[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

[Nacho Gonzalez]

Dear Dr. Tam,
I would consider HLH within PID (Gata2 or ALPS) or another PID. Did you
check for NK bright? vitB12 or sFASL? DNT? Under IS therapy HLH may behave
mildly for a while.  Do you have a degranulation/cytotoxicity assay?
Best regards,

Luis Ignacio Gonzalez-Granado
Immunodeficiencies Unit
Hospital 12 de Octubre
Madrid.
Spain
El 01/12/2014 21:04, "Jonathan Tam" <kiditamae at gmail.com> escribió:

> 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
>
> Phone: 323.361.2501
>
> Fax: 323.361.1191
>
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