[CIS PIDD] [cis-pidd] 16 y/o F with lung and CNS lesions, lymphopenia, absent NK cells, hypocellular bone marrow and lymphohistocytic infiltrate in lung

[Jonathan Tam]

Thank you everyone for your responses.

Dr. Chase - yes, he did have TPMT testing prior to starting azathioprine
and it was normal.

Dr. Gonzales and Dr. Weimer - we just recently sent studies for ALPS and
are waiting for them (as they are send out).  I looked at the flow and
since the CD56+ are so low it's hard to say anything about bright versus
dim sets.  We didn't send NK cytotoxicity out because of the low numbe rof
NK cells, but we may just to see.  Soluble IL2R levels are similarly
pending.  HSV from the CSF was negative.  Her family has refuse brain
biopsy.

Dr. Rosenzweig and Dr. Grimbacher - we'd love to test for CTLA4
haploinsufficiency.  Don't they all have some form of hypogam though?
Could she still have it with her level of immunoglobulins? (IgG 787 mg/dL,
IgM 130 mg/dL, IgA 114 mg/dL, IgE 119 kU/L)
Dr. Wysocki - She hasn't fully met criteria for HLH, but we still have a
few things pending.

Dr. Mordaunt - she was developmentally normal prior.  She was a normal 16
y/o girl, may be a little emotionally labile, but that's probably normal.

Lung biopsy result from NIH return similar to prelim results from Denver.
Interstial lymphohistiocytic infiltrate and marked edema.  PCR for T cell
receptor gene rearrangement revealed no clonal pattern.

Thanks again.


On Mon, Dec 1, 2014 at 3:02 PM, Christian Wysocki <
Christian.Wysocki at utsouthwestern.edu> wrote:

> This sounds somewhat similar to a case of HLH I saw while I was a fellow
> at Yale a couple of years ago, which turned out to be a PRF1 deficiency
> presenting late (mid-20s female).  The presentation was fevers,
> pancytopenia, reticulonodular pulmonary infiltrates (ongoing for months),
> and an ADEM-like picture in the CNS. Interestingly, the ferritin had been
> trending in the in the 300s-400s for the first several weeks she was
> hospitalized, while her ADEM was managed with high dose steroid and IVIG.
> A soluble CD25 was sent when the ferritin was noted to reach 2000.  The
> soluble CD25 at that time was 55,000.  Notably, similar atypical
> lymphohistiocytic infiltrates (without obvious hemophagocytosis) were seen
> on her brain biopsy.
>
> Has fever been a consistent part of this, has she been pancytopenic, and
> does she have splenomegaly, hypofibrinoginemia, hypertriglyceridemia?  Does
> she meet or has she met, criteria for HLH?
>
> Christian Wysocki MD, PhD
> Assistant Professor
> UT Southwestern Medical Center
> Division of Allergy and Immunology
> 5323 Harry Hines Boulevard, F4.100B
> Dallas, TX 75390-8859
> Ph: 214-648-8909
> Fax: 214-648-9102
>
>
>
>
>
> -----Original Message-----
> From: Rosenzweig, Sergio (NIH/CC/DLM) [E] [mailto:srosenzweig at cc.nih.gov]
> Sent: Monday, December 01, 2014 3:01 PM
> To: CIS-PIDD
> Subject: Re: [cis-pidd] 16 y/o F with lung and CNS lesions, lymphopenia,
> absent NK cells, hypocellular bone marrow and lymphohistocytic infiltrate
> in lung
>
> Hi Tam, did you consider CTLA4 haploinsufficiency?
> Sergio
>
> Sergio D. Rosenzweig, MD, PhD
> 10 Center Dr., Bldg. 10, DLM, CC 2C-410F Bethesda, MD 20892 Phone (301)
> 451 8971 Fax (301) 402 1884 Cell (240) 361 7617 Pager 102 10678
> srosenzweig at cc.nih.gov<mailto:srosenzweig at cc.nih.gov>
>
> Disclaimer: The information in this e-mail and any of its attachments is
> confidential and may contain sensitive information. It should not be used
> by anyone who is not the original intended recipient. If you have received
> this e-mail in error please inform the sender and delete from your mailbox
> or any other storage devices. National Institutes of Health shall not
> accept liability for any statements made that are senders own and not
> expressly made on behalf of the NIH by one of its representatives.
>
> From: Jonathan Tam <kiditamae at gmail.com<mailto:kiditamae at gmail.com>>
> Reply-To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:
> cis-pidd at lists.clinimmsoc.org>>
> Date: Monday, December 1, 2014 3:00 PM
> To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:
> cis-pidd at lists.clinimmsoc.org>>
> Subject: [cis-pidd] 16 y/o F with lung and CNS lesions, lymphopenia,
> absent NK cells, hypocellular bone marrow and lymphohistocytic infiltrate
> in lung
>
>
>  I would like any input possible on a case of a 16 y/o girl with 10 month
> h/o neurologic changes  with disseminated CNS lesions on MRI, then acute
> development of  hypoxemia and extensive nodular and ground-glass opacities
> throughout the lungs progressing to respiratory failure, found to have
> lymphopenia, absent NK cells now improved following steroids and IVIg.
>  She was on azathioprine from 6/2014 -10/29/14.  Her lung biopsy shows
> diffuse lymphohistiocytic proliferation and she has hypocellular bone
> marrow.
>
>
>
> Case:
>
> 16-year-old female who initially presented to OSH 12/ 2013 with bilateral
> lower extremity spasticity and urinary retention.  She was initially
> diagnosed with ADEM by the OSH and responded well to 5 days of IV
> solumedrol with outpatient taper. She had symptomatic recurrence and in Feb
> 2014 presented her at CHLA with improvement on steroids. By June 2014, she
> was started on azathioprine (stopped 10/29/14) the working diagnosis of
> antibody-negative NMO vs. MS.  Neuro-ophthalmology evaluation July 2014
> showed no ocular manifestations.
>
>
>
