[CIS-PAGID] 15 yo with ILD

[Jan Rohr]

Dear Mrs. Ciaccio,

in line with the suggestions from A. Junkers, the combination of  
granulomatous lung disease, neuropathy, pancytopenia,  
hepatosplenomegaly and hypogammaglobulinemia reminds me of XLP and/or  
atypical courses of  familial hemophagocytic lymphohistiocystosis  
(FHL). We have recently described a couple of atypical / late-onset  
FHL patients with very similar symptoms to the ones you mention.

Kind regards,

Jan



Dr. med. Jan Rohr
Centre of Chronic Immunodeficiency
Freiburg University Hospital
Mathildenstrasse 1
79106 Freiburg
Germany

Tel: 		+49-(0)761-270 4301
Fax: 	+49-(0)761-270 4599

E-mail: 	jan.rohr at uniklinik-freiburg.de
URL: 	http://www.uniklinik-freiburg.de/kinderklinik/live/forschung/ 
immunologie.html
URL: 	http://www.cci.uniklinik-freiburg.de/index.html



Haematologica. 2010 Dec;95(12):2080-7. Epub 2010 Sep 7.
Atypical familial hemophagocytic lymphohistiocytosis due to mutations  
in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases.

Rohr J, Beutel K, Maul-Pavicic A, Vraetz T, Thiel J, Warnatz K,  
Bondzio I, Gross-Wieltsch U, Schündeln M, Schütz B, Woessmann W,  
Groll AH, Strahm B, Pagel J, Speckmann C, Janka G, Griffiths G,  
Schwarz K, zur Stadt U, Ehl S.

Centre of Pediatrics and Adolescent Medicine, University Medical  
Centre, Freiburg, Germany.
Abstract
BACKGROUND: Familial hemophagocytic lymphohistiocytosis is a genetic  
disorder of lymphocyte cytotoxicity that usually presents in the  
first two years of life and has a poor prognosis unless treated by  
hematopoietic stem cell transplantation. Atypical courses with later  
onset and prolonged survival have been described, but no detailed  
analysis of immunological parameters associated with typical versus  
atypical forms of familial hemophagocytic lymphohistiocytosis has  
been performed.

DESIGN AND METHODS: We analyzed disease manifestations, NK-cell and T- 
cell cytotoxicity and degranulation, markers of T-cell activation and  
B-cell differentiation as well as Natural Killer T cells in 8  
patients with atypical familial hemophagocytic lymphohistiocytosis  
due to mutations in UNC13D and STXBP2.

RESULTS: All but one patient with atypical familial hemophagocytic  
lymphohistiocytosis carried at least one splice-site mutation in  
UNC13D or STXBP2. In most patients episodes of hemophagocytic  
lymphohistiocytosis were preceded or followed by clinical features  
typically associated with immunodeficiency, such as chronic active  
Epstein Barr virus infection, increased susceptibility to bacterial  
infections, granulomatous lung or liver disease, encephalitis or  
lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced  
memory B cells. Most patients had a predominance of activated CD8(+)  
T cells and low numbers of Natural Killer T cells. When compared to  
patients with typical familial hemophagocytic lymphohistiocytosis, NK- 
cell cytotoxicity and NK-cell and CTL degranulation were impaired to  
a similar extent. However, in patients with an atypical course NK- 
cell degranulation could be partially reconstituted by interleukin-2  
and cytotoxic T-cell cytotoxicity in vitro was normal.

CONCLUSIONS: Clinical and immunological features of atypical familial  
hemophagocytic lymphohistiocytosis show an important overlap to  
primary immunodeficiency diseases (particularly common variable  
immunodeficiency and X-linked lymphoproliferative syndrome) and must,  
therefore, be considered in a variety of clinical presentations. We  
show that degranulation assays are helpful screening tests for the  
identification of such patients.




Am 04.01.2011 um 23:27 schrieb Junker, Anne:


> Consider XLP – SAP deficiency.  We described a case who presented  

> in infancy with VAHS, and over the years developed  

> hypogammaglobulinemia, retinitis, lung disease and progressive  

> neuropathy.  At autopsy EBV inclusions were evident in vasculitic  

> lesions.

