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CD4 lymfopénia – primárna alebo sekundárna imunodeficiencia

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1 CD4 lymfopénia – primárna alebo sekundárna imunodeficiencia
Štefan Raffáč 5. Fórum imunodeficiencií, Košice, september 2017

2 ÚVOD Idiopatická CD4 T lymphocytopenia (ICL) je immunodeficiencia definovaná od r.1992 -the United States Centers for Disease Control (CDC) ako.. Abs.počet CD4 T-ly <300/mm3 alebo < 20% celkového počtu T ly viac než raz nameraných s odstupom 6 týždňov; ICL sa považuje za heterogénny syndróm nespôsobený infekčným agens „no evidence“ infekcie HIV, HTLV; vylúčenie immunodeficiencie alebo terapie spojenej s poklesom CD4 T ly Pacienti s ICL môžu mať oportunne infekcie ako dôsledok hlbokého deficitu bunkami mediovanej imunitnej odpovede. Dina S. Ahmad,Idiopathic CD4 Lymphocytopenia: Spectrum of opportunistic infections, malignancies, and autoimmune diseasesAvicenna J Med. 2013

3 Patofyziológia ICL ICL je charakterizovaný zvýšenou CD95+ expresiou s excesívnou apoptózou vedúcou k lymfocytopénii. C-X-C chemokine receptor type 4 (CXCR4) – porucha na T ly s ICL, zlepšenie „CXCR4 trafficking“ liečbou interleukinom 2 (IL-2). Mutácie génov: nunc-119, MAGT 1, Rag CD8 +T ly-pénia (< 180/mm3) a stupeň CD4+ T-ly aktivácie (expresia HLA-DR) sa spája so zlou prognózou .( Zonios DI et al.) ICL sa spája s nárastom podielu naivných a „transitional B ly“ a zvýšenými sérovými hladinami IL-7. Nízke hladiny B ly alebo aj kompletná absencia B ly môžu byť súčasťou ICL Zonios DI, Falloon J, Bennett JE, Shaw PA, Chaitt D, Baseler MW, Adelsberger JW, Metcalf JA, Polis MA, Kovacs SJ, Kovacs JA, Davey RT, Lane HC, Masur H, Sereti I. Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors. Blood. 2008;112:287–294. 33. Zonios DI, Falloon J, Bennett JE, Shaw PA, Chaitt D, Baseler MW, Adelsberger JW, Metcalf JA, Polis MA, Kovacs SJ, Kovacs JA, Davey RT, Lane HC, Masur H, Sereti I. Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors. Blood. 2008;112:287–294.

4 Profylaxia a liečba Neexistujú špecifické guideliny pre profylaxiu, monitoring a liečbu ICL. Prophylaxia oportúnnych infekcií sa opiera o menežment používaný pri HIV s rozvinutým ochorením . Monitoring CD4 ly á 4m pre stabilných pacientov bez infekcií. sledovanie ICL pacientov častejšie počas prvých 3 rokov pre zvýšené riziko závažných infekcií jako aj možnosť normalizácie počtu CD4 T-ly Cryptococcosis a idopatická CD4 lymphocytopenia (ICL) je reportovaná komplikácia. IL-2 -signifikantný účinok na zvýšenie počtov CD4 ly Liečba IL-2 sa používa v prípade oportúnnej infekcie spojenej s ICL. Therefore, one cannot compare the effectiveness of these regimens. The relapse rate of cryptococcal infections in ICL patients is low compared to HIV patients. ICl patients with cryptococcal infections have a favorable outcome in general.[22]Once those patients develop signs of infection, they need close attention. In the prospective study by Zonios et al., the CD4 T-cell counts in their patients remained less than 300/mm3 for several years with absence of progression of lymphocytopenia over timeOne-fifth of patients resolved their lymphocytopenia within 3 years of diagnosis Zonios et al. in another study followed 11 patients with cryptococcosis and idiopathic CD4 lymphocytopenia (ICL) referred to their institution, as well as 42 similar cases reported in the literature. Different treatment regimens were used in cryptococcal infections. Therefore, one cannot compare the effectiveness of these regimens. The relapse rate of cryptococcal infections in ICL patients is low compared to HIV patients. ICl patients with cryptococcal infections have a favorable outcome in general.[22] The idea of IL-2 came from its use in HIV patients with CD4+ lymphopeniaLimited data from those reports support IL-2 as a relatively safe and potentially effective treatment for ICL patients with opportunistic infections, especially when combined with conventional treatment regimens.[30,50,72,93,101]