> She was admitted 10/15/14-10/18/14 with worsening bilateral lower
> extremity spasticity and urinary retention; repeat brain/spine MRI showed
> "Multiple patchy scattered foci of T2 hyperintensity throughout the
> cervical and thoracic spinal cord, increased in number and enhancement
> since the prior MRI spine of 7/31/2014.
>
>
>
> 10/24/14 she presented with 3 days of dyspnea, dry cough, and fevers to
> Tmax 101.  CT chest/abdomen/pelvis was significant for diffuse nodular and
> ground-glass opacities in both lungs as well as a lesion in spleen. Her
> hypoxemia worsened and eventually needed intubation and transfer to PICU.
> She slowly improved on high dose steroids and high dose IVIg.  During her
> PICU stay she developed hypercalcemia (now resolved).  Extensive work-up
> was performed looking for malignancy and paraneoplastic process but all
> negative.  Bone marrow biopsy showed hypocellular marrow.
>
>
>
> Labs:
>
>
>
> Absolute monocytes have ranged from 100-900 (despite monocytes in
> discussion with NIH for GATA2 testing)
>
>
>
> Lymphocyte enumeration (11/10/14) -only off azathioprine 12 days
>
>
>
> Low absolute lymphocyte count (ALC 560).
>
> Low absolute CD4 T cell count (CD4+ H 68.2 %, 383 Cells/uL).
>
> Low absolute CD8 T cell count (CD8+ 19.9 %, 112 Cells/uL).
>
> CD45RA 66%
>
> CD25+CD127dim/CD4 4%
>
> The T cell compartment demonstrates an increase in their activation state
> (HLADR+ CD3+ 11%).
>
>
>
> The absolute value of NK called is significantly decreased for age (CD16+
> CD56+ 4 Cells/uL).
>
> The percentage of NK cells is low (0.7 %).
>
>
>
> Low absolute B cell count (C19+10.1 %, 57 Cells/uL).
>
>
>
> IgD+ CD27-Cd19+/CD19 90%
>
> IgD+ CD27+Cd19+/CD19 7%
>
> IgD-CD27+Cd19+/CD19 2%
>
>
>
> IgG 787 mg/dL
>
> IgM 130 mg/dL
>
> IgA 114 mg/dL
>
> IgE 119 kU/L
>
>
>
> Tetanus ab 0.69 I.U./mL
>
> H Flu ab  1.88 mcg/mL
>
> Pneumococcal ab 0/13 protective; <0.3 mcg/mL for all 23 serotypes
>
>
>
> NBT (11/10): normal
>
>
>
> -BAL path (10/28): Macrophages, lymphocytes, and bronchial epithelial
> cells. Gram stain negative for intracellular bacteria. GMS stain negative
> for fungi, including pneumocystis.
>
> -BAL cell count (10/28): 2000 RBC, 258 WBC (86%L)
>
>
>
> Lung Biopsy (prelim per Dr. Dishop University of Colorado):   Diffuse
> lymphohistiocytic proliferation, consistent with immunologic dysregulation.
>
>
>
> The abnormal lymphohistiocytic infiltrate appears benign, and there is no
> evidence of lymphoma. The pattern is abnormal in that there are no reactive
> lymphoid follicles (germinal centers) and instead is composed of sheets of
> predominantly T lymphocytes and histiocytes, spanning the interstitium,
> perivascular regions, and peribronchiolar regions. Absence of CD 56
> staining is consistent with the history of absent NK cells in the
> peripheral blood , and supports a form of immunodeficiency or immune
> dysregulation.
>
>
>
> -Chromosomal microarray CSF (11/6): normal
>
> -Paraneoplastic ab panel (10/17): negative
>
>
>
> -BM bx  path (11/13): Hypocellular bone marrow (30-40%) with trilineage
> hematopoiesis and no morphologic or immunophenotypic evidence of a
> lymphoproliferative process.
>
>
>
> -ANA (10/15): undetected
>
> -dsDNA (10/27): negative
>
> -Cold agglutinin (10/27): negative
>
> -ENA-RNP (10/27): negative
>
> -ENA-Sm Ab (10/27): negative
>
> -Proteinase-3 ab (C-ANCA) (10/27): negative
>
> -Myeloperoxidase ab (P-ANCA) (10/27): negative
>
> -FVIII assay (11/17): normal
>
> -ACE serum (10/27): normal
>
> -ACE CSF (11/6): negative
>
> -ESR (10/27): 7
>
> -Ferritin (multiple): 264-308
>
> -IL-6 (11/5): 6.82
>
> -C3 (11/15): normal
>
> -C4 (11/15): normal
>
> -Total complement (10/27): 312
>
> -Total complement send out (11/15): 292
>
>
>
> Infectious labs:
>
> -Bacterial gram stain and cx (CSF): negative
>
> -Bacterial gram stain and cx (BAL): negative
>
> -Bacterial gram stain and cx (lung bx): negative
>