>

> Jan P. Dutz, Loralyn Benoit, Xiaoxia Wang, Douglas J. Demetrick,  

> Anne Junker, Derek de Sa, and Rusung Tan

> Lymphocytic vasculitis in X-linked lymphoproliferative disease

> Blood, Jan 2001; 97: 95 - 100.

>

>

>

> Anne K. Junker, MD, FRCP(C)

> Associate Professor, Pediatrics

> Director, Clinical Immunology Service, BC Children's Hospital

> Director, Clinical & Population Studies, Child & Family Research  

> Institute

> Director, Maternal Infant Child Youth Research Network of Canada/ 

> Reseau de Recherche en Sante des Enfant et des Meres (MICYRN)

> K4-223 4480 Oak Street

> Vancouver, British Columbia

> Canada  V6H 3V4

> phone: 604-875-3591

> fax: 604-875-2414

> email: ajunker at cw.bc.ca

>

>

> From: pagid-bounces at list.clinimmsoc.org [mailto:pagid- 

> bounces at list.clinimmsoc.org] On Behalf Of Ciaccio, Christina, E

> Sent: Tuesday, January 04, 2011 1:47 PM

> To: 'pagid at list.clinimmsoc.org'

> Subject: [CIS-PAGID] 15 yo with ILD

>

> Hello all.  Happy New Year.  I have a 15 yo that I’ve been  

> following that I would love help with…

>

> Presented in July of 2009 with acute respiratory symptoms,  

> consisting of cough, fatigue, and hypoxemia.  PFTs revealed a very  

> low diffusion capacity of approximately 40%.  Extensive ID work up  

> was negative for infection (tuberculosis, EBV, CMV, HHV6,  

> influenza, Legionella, Mycoplasma, HIV), including fungal infection  

> (Histoplasma).  Lab work up for vasculitis (negative ANA, RF, MPO,  

> PR3, cardiolipins, B2 glycoprotein 1), and sarcoid (negative ACE)  

> was negative at this time.  His initial quantitative  

> immunoglobulins were: IgG 685, IgM 89, IgA 188, and IgE 983. His  

> immunoglobulins at that time were: IgG 561, IgM 74, IgA 139.  

> +tetanus and haemophilus influenzae titers.  Oxidative burst was  

> normal.  A thorough home assessment by environmental hygienists  

> revealed no obvious cause of hypersensitivity pneumonitis except  

> for a trombone which Tyler stopped playing at initial presentation.

>

> Initial wedge lung biopsy was completed in September 30, 2009 and  

> was investigated by several pathologists across the country.  The  

> biopsy was read by our pathlogists as : “PERIBONCHIOLAR NON- 

> NECROTIZING GRANULOMATOUS INFLAMMATION. BRONCHIOLITIS  

> OBLITERANS.”   Further discussion from pathologists is reported below.

>

> Repeat assessment for a further systemic granulomatous process (CT  

> scan of chest and abdomen) revealed no further evidence of  

> granulomatous disease.  The patient did no respond to prednisone  

> 40-60mg/day.  Pulse solumedrol and cyclophosphamide were started.  

> After the cyclophosphamide was started, he developed  

> hypogammaglobulinemia (IgG of 279, IgA of 49.7, and IgM of 14. He  

> was also noted at this time to be slightly lymphopenic (1247mm3)  

