Kök hücre nakli yapılan primer immün yetmezlik olgularının retrospektif değerlendirilmesi
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Tarih
2017
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Ege Üniversitesi, Tıp Fakültesi
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info:eu-repo/semantics/openAccess
Özet
Giriş ve Amaç: Primer immün yetmezlikler (PİY) immün sistemin doğuştan gelen bozuklukları nedeniyle oluşur ve tekrarlayan bakteriyel, viral, protozoal ve mantar enfeksiyonları, otoimmünite alerji ve maligniteye yatkınlık gibi bulgularla karşımıza çıkar. Erken tanı ve tedavi primer immün yetmezlik hastalıklarında hayat kurtarıcıdır. Kök hücre nakli bu gruptaki birçok hastalık için tek küratif tedavi seçeneğidir. Özellikle ağır kombine immün yetmezlikler pediatrik acil hastalıklar grubundan olup bu hastalıktan şüphelenildiğinde hızlıca ileri merkezlere yönlendirilmelidirler. Bu çalışmada hastanemiz Çocuk İmmünoloji Bilim Dalı tarafından takip edilen ve Pediatrik Kök Hücre Transplantasyon Ünitesi tarafından kök hücre nakli yapılan primer immün yetmezlik olgularının retrospektif olarak nakil öncesi ve sonrası klinik ve laboratuvar özellikleri, nakil süreci, nakil başarısına ve sonrasında prognoza etki eden faktörlerin incelenmesi amaçlanmıştır. Gereç ve Yöntem: Çalışmaya, Ege Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı, Çocuk İmmünüloji Bilim Dalı'nda tanısı konularak izleme alınan ve Pediatrik Kök Hücre Nakil Ünitesi tarafından Ağustos 1998 ve Ocak 2017 yılları arasında kök hücre nakli uygulanan 57 hasta alındı. Hastalar 2015 IUIS primer immün yetmezlikler sınıflandırmasına göre sınıflandırıldı. Başlıca AKİY, AKİY dışı kombine immün yetmezlikler (KİY) ve diğer primer immün yetmezlikler olarak 3 ana grupta incelendi. İmmün fenotiplerine göre AKİY' ler T-BNK+, T-B+NK+ ve T-B+NK- gruplarına ayrıldı. T+ kombine immün yetmezlikler (leaky AKİY), DOCK8 eksikliği, CD40 eksikliği, CD40L eksikliği, Artemis defekti, MHC sınıf 2 eksikliği, ZAP70 eksikliği, Omenn sendromu, Pürin nükleozid fosforilaz eksikliği ve Wiskott-Aldrich sendromu AKİY dışı kombine immün yetmezlikler grubunu oluşturdu. Kronik granülomatöz hastalık, Chediak Higashi sendromu, Griscelli sendromu, İnterferon-gamma reseptör 1 komplet defekti, İL10 reseptör defekti ve yaygın değişken immün yetmezlik olguları diğer primer immün yetmezlikler grubuna alındı. Çocuk İmmünoloji Bilim Dalı izlem dosyaları, Pediatrik Kök Hücre Nakil Ünitesi izlem dosyaları ve elektronik kayıtlardan hastalara ait ilk başvuru bilgileri, tanıdan transplantasyona kadar geçen süreç, transplantasyon ve sonraki izlem döneminde klinik ve laboratuvar özellikleri, uygulanan tedaviler incelendi. İstatiksel analiz, IBM SPSS Statistics 23 programı ile yapıldı. Bulgular: Başvuru ve demografik özellikler incelendiğinde başvuru