> -Bacterial gram stain and cx (bm bx): negative
>
> -Mycoplasma PCR (BAL): negative
>
> -ASO (10/15): negative
>
> -Lyme EIA (10/17): negative
>
> -Babesia microti IgG and IgM (10/31): negative
>
>
>
> -M. tuberculosis PCR (BAL): negative
>
> -M. avium DNA (BAL): negative
>
> -M. intracellularae (BAL): negative
>
> -Quantgold (10/26): negative with good mitogen response
>
> -PPD (10/29): 0mm induration
>
> -AFB stain sputum (10/27, 10/28): negative
>
> -AFB stain (BAL): negative
>
> -AFB stain (lung bx): negative
>
>
>
> -Fungal stain and cx (CSF): negative
>
> -Fungal stain and cx (sputum): negative
>
> -Fungal stain and cx (BAL): negative
>
> -Fungal stain and cx (lung bx): negative
>
> -Fungal stain and cx (bm bx): negative
>
> -Aspergillus ag (BAL): negative
>
> -Galactomannan (10/29): negative
>
> -Cryptococcal ag (BAL): negative
>
> -Cryptococcal ag (serum) 10/29: negative
>
> -PCP PCR (BAL): negative
>
> -Fungitell (10/29): negative
>
> -Cocci CF serum (10/27): negative
>
>
>
> -RVP 1 and 2 (NP): negative
>
> -RVP 1 and 2 (BAL): negative
>
> -HSV 1&2 PCR NP wash (10/27): negative
>
> -VZV PCR NP wash (10/27): negative
>
> -CMV PCR NP wash (10/27): negative
>
> -CMV PCR (bm bx): negative
>
> -EBV PCR serum (11/13): negative
>
> -EBV PCR (bm bx): negative
>
> -EBV and EBER (lung bx): negative
>
> -EBV IgG, IgM, EBNA (11/5): negative
>
> -Adenovirus PCR(bm bx): negative
>
> -HHV6 (bm bx): negative
>
> -West nile IgG IgM (CSF): negative
>
> -Enterovirus PCR (CSF): negative
>
> -HIV ab (11/10): non-reactive
>
> -HTLV I/II Western Blot (10/15): non-reactive
>
>
>
> -Toxoplasma IgG serum (11/15): negative
>
>
>
> -Can't find Toxocara, Brucella, Ehrlichia, Anaplasma, Chlamydia DAA
>
> -16s and 18s/ITS sequencing (bm bx): pending
>
> -AFB cx (bm bx, lung): pending
>
>
>
> Antibiotics courses:
>
> Azithromycin (10/24-10/28)
>
> Ceftriaxone (10/24-10/25), then Unasyn (10/26-10/30), then Cefepime
> (10/30-11/3)
>
> Fluconazole (10/29- 11/4)
>
> Clarithromycin (10/29-11/5) for non-tuberculous mycobacteria
>
> RIPE: (10/29-11/4)
>
> Vancomycin (11/8-11/12)
>
> Cefepime (11/9 - 11/25)
>
> Doxy (11/13 - ) Plan for a 14 day course, last day 11/26
>
> Ambisome ( 11/14 - 11/25)
>
>
>
> Imaging:
>
>
>
> -CT chest/abd/pel (10/30): 1. Diffuse nodular and groundglass opacities
> throughout the lungs, most significant and consolidative within the lower
> lobes suggestive of diffuse fungal, typical, and/or atypical pneumonia. 2.
> Splenomegaly with large hypodense lesion arising from the superior anterior
> portion. Question of adjacent gastroesophageal involvement. Multiple other
> scattered hypodensities throughout the splenic parenchyma. Differential
> considerations include lymphoma versus disseminated fungal or granulomatous
> (TB, sarcoid) disease. 3. Hilar lymphadenopathy. 4. Enlarged
> gastroepiploic/perisplenic lymph nodes. Multiple perisplenic subcentimeter
> lymph nodes. 5. Hepatomegaly.
>
>
>
> -MRI Brain w/ and w/o contrast (10/17): Interval marked increase in size
> and number of now innumerable T2 hyperintense, enhancing, punctate foci
> throughout the brain parenchyma, brainstem, and throughout the cerebellum,
> with some of these lesions likely leptomeningeal in location. Some of these
> lesions also demonstrate mild diffusion restriction. Differential
> considerations again include lymphoma, infectious and noninfectious
> granulomatous disease, as well as metastatic disease from an unknown
> primary malignancy. Demyelinating processes such as multiple sclerosis are
> less likely given the distribution of these enhancing foci.
>
>
>
> -MRI spec (10/17): MRS is not specific considering the large partial
> volume of surrounding tissue. The nevertheless elevated Cho and Lac may
> indicate significant abnormal Cho and Lac levels within lesions when
> extrapolated.
>
>
>
> -MRI cervical and thoracic spine (10/17): Multiple patchy scattered foci