> with a CD3 absolute count of 686mm3, (CD4=511mm3 and CD8=150mm3),  

> CD19 absolute count of 511mm3, and a CD16/CD56 NK cell count of  

> 37mm3. Replacement SCIG was instituted.  At the end of his 6 month  

> induction, his lungs were vastly improved via CT scan and his DLCO  

> improved to approximately 50%.  However, as he was finishing this 6  

> month induction (and weaning to steroids < 10mg/day), he began  

> having right foot and left hand neuropathy and pancytopenia.  He  

> became severely hypercalcemic, with renal compromise.  No evidence  

> of malignancy was found (bone marrow biopsy x 2 negative, CT scan  

> of neck through pelvis was negative except for splenomegaly and  

> mild hepatomegaly (without focal lesions), PET scan unrevealing  

> except for the spinal lesions I will discuss below).  He had a  

> mildly elevated ACE at this time as well as 1,25 vit D.  As no  

> enlarged lymph nodes were found, a lip biopsy was performed but was  

> unrevealing (no evidence of pallisading histiocytes, or a  

> multinucleated giant cell )  Regarding the neuropathy EMG was not  

> revealing, but an MRI of his spine showed enlargement and  

> enhancement of the bilateral exiting nerve roots of C7, C8 as well  

> as at the nerve roots of L3, L4, L5 and S1.  Lesions were not  

> conducive to biopsy.  Prednisone was again started (40mg daily).   

> (Mechanic LJ Dikman S Cunningham-Rundles C. Granulomatous disease  

> in common variable immunodeficiency. Annals of Internal Medicine  

> 1997;.Volume 127: 613-617)  Since this time, his hypercalcemia has  

> resolved and his WBC count has finally normalized. He remains  

> thrombocytopenic and severely lymphopenic (absolute count 181mm3;  

> CD3=121mm3; CD4=101; CD8=16mm3; CD16/56=4; very low response to  

> ConA, PHA, candida and tetanus and borderline response to PWM).   

> His IgA and IgM levels have paradoxically recovered and his SQIG  

> dose is being decreased due to high IgG levels. His neurologic  

> symptoms have drastically worsened and this is now his major  

> complaint. Recently, he has developed new infiltrates on chest XR  

> and CT which cannot be reached by IR or bronchoscopy and family is  

> hesitant for repeat wedge biopsy (has now had 3 lung biopsies).   

> Repeat testing for Histoplasma and Bartonella were negative.   

> Quantiferon could not be interpreted due to lack of proliferation.

>

> Is this GLILD with CVID (although immunoglobulins are recovering  

> off Cytoxan)?  Sarcoidosis?  We have labeled him the very generic  

> systemic granulomatous disease with immune dysregulation/ 

> lymphopenia (we’ve never actually seen a great granuloma, though).   

> As his neurologic symptoms have not responded to prednisone (with  

> recent pulse Solumedrol), any suggestion for further treatment?   

> Infliximab?

>

> Thanks so much for everyone’s input.

>

> Chrissy

>

> Christina Ciaccio, M.D.

> Faculty, Allergy, Asthma and Immunology

> Children's Mercy Hospitals and Clinics

> 2401 Gillham Road

> Kansas City, Missouri  64108

> 816-234-3097 (phone)

> 816-346-1301 (fax)

>

> Further discussion from pathology was as follows: There is a  

> nodular, peribronchial mixed inflammatory infiltrate. Many of the  

> inflammatory cells are epithelioid histiocytes.  Poorly formed non- 

> necrotizing granulomas are occasionally seen in the interstitium.   

> Also present in the areas of nodular inflammatory infiltrate are  

> many lymphocytes, foamy histiocytes and occasional plasma cells.   

> Rare multinucleated giant cells are present.  Well-formed sarcoidal  

> granulomas are not present.  There are also tufts of newly formed  

> granulation tissue consistent with bronchiolitis obliterans.   

> Occasional granulation tissue nodules are seen the lamina of  

> bronchioli.  The lung tissue adjacent to the nodular infiltration  

> shows interstitial lymphocytic infiltrate.  The lung parenchyma  

> away from the nodules is essentially unremarkable.  No vasculitis  

> is identified.  No lymphoid follicles with germinal centers are  

> seen in the biopsy.  GMS and AFB are negative for microorganisms.   