5 Štúdia Volume 93(2);  2014 Mar Idiopathic CD4 Lymphocytopenia: Clinical and Immunologic Characteristics and Follow-Up of 40 Patients Alexis Régent, et al, for the French Idiopathic CD4 T Lymphocytopenia Study Group*Medicine (Baltimore) 2014 Mar; 93(2): Published online 2014 Mar 4. doi:  /MD PMCID: PMC

6 Výber pacientov do štúdie
CD4 T-ly < 300/mm3 alebo < 20% z celkového počtu T ly na základe 2 ch meraní v 6-týždňo vom odstupe; „non HIV-1/2“ alebo HTLV-1/2 absencia definovanej immunodeficiencie alebo liečby spojenej so zniženými hladinami CD4 T ly. Pacienti boli sledovaní za účelom vylúčenia primárnej alebo sekundárnej imunodeficiencie viral infection ( HIV, HTLV, transient viral infection), tuberculosis, malignancy, autoimmune / inflammatory disorders (Sjögren sy, sarcoidosis, sys. lupus erythematosus, granulomatosis with polyangiitis) or other causes of acquired lymphocytopenia. Searches for a known immunodeficiency were performed according to knowledge at the time of diagnosis and during follow-up. Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

7 Exklúzne kritéria prospektívna štúdia zahŕňajúca 59 pacientov 19 pacientov bolo sekundárne vyradených, pretože nespĺňali CDC kritéria pre ICL: 8 pacientov malo CD4 Tly ≥ 300/mm3, Iné exklúzne príčiny (11 pacientov) boli: sarcoidosis (n = 3), malignant lymphoma (n = 1), multiple myeloma (n = 1), Sjögren syndrome (n = 1), splenomegaly secondary to portal thrombosis (n = 1), anorexia nervosa (n = 1), exudative enteropathy (n = 1), common variable immunodeficiency (CVID) (n = 1), tuberculosis (n = 1). Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

8 Klinické manifestácie
Sledovaných 40 pts (24 žien), priemerný vek: 44,2 ± 12,2 [19–70] rokov v čase dg., priemerný čas sledovania: 6,9 ± 6,7 (0.14–24.3) roka. pacienti s ICL od I/1991 do VI/ 2012 21 pacientov malo ľahkú hypogammaglobulinémiu, ale znížené hladiny IgG nenapĺňali kritéria pre CVID. 11 pacientov dostávalo profylaxiu trimethoprim Pacienti boli klasifikovaní do 3ch skupín na základe klinickej a/alebo lab. manifestácie v čase dg alebo počas sledovania : autoimmunita/inflammacia, infekcia, malignita Patients’ clinical characteristics at the time of diagnosis are detailed in Table ​Table1.1. initial symptoms of any infection known to be associated with lymphocytopenia and any symptom related to autoimmune diseases. During follow-up, unusual infections, neoplasms, and symptoms related to autoimmune diseases were recorded. Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

9 Klinické manifestácie - Infekcia/AIDS:
Infekcia sa rozvinula u 25 pts v čase dg/počas sledovania. 12 pacientov - human papillomavirus (HPV): bradavice (n = 5), kondyloma (n = 3), Bowenoid papulomatosis (n = 3), pseudo-epidermodysplasia verruciformis (n = 4), anogenitalna dysplasia (n = 2), molluscum contagiosum (n = 2). 6 pacientov - Cryptococcus neoformans všetci - meningitis ,1 chirurgické riešenie pneumonie s cryptococcal inf. 14 pacientov - acquired immunodeficiency syndrome (AIDS) Ďalšie oportúnne infekcie: recurrent Alternaria sps., Nocardia brasil. inf. (Table ​(Table2).2). Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

10 Klinické manifestácie - autoimunita/inflamácia
14 pacientov malo autoimmúnne a/alebo inflammatórne manifestácie, immune thrombocytopenic purpura (ITP) (n = 5), autoimmune hemolytic anemia (AIHA) (n = 3), CNS vasculitis (n = 1), Goodpasture sy (n = 1), gr. II. Duoden. villous atrophy (n = 1), M. Crohn (n = 1), antiphospholipid syndrome (n = 1), seronegative polyarthritis (n = 1), vitiligo (n = 1), Guillain-Barre sy (n = 1) , Hashimoto thyroiditis (n = 1). These manifestations were not related to therapy except for the AIHA and Goodpasture syndrome of P26, which appeared during and 3 years after IL-2 therapy, respectively. Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

