[CIS-PAGID] Autoimmune neutropenia and CVID - need advice

[Hsu, Florence]

Good question — I suppose it's the combination of ANC 0, apparent lack of response to G-CSF when tried at an outside hospital in the setting of an infection, and the fact that she is having some infections — certainly more than before, and she recently had some oral mucositis.  Now on top of it all, her total IgG and IgM are "normal", so it'll be even harder to convince her she needs IV or SCIG.
How often have people seen IgG and IgM levels normalize in a case like this?  I am assuming it's the stress of her neutropenia and possibly infections driving a polyclonal humoral response.

Ida

From: <Kumar>, Ashish <Ashish.Kumar at cchmc.org<mailto:Ashish.Kumar at cchmc.org>>
Reply-To: "pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>" <pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>>
Date: Sunday, May 20, 2012 1:04 PM
To: "pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>" <pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>>
Subject: Re: [CIS-PAGID] Autoimmune neutropenia and CVID - need advice

What is the indication to treat this neutropenia – just the number? If her marrow capacity to produce neutrophils is normal, which looks like it is, then the risk of infection from the neutropenia is not that high. Treating with steroids in this situation will only add more morbidity. Rituximab is better tolerated and less likely to cause serious problems but I urge that you consider the cost-benefit ratio. In my small experience, I have treated patients like this with observation only  - one young woman has had an ANC of 0 for 3-4 years now; and no infections, granted while on IVIG.

Ashish Kumar

From: pagid-bounces at list.clinimmsoc.org<mailto:pagid-bounces at list.clinimmsoc.org> [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Nacho Gonzalez
Sent: Sunday, May 20, 2012 10:50 AM
To: pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>
Subject: Re: [CIS-PAGID] Autoimmune neutropenia and CVID - need advice


I have a similar patient (now 9y.o) with brain granuloma three years ago.She developed autoimmune neutropenia,anemia and thrombopenia. Rituxan worked well (Charlotte's has experience in this condition... See previous discussions in this mailing list). Due to chronic hepatitis and lung disease she is now under cyclosporine...uneventfully. So I would try with rituxan,works well with autoimmune citopenias refractory to steroids and immunoglobulins.
Best regards,

Luis Ignacio Gonzalez Granado
Immunodeficiencies unit
Hospital 12 octubre
Madrid.Spain
El 20/05/2012 16:21, "Hsu, Florence" <ida.hsu at yale.edu<mailto:ida.hsu at yale.edu>> escribió:
Dear all,

I am looking for some advice and insight into a challenging case, I'd appreciate any help!

We have a young woman (22 yo) under our care with history of CVID diagnosed incidentally at age 11 (in setting of Lyme meningitis), managed conservatively without IVIG (just PRN antibiotics) due to minimal infection history, and lost to follow-up, until she presented a fewmonths ago with severe neutropenia, anti-neutrophil antibody positive, ANC 0.

She is anemic and direct Coomb’s positive now as well.  BM biopsy was hypercellular with prominent lymphoid aggregates and small granulomas consistent with CVID, FISH and cytogenetics were normal.  She had no significant response to an initial trial of G-CSF.

Of note, this patient has been extremely resistant to therapy to date, refusing IVIG, as she has “managed so well” clinically without it so far, and quite frankly she is having a hard time accepting the fact that she has a serious illness that may require aggressive therapy.

My first question is:  what are the best therapeutic options for the neutropenia?  We are considering rituximab, but the hematologists here have limited experience with this in the setting of AIN.  She has also been very resistant to IVIG, which we feel is important for her to receive prior to any rituximab, as that would affect her already defective humoral immunity.  Should we just startwith corticosteroids, and how safe is that without IgG coverage?

Question #2:  Her IgG levels have actually increased from 388 in 2009, to 565 (around the onset of her neutropenia this spring), to 950 a month later!  We assume that this is not “normal” IgG, as she historically has not been able to mount a significant response to vaccinations, and recently had little IgG2 but elevated IgG3, would others agree?  Has anybody seenthis before, and does she still warrant IgG replacement (with or without her neutropenia)?  Recent CT done at outside hospital (in setting of bronchial infection at onset of neutropenia) did show mild mediastinal/para-aortic lymphadenopathy, splenomegaly, mild bronchiectatic changes, and bilateral nodular infiltrates <2cm size

Question #3:  She is returning tomorrow for repeat post-vaccination titers (conjugated pneumococcal, meningococcal, and Tdap) – what other labs would you suggest we check?

Thank you so much for your help!!!

