[CIS-PAGID] 15 yo with ILD

[Ciaccio, Christina, E]

All-

Thank you for all the assistance with this case!  I will keep you updated.

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)
________________________________
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Jan Rohr
Sent: Tuesday, January 11, 2011 12:34 PM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS-PAGID] 15 yo with ILD

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<mailto: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.<javascript:AL_get(this,%20'jour',%20'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<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rohr%20J%22%5BAuthor%5D>, Beutel K<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Beutel%20K%22%5BAuthor%5D>, Maul-Pavicic A<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Maul-Pavicic%20A%22%5BAuthor%5D>, Vraetz T<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Vraetz%20T%22%5BAuthor%5D>, Thiel J<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Thiel%20J%22%5BAuthor%5D>, Warnatz K<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Warnatz%20K%22%5BAuthor%5D>, Bondzio I<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Bondzio%20I%22%5BAuthor%5D>, Gross-Wieltsch U<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Gross-Wieltsch%20U%22%5BAuthor%5D>, Schündeln M<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sch%C3%BCndeln%20M%22%5BAuthor%5D>, Schütz B<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sch%C3%BCtz%20B%22%5BAuthor%5D>, Woessmann W<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Woessmann%20W%22%5BAuthor%5D>, Groll AH<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Groll%20AH%22%5BAuthor%5D>, Strahm B<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Strahm%20B%22%5BAuthor%5D>, Pagel J<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Pagel%20J%22%5BAuthor%5D>, Speckmann C<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Speckmann%20C%22%5BAuthor%5D>, Janka G<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Janka%20G%22%5BAuthor%5D>, Griffiths G<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Griffiths%20G%22%5BAuthor%5D>, Schwarz K<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Schwarz%20K%22%5BAuthor%5D>, zur Stadt U<http://www.ncbi.nlm.nih.gov/pubmed?term=%22zur%20Stadt%20U%22%5BAuthor%5D>, Ehl S<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Ehl%20S%22%5BAuthor%5D>.

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<mailto: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<mailto: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."



-------------- next part --------------
An HTML attachment was scrubbed...
URL: <http://seven.pairlist.net/mailman/private/pagid/attachments/20110113/42fd8842/attachment-0001.htm>