11 Klinické manifestácie -malignita
2 pac. - lymfóm (null phenotype lymfom a non-Hodgkin lymfom) 3 pac. - solidný tumor. 1 pac. - Castleman choroba a pľúcna hypertenzia 3 pac. - cirrhosis neznámej etiol. 8 pac. - infekcia a autoimunita, 4 pac. – infekcia a malignita. Žiaden pacient nemal autoimunitu a malignitu, alebo infekciu, autoimunitu a malignitu. 8 pac. - ľahké resp. žiadne symptómy Biological heterogeneity of patients with idiopathic CD4 lymphocytopenia (ICL) at diagnosis and clinical manifestations during follow-up. A. Classification of patients with ICL by main clinical manifestations (n = 40); (B) lymphocyte subpopulation deficiencies (Figure ​(Figure11ANo patient had autoimmunity and malignancy, and no patient had infectious, autoimmune, and malignant manifestations. Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

12 Imunologické parametre
V čase dg: Priemer CD4 -127/mm3 (4-294). Priemer CD8 236/mm3 (1-1293), CD19 113/mm3 (3-547), NK : 122/mm3 (5-416). 24 pac. - CD8 T- deficiencia, 32 pac. - CD19 B- deficiencia, 8 pac. - CD3-CD16+CD56+ NK deficiencía Abs.počet CD4, CD19, CD8, NK pozitívne koreloval so závažnosťou lympénie. Reziduálne CD4 Tly vykazovali zvýšenú expresiu HLA-DR+ a CD45RO+ a redukovanú expresiu naivných markerov (CD45RA+) respectivelyAbsolute CD4, CD19, CD8, and NK cell counts were positively correlated with severity of lymphocytopenia. Proportions of each lymphocyte population were modified by severity of lymphocytopenia: that of CD8 T cells decreased with the severity of lymphocytopenia (p = 0.01). (Table ​(Table4).4(Figure ​(Figure1B).1B). (Figure ​(Figure2A).2A(Figure ​(Figure2B)2B) (data not shown). Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

13 Follow-Up a prognóza Pacienti s infekčnou manifestáciou mali signifiantne nižšie NK bb v čase diagnózy; Pacienti s autoimunitou mali signifikantne vyššie CD3+, CD8+ a CD8+CD45RO+ T-ly ; Pacienti s malignitou mali nízke CD4+CD45RA+ a CD8+CD45RO+ T-ly 6 pac. (15%) počas sledovania zomreli: cerebral inf. Mycobacterium tuberculosis ; anaplastic lymphoma (null phenotype) ; pancreatic adenoCa ; epidermoid Ca of the cheek; respiratory failure related to pulmonary arterial hypertension ; and multiorgan failure due to septic shock - Escherichia coli infection . Iniciálny počet CD4 T-ly <150/mm3 a nízky počet NK bb (< 100/mm3) alebo nízky počet NK bb (<100/mm3) boli prognostickým markerom mortality. (Table ​(Table5).5). (Figure ​(Figure44). Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

14 Záver 35% pacientov s ICL rozvinulo autoimúnne manifestácie.
oportúnne infekcie sú bežným prejavom, 1/3 pacientov mala „HPV-related“ prejavy, CD4 T lymfocytopénia sa často spájala s CD8, CD19, a/alebo NK deficienciou, počet CD4 T-ly <150/mm3 a NK bb (<100/mm3) alebo nízky počet NK bb (<100/mm3) môže reprezentovať zlú prognózu, dlhodobé prognózy u pacientov sa môžu vzťahovať na iniciálnu CD4 a NK bunkovú deficienciu, Na identifikáciu pacientov s možným benefitom z IL2 liečby sú potrebné väčšie štúdie. The outcome has improved since ICL was first described. In conclusion, ICL is a heterogeneous disorder often associated with deficiencies in CD8, CD19, and/or NK cells. Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

