[CIS-PAGID] Tough case

[Wilmer Cordova Calderon]

•IF not reached a definitive diagnosis
•WHAT TREATMENT IMMUNE SUPPORT WE WILL NEED OPTIMIZATION?

2012/3/23 Pere Soler Palacin <psoler at vhebron.net>


>

> Dear colleagues, we'd really appreciate your thoughts about this tough

> case we are currently facing since we are in an impasse and the patient is

> severely ill.

>

>

>

> Fifteen month-old boy, with severe skin involvement, spleen and liver

> enlargement and hemolytic anemia that presents recurrent episodes

> compatible with macrophage activation syndrome.

>

> Clinical manifestations began at the age of 9 months with haemolytic

> anemia (positive direct Coombs test) and splenomegaly. Immunoglobulin

> plasma levels were increase. (Ig G above 1000 mg/dL and both IgA and IgM

> above 200 mg/dl) and lymphocyte subsets analysis yielded mild lymphopenia

> (1280 /mm3. Lymphocyte subpopulations at the onset of the manifestations,

> CD3+: 35% (448 /mm3), CD4+:22% (281.6 /mm3); CD8+: CD8+: 13%, (140.8 /mm3),

> CD19+: 537.6 /mm3, CD156+16+: 294.4 /mm3.

>

>

>

> Corticosteroid therapy and high dose IVIG were started ant that point, and

> since anemia was refractory to these treatments, the patient was put on

> rituximab (5 doses). The patient needed repeated (not irradiated) blood

> transfusions.

>

> At 11 months of age and because of the persistence of anemia, he was

> switched to cyclosporine and mycophenolate mofetil afterwards since ALPS

> was suspected (although DNT cells biological markers were absent). Few days

> later fever, pancytopenia and severe rash occurred and MMF was changed to

> sirolimus without significant clinical improvement. Bone marrow aspirate

> was performed and informed to be normal.

>

> The patient was sent to our centre at that point (14 mo). Physical

> examination showed hepatosplenomegaly, generalized lymphadenopathy, severe

> erytroderma with scaly skin that sheds off and pruritus (see figure).

>

> At that moment, we considered five diagnostic options:

>

> -          *Histiocytosis*: skin biopsy ruled it out.

>

> -          *Cutaneous T-cell lymphoma (Sezary):* skin biopsy ruled it out

> and it’s only seen in adult patients.

>

> -          *ALPS/DALD:* Neither DNT cell nor biomarkers were found. No

> mutations in *TNFRSF6* (FAS) or *KRAS* genes. No DNT in lymph node biopsy.

>

> -          *Hemophagocytic** lymphohistiocytosis (HLH):* initial NK cells

> cytotixicity and degranulation assays were abnormal and the patient

> presented elevated ferritin (90.000 ng/mL), tryglicerides (400 mg/dl)

> levels and hypofibrinogenemia. CD25s was 1700. BM aspirate and lymph node

> biopsy showed some signs of hemophagocytosis. Nevertheless, when

> immunosuppressant drugs were tapered enough, NK cyto and degranulation

> assays return to normal. Perforin expression was normal in CD8 and NK

> cells. Skin was not compatible with HLH.

>

> *      -      Leaky-SCID with Omenn or GVHD (maternal or

> post-transfusional):*

>

> -          Lymphocyte subpopulations, data from our center at age 11

> months: CD3: 96% (3.973X109/L), CD4: 80% (3.296X109/L), CD8: 16% (0.668X10

> 9/L), 0% B cells (CD19+), 1% NK cells CD56+16+)

>

> -          T cell population mostly activated expressing HLA-DR CD4: 58%

> and  CD8: 87%.

>

> -          90% of CD3 T cells with effector memory pheenotype

> (CD45RO+CCR7-)

>

> -          TCR ab/gd phenotype was evaluated 93.3%/5.3%.

>

> -          CD3 and CD2 expression did not show significant differences

>

> -          Absence of B cells (secondary to RTX infusion).

>

> -          NK cells 1.6% (0.066X109/L),

>

>       -      Proliferation to PHA, PHA+IL2, IL2 and anti-CD3+IL2 was

> normal, PMA+ionomic slightly decreased and anti-CD3 response severely

> depressed.

>

>

>

> -          Hypogammaglobulinemia was thought to be secondary to RTX too.

> Proliferation assays were significantly low and TCR was oligoclonally

> expressed. Chimerism assays did not show maternal or transfusional cells

> and skin biopsy was not compatible with OS. Only port-a-cath infection due

> to *P. aeruginosa* and diarrhoea due to Norovirus were demonstrated as

> significant infections. Visceral leishmaniasis has been ruled out.

>

>

>

> We tried to tapper all immunosuppressant drugs to better evaluate his

> “own” immunological status. The patient remained hematologically stable

> (only needing weekly IVIG to maintain normal Hb levels) but skin

> progressively worsened to severe and became the main clinical problem in

> our patient.

>

> Skin biopsy showed a psoriatic dermatitis and hair was normal when

> observed at optic microscope.

>

> The patient has presented two new episodes of fever, increase of spleen

> and liver size, cytopenias and skin involvement and we decided to start

> HLH-2004 protocol (VP-16 not yet) and the patient only improved

> transiently.

>

>

>

> Since, psoriatic dermatitis is described to be associated to IPEX and

> IPEX-like syndrome we analyzed FOXP3 and CD25 and were found to be normal.

> Inborn metabolic disorders) have been properly ruled out.

>

>

>

> Thanks in advance,

>

>

>

> Pere.

> Pere Soler Palacín, MD, PhD. Pediatric Infectious Diseases and

> Immunodeficiencies Unit. Hospital Universitari Vall d'Hebron.     Assistant

> Professor. Universitat Autònoma

> de Barcelona.

> Passeig de la Vall d'Hebron 119-129.

> 08035 Barcelona. Spain.

> Tel: 0034934893140. Fax: 0034934893039.

> E-mail: psoler at vhebron.net; 34660psp at comb.cat. Web: www.upiip.com.

>

>

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