM as
> being a red herring -- that there is some other reason to explain the
> thrombocytopenia -- and the IgM is an epi-phenomenon after the same defect.
>
> (I do not know if there is a direct way to test for platelet-binding IgM's)
>
> As such, as an alternative to sirolimus, I would posit that it is possible
> either plasmapheresis or rituximab may have a beneficial effect, as well.
> (others may disagree)
>
> The concern for any immunouppressive, of course, is that the patient may
> get worse if the underlying latent infection is left undiagnosed (and
> untreated). Potentially higher if the infection is the cause of the
> autoimmune phenomenon. I am unfamiliar with the "usual suspects" for a
> child living in Western Australia (for us here, it is routine to have to
> rule out Histoplasma, Blastomyces, and sometimes Coccidioides). For the
> more generic patient, I would recommend ruling out HIV, Mycoplasma,
> parvovirus B19, HSV, CMV, EBV, and HHV-6 and -8 by PCR's. (I understand
> her HHV-6 IgM is positive -- blood PCRs would rule out if the child has an
> active HHV-6 infection, or if this is a false positive). THe past receipt
> of IVIG will complicate interpretation of serologic testing, of course.
> Tuberculosis should be ruled out by both PPD and Quantiferon (or TB.SPOT)
> testing, as she has received some immunosuppresion already. If the child
> has farm or animal exposure, Francisella, Leptospira, and Brucella must be
> ruled out (and Bartonella and Toxoplasma, if cats are in the house).
> 'Might be easiest to refer the child to an infectious disease pediatrician
> (if you haven't already), with the request to rule out infectious causes in
> a child with past and impending pharmacologic immunosppression.
>
> If there is an indolent infection identified, I would suggest that there
> are even odds that "taking care" of the infection may resolve the
> thrombocytopenia. Among the oldest mantras I've been taught -- an uncommon
> presentation of a common disease is more common than a common presentation
> of an uncommon disease.
>
> Good luck with the case.
>
> - Karl
>
> Karl O. A. Yu, M.D., Ph.D., F.A.A.P.
> Instructor of Pediatrics (Pediatric Infectious Diseases) University of
> Chicago - Comer Children's Hospital
> 5841 S Maryland Ave, MC 6054, Chicago IL 60637
> Pager: 773-702-6800 x1744
> Fax: 773-702-1196
> Lab phone (Bubeck Wardenburg laboratory): 773-834-6976
>
>
> ________________________________________
> From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
> Sent: Monday, February 29, 2016 4:02 AM
> To: CIS-PIDD
> Subject: VS: [MARKETING]Re: [cis-pidd] Refractory thrombocytopaenia,
> splenomegaly and high IgM
>
> Just a note:
>
> Stephan and I seem to agree on a potential diagnosis: APDS type I= PIK3CD
> (APDS type II = PIK3R1).
>
> Especially if naïve T cells low and TEM, TEMRA hi, these would support
> together with the progressive loss of B cells.
>
> However the ddg is broad, like Markus notes:
> " any (pseudo-)hyper-IgM and alps/cvid-like syndrome"
>
> Let us know what - if anything - you eventually find.
>
> ATB,
>
> Mikko
>
> -----Alkuperäinen viesti-----
> Lähettäjä: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
> Lähetetty: 29. helmikuuta 2016 11:43
> Vastaanottaja: CIS-PIDD
> Aihe: [MARKETING]Re: [cis-pidd] Refractory thrombocytopaenia, splenomegaly
> and high IgM
>
> Thank you all for your replies.
>
> Markus, she has metabolically active axillary, para-aortic, external iliac
> and inguinofemoral lymph nodes on PET scan although the nodes were not
> enlarged, and appearance on PET scan were stable when repeated 1 month
> later. We have not measured alphe-fetoprotein or checked for cold
> agglutinins (she has had a negative direct Coombs test). She has responded
> to varicella and rubella vaccination, pneumococcal IgG2 antibodies are
> 7mg/L (has not been vaccinated since receiving her primary course of
> pneumococcal conjugate vaccine as an infant), tetanus antibodies pending.
> There was occasional haemophagocytosis seen in lymph node but not in bone
> marrow, and ferritin is at the lower end of normal range. We haven't
> investigated for leishmaniasis, and I'll ask the family specifically about
> history of malignancy.
>
> Clinically there are no signs of autoimmunity or inflammation and the only
> significant abnormalities on examination are the large spleen and
> bruising. ESR remains high with normal CRP. The patient feels very well
> and would have continued playing football regularly if the haematologists
> had not recommended she stop while her platelet count is so low.
