[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

[Bodo Grimbacher]

CTLA-4 deficiency may have normal IgG serum levels, especially at the
beginning of the disease.
However, I agree, that many CTLA-4 patients range between 500 -600 mg/dL
when they are diagnosed (which becomes worse with progression of disease
and loss of peripheral B cells).
Moreover, your patient is not so far away from hypogammaglobuliemia, and I
would not be surprised if he is IgG2-deficient already.

For genetic testing, please send genomic DNA to:

AG Grimbacher
℅ Katrin Hübscher
CCI, 2nd floor
Engessertraße 4
79108 Freiburg
Germany

Thanks, Bodo


****************************************
Univ.-Prof. Dr. med. B. Grimbacher
Scientific Director
CCI-Center for Chronic Immunodeficiency
UNIVERSITÄTSKLINIKUM FREIBURG
Tel.: 0761 270-77731  Fax: -77744
Engesserstraße 4, 79108 Freiburg
bodo.grimbacher at uniklinik-freiburg.de
http://www.uniklinik-freiburg.de/cci









Am 02.12.14 19:43 schrieb "Jonathan Tam" unter <kiditamae at gmail.com>:

>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
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>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 <tel:323.361.2501>
>Fax: 323.361.1191 <tel:323.361.1191>
>
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