15 Kazuistika 1., muž, M.R., 56 r. Kazuistika 1., muž, M.R. 56 r.
6/2016 I. Int. klinika: Dg. Febrility n.s., susp. to autoimmune cholangoitis (MRCP) PET/CT Intersticial bronchopneumonia, mediastinal LAP, H-S.megalia → respir. insuf. CD4+ lymfopénia, monocytopenia, NK-penia ATB, ATM, imunomodulácia (polyoxidonium, IVIG) → parcial klinická odpoved ANA, ENA negat, CIK ↑: vasculitis necrotisans pľúc - methylprednisolon → klinická odpoveď 7/2016 NÚTPCHaHCH, Vyšné Hágy: biopsia pľ LU: – bez malignity, reaktivne zmeny, methylprednisolon + cyclophosphamid. 8/2016 I. Int,kl.UNLP: Febrility, pancytopénia -ťažká neutroárnania , proteinúria and nefrotický syndrom Susp. autoimm. Multiorganové poškodenie: KD: ľahká hypercelularita , bez dysplázie Renal biopsia: bez znakov pre vasculitis, glomerulonephritis, IF negat. Pulmonary histology: aleveolarna proteinóza !!! EBV PCR, IgM EBNA pozit - susp. EBV choroba Methylprednisolon + ATB 11/2016 Progresia resp. insuficiencie, PNO, Urgentná resuscitácia.... Exitus letalis Autopsia nebola uskotočnená na žiadosť rodiny ! Dif. Dg febrilít, pnuemónie a imun. Parametrov – opakovane komplexne mikrobiologické vyšetrenia vrátane vylúčenia HIV. Národného ústavu tuberkulózy, pľúcnych chorôb a hrudníkovej chirurgie Vyšné Hágy - Histology from lung tissue was not to done because of progression of febrilities and pneumonitis . Pnacytopenia, no sufficient efect of G-CSF , trombocytopenia - diferentiantion – trepanobiopsy of bone marrow Skratky: ATB – antibiotiká ATM – antimykotiká ICU – intensive care unit (JIS-ka) PNO - pneumothorax

16 Kazuistika, muž, M.R. 56 r. Laboratórne parametre

17 POTVRDENÉ POTVRDENÉ Kazuistika 1, muž, M.R., 56 r.
Imunologické vyšetrenie Dg. Sepsa, alveolárna proteinóza v koincidencii s PID – idiopathic CD4+lymphopenia (ICL), sporadická monocytopenia (monoMAC sy), dif.dg Infekčné komplikáciekombinovanej etiológie, autoimmune multiorgane damage symptoms Doporučenie: Imunoprofil – celulárna imunita, IgG,A,M,E,D, podtriedy igG, Genetické vyšetrenie - Brno/CZ: X-lymphoprolipherative sy. (SH2D1A, BIRC4) GATA 2 deficiency Dif.dg. susp. MDS Liečba: Transfer f. 1 amp sc daily, G/GM-CSF, IL-2 POTVRDENÉ POTVRDENÉ

18 Kazuistika 2, Žena, J.F., 46 r. IX/ 2015 Ca mamae - stp.OP, CHT (6x), RAT ( Gy) XI/16 – febrilný stav XII/16 – bronchopneumonia dolný a stredný pľ.lalok (CT ,bronchoskopia) XII/16 – I/17 – hospitaliácia Inf.kl. I/17– ATB: azitromycin p.o, medoflucon p.o, ceftriaxom iv, biseptol iv I/17 – IX/17- Transfer factor Dif.dg ICL Celulárna imun.[Mo] 0,50 10^9/l [Leu] 6,30 10^9/l [N] 4,98 10^9/l [Ly] 0,69* 10^9/l [N%] 79 % [Eo%] 2 % [Ba%] 0 % [Mo%] 8 % [Ly%] 11* % [Iné%] 0 % [CD3+%] 76,00 % [CD4+%] 42,00 % [CD8+%] 35,00 % [CD3+Dr+%] 18,00* % [CD19+%] 18,00* % [NK%] 7,00* % [CD3+] 0,53* 10^9/l [CD4+] 0,29* 10^9/l [CD8+] 0,24 10^9/l [CD4+/CD8+] 1,20 [CD19+] 0,12 10^9/l [NK] 0,05* 10^9/l [ Celulárna imun.[Mo] 0,46 10^9/l [Leu] 6,60 10^9/l [N] 5,21 10^9/l [Ly] 0,73* 10^9/l [Eo] 0,15 10^9/l [N%] 79 % [Eo%] 3 % [Ba%] 0 % [Mo%] 7 % [Ly%] 11* % [Iné%] 0 % [CD3+%] 75,00 % [CD4+%] 30,00 % [CD8+%] 43,00* % [CD3+Dr+%] 23,00* % [CD19+%] 9,00 % [NK%] 14,00 % [CD3+] 0,54* 10^9/l [CD4+] 0,22* 10^9/l [CD8+] 0,31 10^9/l [CD4+/CD8+] 0,70* [CD19+] 0,07* 10^9/l [NK] 0,10 10^9/l Onko liečba – tamoxifen – CD4+Lymfopenia !!!