>
> Mikko, the genetic testing available locally will allow us to include your
> helpful suggestions, and I'll check her IgG subclasses.
>
> Stephan, we haven't assessed naive/memory and T cell activation yet but it
> is planned for this week when she returns for a repeat PET scan.
>
> Kind regards,
> Michael
>
>
> On 29/02/2016, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> wrote:
> > Naive CD4? APDS?
> > SE
> >
> > Beste Grüße
> >
> > Prof. Dr. Stephan Ehl
> > Medizinischer Direktor
> >
> > UNIVERSITÄTSKLINIKUM FREIBURG
> > CCI - Center for Chronic Immunodeficiency
> >
> > Breisacher Str. 117 - 2. OG, 79106 Freiburg i. Brsg., Germany
> > phone: +49(0)761.270-77300
> > Sekretariat +49(0)761.270-77550 fax +49(0)761.270-77600
> > e-mail:
> > stephan.ehl at uniklinik-freiburg.de<mailto:stephan.ehl at uniklinik-freibur
> > g.de>
> >
> > Von: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
> > Gesendet: Montag, 29. Februar 2016 09:40
> > An: CIS-PIDD
> > Betreff: Re: [cis-pidd] Refractory thrombocytopaenia, splenomegaly and
> > high IgM
> >
> > Dear Michael, another idea,
> > Was leishmania infection and hemophagocytosis excluded? Probably she
> > would be more ill, though. Did you check ferritin and sIL2R?
> >
> > Univ.-Prof. Dr. Markus G. Seidel | Päd. Häm. Onk. | Med. Univ. Graz |
> > Auenbruggerpl. 38, A-8036 Graz, Austria | Tel +4331638512621 | Fax
> > +4331638513717 | Secr +4331638513485 | Bitte keine dringenden
> > Patienteninformationen per Email | sent from my mobile phone | please
> > excuse typos
> >
> > Am 29.02.2016 um 04:42 schrieb CIS-PIDD
> > <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>:
> >
> > Dear all,
> >
> > We are seeing a patient in Perth, Western Australia, together with our
> > haematology colleagues who has refractory thrombocytopaenia and
> > splenomegaly. She is a 10 year old girl, no significant past medical
> > history prior to this episode. Dad (part Japanese and born in
> > Australia), mum (Romanian) and a 7 year old brother are all well. No
> > family history of autoimmune, lymphoproliferative or immunodeficiency
> > diseases. She has received routine childhood vaccinations without
> adverse reactions.
> >
> > She had a systemic illness in September 2015 lasting 5 days with high
> > fevers and generalised aches. About 1-2 weeks later, Mum noticed
> > increased bruising with blood tests confirming thrombocytopaenia
> > (platelet count 2 x 10^9/L).
> >
> > On initial review in November 2015, the patient felt well with no
> > weight loss, fevers or sweats. She had petechiae and ecchymoses with
> > marked firm splenomegaly ~10cm below costal margin.
> >
> > Initial investigations
> > Full blood picture - normocytic anaemia (Hb 10g/dL), mild neutropaenia
> > 1.1 x 10^9/L, lymphocytes 1.9 x 10^9, a few atypical lymphocytes on
> > blood film suggestive of viral infection
> >
> > Ferritin 39mcg/L (normal 20-100), transferrin saturation slightly low
> > at 10%. Normal Vitamin B12 (540pmol/L) Normal UEC, liver function and
> > LDH EBV and CMV IgG and IgM negative IgG 10.6, IgA 0.5, IgM 16.3 g/L,
> > no paraprotein
> > C3 is slightly low at 0.69g/L, normal C4 0.29g/L ESR 70mm/hr, CRP
> > normal
> >
> > Raised lambda > kappa serum free light chains (ratio of kappa:lambda
> > borderline low).
> >
> > Negative ANA, dsDNA, lupus anticoagulant, rheumatoid factor.
> > Weak positive IgM anti-cardiolipin, moderate IgA B2GPI; negative IgG
> > aCL and B2GPI.