yaşı ve tanı yaşı ortancası AKİY grubunda daha düşük olup tanı grupları arasında istatistiksel olarak anlamlı fark tespit edildi (sırasıyla p=0.003 ve p=0.004). En sık başvuru yakınması tüm gruplarda tekrarlayan enfeksiyonlardı. Başvuru yakınmalarında içinde büyüme geriliği en sık AKİY grubunda (p=0.048), tekrarlayan abse en sık diğer PİY grubunda (p=0.001) görüldü. İlk başvuru laboratuvar bulgularında lökosit, mutlak nötrofil, lenfosit sayıları, IgG, IgM, IgA ve lenfosit alt grupları AKİY grubunda daha düşüktü (p<0.005). Tanı gruplarına göre izlemdeki komplikasyonlar incelendiğinde mikobakteriyel enfeksiyon diğer PİY, CMV enfeksiyonu KİY grubunda sıklıkla görüldü (p=0.001). Transplant yaşı, tanı ve transplantasyon arası geçen süre AKİY grubunda diğer gruplara göre daha kısa idi (p<0.001). Onbir hastaya hazırlık rejimi verilmedi. Tüm grupta 37 hastaya myeloablatif, 4 hastaya non-myeloablatif, 5 hastaya RİC (Reduced intensity conditioning) protokolü uygulandı. Tüm gruba bakıldığında 41 (%71.9) hastada median 16. günde nötrofil, 32 (%55.4) hastada median 24. günde trombosit engrafmanı oldu. Nakil sonrası BCG ilişkili komplikasyon görülen 8 hastanın 5'i AKİY grubundandı (p=0.018). Tanı gruplarına göre 1., 2. ve 12. ay kimerizm değerleri incelendiğinde 1. ve 12. ay kimerizm oranları AKİY grubunda istatistiksel olarak düşük bulundu (p<0.05). Tanı gruplarına göre 1., 2. ve 12. ay lenfosit alt grupları karşılaştırıldığında CD3+ T hücre, CD19+ B hücre, CD3-CD16+/56+ doğal öldürücü hücre (NK) oranları arasında anlamlı fark saptanmadı (p>0.05). AKİY grubunda tanı yaşı ortancası (p =0.008), transplant yaşı ortancası (p =0.007), tanı ve transplant arası geçen sürenin ortancası (p=0.036) yaşayanlarda kaybedilenlere göre daha kısa tespit edildi. Transplantasyon öncesi kronik akciğer hastalığı (p=0.024), malnütrisyon (p=0.008), donör tipi (p=0.032) ve transplantasyon öncesi Lansky skoru (p=0.001) yaşayan ve kaybedilen hastalar arasında istatistiksel olarak anlamlı fark bulundu. Kaybedilen hastaların ölüm nedenleri arasında en sık nedeni akciğer enfeksiyonu oluşturdu. Donör tipine göre overall survival tüm grupta %67.3, MSD grubunda %89.5, MRD grubunda %75, MUD grubunda %58.3 idi, MMRD transplantların tümü kaybedildi. Sonuç: Primer immün yetmezliklerin ağır formlarının küratif tedavisinde KHN Türkiye' de halen devam eden uygulamadır. Hastalarımızda altta yatan immün yetmezliklerine bağlı transplantasyon öncesi dönemde eşlik eden morbiditelere (malnutrisyon, kronik akciğer hastalığı, CMV enfeksiyonu) rağmen hastalarımızın kök hücre nakil sonuçları tatmin edicidir. Ülkemizde birinci basamak hekimlerinin erken teşhis konusunda eğitimleri ile farkındalıklarının arttırılması ve AKİY' lerin yenidoğan tarama programına dahil edilmesi ile PİY hastalarında daha iyi sağkalım oranları sağlanabilir.
