[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]

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

---
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=45797030
or send a blank email to leave-45797030-183939985.3ea13d40a15475ac00ebbd9cd8a37d6d at lists.clinimmsoc.org
-------------- next part --------------
An HTML attachment was scrubbed...
URL: <https://pairlist7.pair.net/pipermail/pagid/attachments/20141201/2181b9ad/attachment-0001.html>