[CIS PIDD] LPD in a patient with an uncharacterized immune deficiency

[Heimall, Jennifer]

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-----Original Message-----
From: smith719 at umn.edu [smith719 at umn.edu]
Received: Tuesday, 24 Jul 2012, 12:32pm
To: PAGID list [pagid at list.clinimmsoc.org]
CC: krueg456 at umn.edu [krueg456 at umn.edu]; Wes Miller [mill4991 at umn.edu]
Subject: [CIS PIDD] LPD in a patient with an uncharacterized immune deficiency

Dear all

I am seeing a 5 year old girl from Saudi Arabia with an underlying
diagnosis of
a "combined immune deficiency" and sickle cell disease who was referred
to me for stem cell transplant. She came with 5 pages of medical records so
we
have essentially had to start from scratch. During her evaluations, we
discovered a lymphoproliferative process so my questions are both
diagnostic with regard to her underlying immune deficiency and therapeutic
with regard to her LPD.

Her referral letter indicated low T, B and NK cell numbers as well as
moderate
to severe reduction in T cell proliferation to PHA, but normal immune
globulin
levels and "adequate" pneumococcal titers. She has never received IVIG. She
was
born full-term after a normal pregnancy and weighed 3.5kg at birth. She had
no
issues until approximately 1.5 years of age when she started to develop
frequent sino-pulmonary infections. She is hospitalized every 1-2 months for
these infections and requires IV antibiotics. She has never been admitted to
the ICU, been intubated or required surgical intervention. She has been
maintained on bactrim prophylaxis. Per parents, she has had all recommended
vaccinations with no adverse reactions. No history of autoimmune pathology.

Despite the diagnosis if sickle cell disease, she has never required any
transfusions and her hemoglobin generally runs around 9. Evaluations here
revealed that she has concurrent HPFH so this is essentially a non-issue
with
regard to her need for transplant.

Despite the frequent infections and hospitalizations, she has been growing
and
developing normally. She is at the 25th percentile for weight and height.
She
was attending kindergarten back home and according to her parents, her
teachers
had some concerns about her ability to concentrate, but otherwise she is on
track with her peers.

Her family history is only significant for consanguinity. Her parents are
first
cousins and their parents are also related. There is no family history of
immune deficiency or early childhood deaths. Her parents both have sickle
cell trait. She has a 3 year old sister who is healthy and is an HLA match.
Her
sister's counts are normal, she has normal lymphocyte subsets and
hemoglobin electrophoresis.

Upon arrival to the US, the patient was febrile and was admitted for
evaluation. During this evaluation she was noted to have pan-sinusitis with
bilateral otomastoiditis, bibasilar pneumonia (nodular in appearance) and
extensive mediastinal lymphadenopathy. Despite this, she clinically looked
well. She has no organomegaly and no palpable lymphadenopathy with the
exception of shotty cervical nodes. Morphologically, she has somewhat
widely spaced eyes and low set ears, but no other obvious stigmata. Her
work-up thus far is as follows:

White blood cell count of 2.7 with an ANC of 1.6 and an ALC of 0.4.
Lymphocyte
subsets: Absolute CD3 count 353, absolute CD4 count 118, absolute 8 count
163,
absolute CD19 count 27, absolute CD16/56 count 526. Her CD4-CD8 ratio was
0.72.
IgG level 1270, IgA 199, IgM 524 and IgE less than 2. IgG1 973 (306-945),
IgG2
184 (61-345), IgG3 199 (10-122), IgG4 <1 (2-113.

CH50 of 79 (normal 60-144)

Lymphocyte antigen and mitogen proliferation tests were done, though there
were
insufficient numbers of isolated lymphocytes to validate the assay. Results
were reported anyway which showed absent lymphocyte responses to Candida and
tetanus, low lymphocyte responses to PHA and concanavalin A, and normal
lymphocyte responses to pokeweed mitogen. Repeat tests are in process.

Thymopoiesis panel: TREC copies relative to CD3 T cell count = 289 copies
per
million CD3 T cells. Her absolute CD4 RTE level was 8.1 cells/mcL. T cell
receptor repertoire testing is pending.

Her B-cell subset immunophenotyping is remarkable for significantly
decreased
class switched memory B cells relative to both total B cells and total
memory B
cell pool. The percent total CD27+ memory B cells appear normal due to
relative
expansion of the proportion of marginal zone B cells. The frequency of
plasmablasts is also substantially decreased. All other B-cell subsets
appear
to be quantitatively normal.

Isohemagglutinin titers show an anti-A IgM of 512 and an anti-B IgM of 1024.

Rubeola antibody of 259 (positive and suggests previous exposure and
probable
immunity). Tetanus titer of 0.06 (protective, but greater than 0.15 is
desirable). Diphtheria antibody of 0.06 (protective, but greater than 0.1 is
desirable). Pneumococcal titers are low except for type 23F.

NK cell activity is normal.

HIV 1 and 2 antibodies are negative. All other infectious disease testing
also
negative with exception of BAL tests below.

Echocardiogram reveals normal intracardiac anatomy with good ventricular
contractility and ejection fraction of 65% to 70%.

Chromosome analysis for DiGeorge syndrome is pending. Comparative genomic
hybridization (CGH) is also pending.

A bronchoscopy was performed that revealed 42,000 copies/mL of EBV and 4000
copies/mL of CMV, but was otherwise negative. She was started on IV
antibiotics
and ganciclovir while a lymph node and lung biopsy were arranged.

Though we were expecting infection, her lung biopsy revealed a high grade,
EBV positive diffuse large B cell (CD20+) lymphoma. The surgeon decided the
lymph node biopsy wasn't needed so this was not done. She will be getting
bilateral bone marrow biopsies and an LP today and a PET CT soon for
further staging. She has also developed a lip lesion of unclear etiology
that will be biopsied today.

Any thoughts on diagnosisof her immune deficiency and treatment for her LPD
are greatly appreciated.

The most pressing question at this point is how we should treat her DLBCL.
Given that it is CD20+, we will definitely use rituximab. Would aggressive
chemotherapy (CHOP, EPOCH, other) also be recommended based on the lung
based lesions and pathology alone? Any other thoughts on treatment
strategies?

Any thoughts on the diagnosis of her underlying immune deficiency? Her main
issue seems to be one of thymic output. Given the LPD diagnosis, we are
considering Nijmegen breakage syndrome.

Thanks in advance for your help.

Angie

--
Angela R. Smith, MD, MS
Assistant Professor
Pediatric Blood and Marrow Transplantation
420 Delaware Street SE
MMC 484
Minneapolis, MN 55455
Phone: 612-626-2778
Fax: 612-626-2815
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