> of T2 hyperintensity throughout the cervical and thoracic spinal cord,
> increased in number and enhancement since the prior MRI spine of 7/31/2014.
> Additionally, there is more pronounced leptomeningeal enhancement compared
> to prior exam, particularly involving the lower thoracic spinal cord. Given
> the concurrent findings within the brain, differential considerations again
> include lymphoma, leptomeningeal spread of tumor, or granulomatous disease.
> A demyelinating process is considered less likely. Recommend CSF sampling.
>
>
>
> -LP (11/6): RBC 2, WBC 2(99%L)
>
> -LP (10/15): RBC 1, WBC 2 (100%L)
>
> -MS panel (CSF) (10/15): normal other than oligoclonal bandfs
>
> -Oligoclonal bands (10/15): The patient's CSF contains multiple
> restriction bands that are also present in the patient's corresponding
> serum sample. We are unable to define whether these gammaglobulins are of
> systemic or intracerebral origin
>
>
>
> -NMO/AQP-IgG4 (10/17): negative
>
> -Fundoscopic and anterior chamber exam by ophto (10/29): normal
>
>
>
> -ECHO (11/14): nl
>
>
> --------------------------------
> Jonathan Tam, MD
> Assistant Professor of Pediatrics
> Division of Clinical Immunology & Allergy Children's Hospital Los Angeles
> 4650 Sunset Blvd, MS#75
> Los Angeles, CA 90027
> jstam at chla.usc.edu<mailto:jstam at chla.usc.edu>
> Phone: 323.361.2501
> Fax: 323.361.1191
>
> ---
>
> The CIS-PIDD listserv is supported by:
>
> [http://www.clinimmsoc.org/UserFiles/image/cis-pidd-list-logo_v1.jpg]
> The science & practice of human immunology
>
> P: +1.414.224.8095
> E: info at clinimmsoc.org<mailto:info at clinimmsoc.org>
>
> Not a member of CIS? Please visit www.clinimmsoc.org<
> https://cis.execinc.com/edibo/Signup> to join!
>
> You are currently subscribed to cis-pidd as: srosenzweig at cc.nih.gov
> <mailto:srosenzweig at cc.nih.gov>.
> To unsubscribe click here:
> http://lm.clinimmsoc.org/u?id=207736502.dbed1e35a2a023491d9cd5e9046c558b&n=T&l=cis-pidd&o=45797030
>
> ---
> The CIS-PIDD listserv is supported by the Clinical Immunology Society The
> science & practice of human immunology
>
> P: +1.414.224.8095
> E: info at clinimmsoc.org
>
> Not a member of CIS? Please visit www.clinimmsoc.org to join!
>
> You are currently subscribed to cis-pidd as:
> Christian.Wysocki at utsouthwestern.edu.
> To unsubscribe click here:
> http://lm.clinimmsoc.org/u?id=201777692.ff06d85ed6af3ca6c04f45096f9fefa0&n=T&l=cis-pidd&o=45797313
> or send a blank email to
> leave-45797313-201777692.ff06d85ed6af3ca6c04f45096f9fefa0 at lists.clinimmsoc.org
>
> ________________________________
>
> UT Southwestern Medical Center
> The future of medicine, today.
>
>
> ---
> The CIS-PIDD listserv is supported by the Clinical Immunology Society
> The science & practice of human immunology
>
> P: +1.414.224.8095
> E: info at clinimmsoc.org
>
> Not a member of CIS? Please visit www.clinimmsoc.org to join!
>
> You are currently subscribed to cis-pidd as: kiditamae at gmail.com.
> To unsubscribe click here:
> http://lm.clinimmsoc.org/u?id=187397390.3e243c87711c5b5cb2e1f8a8996084fb&n=T&l=cis-pidd&o=45797746
> or send a blank email to
> leave-45797746-187397390.3e243c87711c5b5cb2e1f8a8996084fb at lists.clinimmsoc.org
>

---
The CIS-PIDD listserv is supported by the Clinical Immunology Society
The science & practice of human immunology

P: +1.414.224.8095
E: info at clinimmsoc.org

Not a member of CIS? Please visit www.clinimmsoc.org to join!

You are currently subscribed to cis-pidd as: pagid at list.clinimmsoc.org.
To unsubscribe click here: http://lm.clinimmsoc.org/u?id=183939985.3ea13d40a15475ac00ebbd9cd8a37d6d&n=T&l=cis-pidd&o=45800825
or send a blank email to leave-45800825-183939985.3ea13d40a15475ac00ebbd9cd8a37d6d at lists.clinimmsoc.org
-------------- next part --------------
An HTML attachment was scrubbed...
URL: <https://pairlist7.pair.net/pipermail/pagid/attachments/20141202/0b47e66b/attachment-0001.html>