19 Kazuistika 2, Žena, J.F., 46 r.

20 Kazuistika 3., muž, M.M., 58 r. CVID autoim.prejavy (Raynaud ff, alopecy, pernicious anemia, leukopenia, trombocytopenia ) CNS demyelination lesions vs. vaskularne, Veruccae vulg. multip. 2015 – extirpácia adenoma gl.parotis, granulomatosis in cicatricae I- II/2017 -Sialoadenitis gl.parotis . ATB , Transfer ff., SCIG II/17 - [S-IgG] 7,44 g/l [S-IgA] 0,72 g/l [S-Ig M] 0,27* g/L III/17 CD4+ 0,22/44% , Leu 2,5 – 3,5 Neu 1,8..2,0, Ly 0,5/20% Dif.dg: ICL Celulárna imun. [Mo] 0,15* 10^9/l [Leu] 2,50* 10^9/l [N] 1,82 10^9/l [Ly] 0,50* 10^9/l [N%] 73 % [Eo%] 1 % [Ba%] 0 % [Mo%] 6 % [Ly%] 20 % [Iné%] 0 % [FA] 97,4 % [FI] 134 [CD3+%] 74,00 % [CD4+%] 44,00 % [CD8+%] 26,00 % [CD19+%] 9,00 % [NK%] 14,00 % [CD3+] 0,37* 10^9/l [CD4+] 0,22* 10^9/l [CD8+] 0,13* 10^9/l [CD4+/CD8+] 1,69 [CD19+] 0,04* 10^9/l [NK] 0,07* 10^9/l ORL: Dg.:K11.2 ???

21 Záver Idiopatická CD4 lymfopénia – ICL –je vzácna heterogénna porucha
často spojená s bunkovou deficienciou CD8, CD19, a NK . Pacienti sa zvyčajne diagnostikujú v strednom vek (priem.:40.7r. ) Dôležité je vylúčiť v rámci diferenciálnej diagnostiky iné príčiny lymfocytopénie (vírus, TBC, lymfó m, imunosupresíva...) Oportúnne infekcie sú bežné a môžu byť zahrnuté do „AIDS-defining illnesses“, pričom manažment je založený na skúsenostiach s liečbou HIV pacientov Dlhodobé prognózy sa môžu viazať na úvodnú CD4 a NK bunkovú deficiencu. V liečbe sa môže uplatniť IL2 avšak na zhodnotenie benefitu tejto liečby sú potrebné ďalšie štúdie. The outcome has improved since ICL was first described. In conclusion, ICL is a heterogeneous disorder often associated with deficiencies in CD8, CD19, and/or NK cells. Malignancies were reported in 18.1% of the patients. Lymphoma with its subtypes, in general, was the most common reported malignancy in ICL patients. Autoimmune diseases were reported in 14.2% patients. Sjogren's disease was the most common reported autoimmune diseases in ICL patientsCD4 lymphocytopenia was found in 9.6% of HIV-negative hospitalized tuberculosis patients and in 4.2% of ambulatory tuberculosis patientsAvicenna J Med Apr-Jun; 3(2): 37–47. doi:  / PMCID: PMC Idiopathic CD4 Lymphocytopenia: Spectrum of opportunistic infections, malignancies, and autoimmune diseases Dina S. Ahmad, Mohammad Esmadi, and William C. Steinmann Author information ► Copyright and License information ► common,1/3 pts exhibiting HPV-related clinical manifestations. CD4 T-cell count <150/mm3 and low NK cell count (<100/mm3) or a low NK cell count (<100/mm3) may represent a poor prognosis Alexis Régent, et alIdiopathic CD4 T LymphocytopeniaMedicine (Baltimore) 2014

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