Sincerely,
Ida Hsu
Section of Allergy and Immunology
Yale University School of Medicine
Phone: (203) 785-4143
Fax: (203) 785-3229


Her labs to date if you are interested, note that she has NEVER received IVIG:

Vaccine history:
Meningitis vaccine – 2008, N. meningitidis IgG undetectable in 7/09
Pneumovax – 8/21/09, responded to 3/12 serotypes
Conjugated pneumococcal and meningococcal  vaccines – 1/15/10 (lost to follow-up, immediate post-vaccination titers not checked, but titers to both were all low when checked in 3/12)

8/15/97
IgG 466
IgA 10
IgM 8
VZV Ab negative

10/27/03
IgG 521
IgA 7
IgG1 361
IgG2 undetectable
IgG3 112
IgG4 undetectable
HIB 0.31
Tetanus <0.10
Flow – lymphopenia noted, predominantly affecting T, NK cells. CD3+ 646, CD4+ 405, CD8+ 189

1/3/09
IgG 405
IgA 10
IgM 26
WBC 2.5
ANC 1790
ALC 380
EBV VCA-IgM positive

7/31/09
IgG 492
IgA <7
IgM 21
IgE <2
Pneumococcal – all <.22 except for serotype 5 – 0.46
Neisseria meningitidis IgG – all undetectable (prev vaccinated for college)
HIB 3.0
Tetanus <0.10
VZV indeterminate
EBV-VCA IgG Positive
Flow cytometry - absolute decrease in T, NK, B cells.  CD3+ 568, CD4+ 349, CD8+ 156, CD45RA+ 225, CD45RA+ 218, NK 31, CD19+ 69

10/12/09
IgG 388
IgA <7
IgM 14
IgE <2
Pneumococcal  3/14 titers >1 - 5, 18C, 19F (post–vaccination on 8/21/09)

7/24/10
IgG 386
IgM 16
IgA 6

Outside hospital 2/27 –3/5/12:
Sputum PCP negative
Influenza A/B Ab negative
Legionella Ag negative
Parvovirus B19 IgG, IgM negative
CMV DNA negative
Strep pneumo Ag negative
IgG 418, IgA 9, IgM 280
Flow cytometry:
CD45+ lymphocytes  0.4
CD3+ 354
CD19+ 18
CD 16/56+ 17
CD4+ 285
CD8+ 59
H/S ratio 4.9 (>1)

CBCs in early March:
WBC 0.8 – 1.3 (as low as 0.7 on 2/27)
ANC 0.1 – 0.2  (as low as 1% of 3.88 on 3/04, 3% of 4.06 on 3/04)
Hgb 10.9 – 12.2
Plts 95 – 107 (as low as 60 on 2/27)

3/07/12
IgG 565
IgM 553
IgA <7
IgE <2
IgG1 308
IgG2 16
IgG3 294 (elevated)
IgG4 <0.2
Histoplasma ID neg
Flow cytometry – marked leukopenia, lymphopenia.  Increase in CD45RO positive cells for age.  Marked non-specific binding of Ig to B cells.  CD4+ 598, CD8+ 101
HIB 1.8
Pneumococcal Abs – all low,<0.26
Tetanus <0.10
N meningitidis negative to A, C, Y, W-135 serogroups
HBV SAb, CoreAb, SAg  negative
HIV 1/2 negative
HCV negative
CMV PCR negative
Parvo B19 PCR negative
DAT Coombs negative
LDH 184
ACE 49
Anti-neutrophil Ab – POSITIVE.  "Neutrophil reactive antibodies (IgM only) and class I HLA antibodies were detected in the patient's sample.  The reactivity against neutrophils was still present following absorption with normal donor platelets (removes class I HLA antibodies)."

3/13
Vitamin B12 1076
Folic Acid 815
DAT negative

4/9/12
IgG 950
IgM 692
IgA 8
B. pertussis Ab 0.2
CBC 1.0/11.7/126, ANC 0.0

5/1/12
ABO Group/Rh B+
Ab screen negative
DAT Positive (IgG Positive, C3 Positive)
CBC 0.7/8.8/128


Imaging:
2/27/12 - CT C/A/P
Mild mediastinal and para-aortic adenopathy
Moderate splenomegaly
Multiple bilateral nodular consolidations <2 cm w/centrilobular infiltrates
Multiple hypodense lesions in both kidneys, up to 1.9cm, may represent renal carbuncle, masses, or less likely infarcts.  Bilateral renal scarring is noted.

5/1/12 CXR
Clustered nodular opacities in the right midlung similar to that seen on prior chest CT from 2/27/2012 and likely represent focal areas of bronchial impaction with possible developing bronchopneumonia. Mild bronchiectatic changes again seen bilaterally, better appreciated on the prior CT.

________________________________
F. Ida Hsu, M.D.
Section of Allergy and Immunology
Yale University School of Medicine
Phone: (203) 785-4143
Fax: (203) 785-3229
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