> >
> > Lympohcyte immunophenotyping on 2 occasions:
> > CD3 (T cells) 84 82 % (58-76)*
> > CD4 (CD4+ T cells) 54 53 % (30-52)*
> > CD8 (CD8+ T cells) 24 23 % (18-40)
> > CD4/8 Ratio 2.25 2.30
> (0.70-2.60)
> > CD19 (B cells) 9 5 % (11-27) *
> > CD16/56 (NK cells) 7 13 % (5-19)
> > CD3 Absolute Count 1008 1558 x10 ^6 /L
> (900-2500)
> > CD4 Absolute Count 648 1007 x10 ^6 /L
> (500-1400)
> > CD8 Absolute Count 288 437 x10 ^6 /L
> (400-1300)*
> > CD19 Absolute Count 108 95 x10 ^6 /L
> (200-500)*
> > CD16/56 Absolute Count 72 228 x10 ^6 /L (100-500)
> > GATED ON CD19+ B CELLS:
> > Naive B (IgD+CD27-) 89.4 %(49.0-100.0)
> > MZL Mem B (IgD+CD27+) 9.2 %
> (2.0-28.0)
> > CD27+ Sw Mem B (IgD-CD27+) 1.1 %
> (1.0-43.0)
> > CD27- Sw Mem B (IgD-CD27-) 0.3 %
> (3.0-10.0)
> > Bone marrow was hypercellular with increased numbers of
> > morphologically normal megakaryocytes and normal haemopoiesis. There
> > was no evidence of infiltration. Cytogenetics: normal (X;X).
> >
> > Treated with high dose IVIg (2g/kg) with no response.
> >
> > PET scan (December 2015): diffuse moderate metabolic activity in
> > spleen associated with some lymphadenopathy.
> > Axillary lymph node excision: Reactive hyperplasia. No evidence of
> > lymphoma or Castleman's disease.
> > No clonal B or aberrant T cell population on flow cytometry of the node.
> > Received IV methylprednisolone x 3 doses in January 2015 with no rise
> > in platelet count.
> > Repeat lymphocyte immunophenotyping in January and February 2016,
> > including TCR studies on double negative T cells
> >
> > Lymphocytes 2.3 1.7 x10 ^9 /L (1.5-7.0)
> > CD3 (T cells) 84 82 % (58-76)*
> > CD4 (CD4+ T cells) 55 57 % (30-52)*
> > CD8 (CD8+ T cells) 23 19 % (18-40)
> > CD4/8 Ratio 2.39 2.95
> (0.70-2.60)*
> > CD19 (B cells) 6 5 % (11-27)*
> > CD16/56 (NK cells) 10 12 % (5-19)
> > CD3 Absolute Count 1932 1394 x10 ^6 /L
> (900-2500)
> > CD4 Absolute Count 1265 952 x10 ^6 /L
> (500-1400)
> > CD8 Absolute Count 529 323 x10 ^6 /L
> (400-1300) *
> > CD19 Absolute Count 138 85 x10 ^6 /L
> (200-500) *
> > CD16/56 Absolute Count 230 204 x10 ^6 /L (100-500)
> >
> > CD3+CD4-CD8- T-cells = 7.7%
> > TCR as a % of CD3+ cells:
> > CD3+CD4-CD8-TCR Alpha/Beta =4.6%
> > CD3+CD4-CD8-TCR Gamma/Delta=2.9%
> > TCR as a % of Lymphocytes:
> > CD3+CD4-CD8-TCR Alpha/Beta =3.5%
> > CD3+CD4-CD8-TCR Gamma/Delta=2.2%
> >
> > The patient remains well, aside from thrombocytopaenia and bruising.
> > Her spleen is still enlarged, IgM now 21.8 g/L, platelets remain low
> > (3 x 10^9/L). EBV and CMV IgM and IgG were negative in both November
> > and February. HHV6 IgG was positive with negative IgM in November, and
> > on repeat in February HHV6 IgM and IgG were both positive.
> >
> > We will arrange sequencing of FAS, FASL, FADD, CASP8 and CASP10
> > (despite the normal vitamin B12), and were planning a trial of
> > sirolimus in advance of a definitive diagnosis based on the
> > encouraging results from recent publications in ALPS and other
> refractory cytopaenias.
> >
> > I'd appreciate any recommendations the group may have on further
> > investigations or treatment options, particularly if you would suggest
> > considering an alternative to sirolimus?
> >
> > Kind regards,
> >
> > Michael
> >
> > Michael O'Sullivan | Consultant | Immunology Fiona Stanley Hospital
> > Level 1, Pathology, 102-118 Murdoch Drive, MURDOCH WA 6150
> > T: (08) 6152 8006<tel:%2808%29%206152%208006> | F: (08) 6152
> > 8051<tel:%2808%29%206152%208051>
> >
> > Princess Margaret Hospital
> > Roberts Road, SUBIACO WA 6008
> > T: (08) 9340 8310<tel:%2808%29%209340%208310> | F: (08) 9380
> > 6246<tel:%2808%29%209380%206246>
> >
> > E:
> > michael.o'sullivan at health.wa.gov.au<mailto:first.last at health.wa.gov.au
> > www.health.wa.gov.au<http://www.health.wa.gov.au/>
>
>
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Allergy Partners of North Texas
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