> Movat stains highlight nodules of organizing fibroblasts in the  

> distal airway.  Interstitial fibrosis is minimal.”  Further  

> evaluation by an outside pathologist included the following: “The  

> etiology the granulomatous process involving the lung in this case  

> remains unexplained, all studies for an infectious process have  

> been negative. This pattern of granulomatous lymphohistiocytic  

> inflammation is very similar to that described in patients with  

> Common Variable immunodeficiency and is one of the patterns of lung  

> involvement in that condition. (Mechanic LJ, Dikman S, Cunningham- 

> Rundles C. Ann Intern Med 1997. Bates CA, Ellison MC, Lynch DA, et  

> at. J Allergy Clin Immuno1 2004) Similar changes have been seen in  

> some other immunodeficiency disorders. It is sometimes considered  

> to be a form of sarcoid associated with CVID; however, the  

> histology is not typical for sarcoid, nor is the clinical  

> presentation in these situations. Whether this is modified sarcoid  

> in an immunodeficient host or is a primary manifestation of CVID  

> has been the subject of wide speculation. It is often associated  

> with similar granulomas in lymphoid or solid organs in CVID  

> patients and is then referred to as "systemic granulomatosis". Such  

> patients can be difficult management problems; steroids have been  

> the mainstay of therapy for the granulomatous/lymphohistiocytic  

> inflammation, and there are reports of the use of infliximab in  

> this setting as well. (Thatayatikom A, Thatayatikom S, White AJ.  

> Ann Allergy Asthma Immunol 2005).

>

> Although this patient does not currently have a diagnosis of CVID  

> or other immunodeficiency

> disorder, we feel that this diagnosis should be clinically  

> excluded. While rare B-cell lymphomas

> arising in the lymphohistiocytic inflammation associated with CVID  

> have been described

> (Reichenberger et al. Respiration 2001; Le Guern et al. Eur J H  

> aematol 2003), there is no

> evidence of a lymphoproliferative disease or lymphoid malignancy in  

> this case. Lymphomatoid

> granulomatosis typically occurs in the setting of EBV positivity  

> and is a B cell proliferation;

> there is no evidence for lymphomatoid granulomatosis in this  

> biopsy; this is not a B cell

> proliferation and EBER is negative. Two hematopathologists from  

> this department, Drs. Sheehan and Curry, have also reviewed this  

> biopsy and find no evidence of lymphoid malignancy or significant  

> atypia”.

>

> Another pathology opinion: “This biopsy shows a nodular  

> lymphohistiocytic infiltrate that is present mainly in  

> peribronchiolar parenchyma. The appearance is similar to that seen  

> in the prior core biopsy (C009-1402) except that no necrosis is  

> present. Foci of organizing pneumonia are seen on the periphery of  

> some of the nodular infiltrates, but they are focal. The lymphoid  

> cells comprise mainly small lymphocytes, but there are also  

> scattered large immunoblast-like cells. Occasional plasma cells are  

> seen as well. The histiocytes form small clusters and sheets, but  

> well-formed granulomas are not present, and there are no giant  

> cells. I find this case extremely difficult. As before, the  

> findings raise the difficult differential diagnosis between an  

> infection (mainly histoplasmosis) and a lymphoproliferative  

> disorder (mainly lymphomatoid granulomatosis). I suspect that it  

> will turn out to be lymphomatoid granulomatosis which is quite rare  

> in young individuals unless there is some type of congenital  

> immunocompromise present. Lymphomatoid granulomatosis is usually  

> graded into three grades with grade 1 being the least atypical and  

> grade 3 the most atypical.  This case would fit into grade 1 which  

> is also the most difficult to treat. The fact that there are  

> nodular infiltrates that replace a portion of lung parenchyma in  

> the absence of an associated interstitial pneumonia excludes  

> hypersensitivity pneumonia from the

> differential diagnosis. Our CD3 staining shows that the majority of  

> lymphoid cells are T-cells. CD20 stains are positive in lesser  

> numbers of cells, but many of the positive cells are large lymphoid  

> cells. There is prominent vascular infiltration and some cells  

> within the vessel walls are B-cells as well. We also performed CD30  

> which stained some of the big cells, and we repeated AFB and GMS  

> stains on both blocks, and they were negative. We also performed in  

> situ hybridization for EB virus RNA, and it was negative on both  

> blocks.  As before, I feel that the changes fit best with  

> lymphomatoid granulomatosis, grade 1. The CD20 staining supports  

> this diagnosis, although the negative in situ hybridization for EB  

> virus DNA is disappointing, but not surprising in this form of the  

> disease. It is, of course, unusual for lymphomatoid granulomatosis  

> to occur in a person of this age without an underlying reason for  

> immunocompromise.”

>

>


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