Introduction and Objective: Primary immunodeficiency disorders (PID) are inherited diseases characterized by impairment of innate or adaptive immunity, leading to recurrent infections, autoimmunity, allergy and susceptibility to malignancy. Early diagnosis and treatment are life-saving in primary immunodeficiency diseases. Hematopoetic stem cell transplantation (HSCT) is a curative treatment for many diseases in this group. Especially severe combined immunodeficiencies are pediatric emergent diseases, and when it is suspected, patients should rapidly be referred to tertiary care centers where HSCT are available. In this study, it was aimed to analyze the clinical and immunological data and immune reconstitution of 57 PID patients that had undergone HSCT. Materials and Methods: The study population was composed of 57 patients who were followed up by Pediatric Immunology and Pediatric Stem Cell Transplantation Departments, Ege University Faculty of Medicine between August 1998 and January 2017. Patients were classified according to 2015 IUIS primary immunodeficiencies classification. Patients were classified in three main groups such as SCID (severe combined immunodeficiency disease), non-SCID combined immunodeficiencies (CID) and other primary immunodeficiencies (other-PID). SCID patients were grouped as T-B-NK+, T-B+ NK+, and T-B+NK- according to their immune phenotypes. T+ combined immunodeficiencies (leaky SCID), DOCK8 deficiency, CD40 deficiency, CD40L deficiency, Artemis deficiency, MHC class 2 deficiency, ZAP70 deficiency, Omenn syndrome, Purine nucleoside phosphorylase deficiency and Wiskott-Aldrich syndrome constituted non-SCID combined immunodeficiency group. Chronic granulomatous disease, Chediak Higashi syndrome, Griscelli syndrome, Interferon-gamma receptor 1 complete defect, IL10 receptor defect and common variable immunodeficiency subjects were grouped as other-PIDs. Information about the demographic features, diagnosis, follow-up period, treatment strategies, transplantation procedures, complications and outcome of HSCT were collected from medical files. Statistical analysis was performed with IBM SPSS statistics 23 program. Results : Median age on admission and age at diagnosis age was lower in SCID group and there was a statistically significant difference among disease groups (p=0.03 and p=0.04, respectively). The most common complaint was the recurrent respiratory infections. Growth failure was more prevalent in the SCID group (p=0.048) and the recurrent abscess was mostly observed in the other PID group (p=0.001). Initial laboratory findings, such as leucocyte, absolute neutrophil and lymphocyte counts, IgG, IgM, IgA levels, and lymphocyte subsets were lower in SCID group (p<0.005). Mycobacterial infections were more common in the other- PID group and CMV infection was commonly seen in CID group (p=0.001). Age at HSCT, and the follow-up period between diagnosis and transplantation was shorter in SCID patients (p<0.001). Eleven SCID patients did not received conditioning regimen, 37 patients had myeloablative, 4 had non-myeloablative protocol, and 5 had RIC (Reduced Intensity Conditioning) conditioning protocol. Median time to neutrophil engrafment was 16 days in 41 patients (71.9%), and it was 24 days in 32 patients (55.4%) for the thrombocyte engrafment. Five out of 8 patients with BCGrelated complication after transplantation were in SCID group (p=0.018). Considering 1st, 2nd and 12th month chimerism values according to the disease groups, 1st and 12th month chimerism ratios were found to be statistically lower in SCID group (p<0.05). There was no statistically significant difference between the ratios of CD3+ T cells, CD19+B cells, CD3-CD16+/56+ natural killer cells (NK) checked on 1, 2 and 12 months after HSCT (p>0.05). The median age of diagnosis age in SCID group (p=0.008), the median age of transplantation (p=0.007), the median interval between the diagnosis and transplantation (p=0.036) were found to be shorter in surviving SCID patients than deceased ones. A statistically significant difference was found between the alive and deceased patients in terms of chronic lung disease before transplantation (p=0.024), malnutrition (p=0.008). Lung infections were the most common cause of death after HSCT. Overall survival was 89.5% in MSD group, 75% in MRD group, and 58.3% in MUD group; all of MMRD transplants were all lost. Conclusion: In terms of the ongoing utility of HSCT, it will remain the mainstay of correcting severe PIDs in Turkey. Despite significant pre-HSCT morbidity from the underlying PID in our patients (malnutrition, chronic lung disease, CMV infection), the outcome of our patients is satisfactory. Efforts to educate primary care physicians on early diagnosis and efoorts to implement newborn screening in our country might result in better survival rates in PID patients.
Introduction and Objective: Primary immunodeficiency disorders (PID) are inherited diseases characterized by impairment of innate or adaptive immunity, leading to recurrent infections, autoimmunity, allergy and susceptibility to malignancy. Early diagnosis and treatment are life-saving in primary immunodeficiency diseases. Hematopoetic stem cell transplantation (HSCT) is a curative treatment for many diseases in this group. Especially severe combined immunodeficiencies are pediatric emergent diseases, and when it is suspected, patients should rapidly be referred to tertiary care centers where HSCT are available. In this study, it was aimed to analyze the clinical and immunological data and immune reconstitution of 57 PID patients that had undergone HSCT. Materials and Methods: The study population was composed of 57 patients who were followed up by Pediatric Immunology and Pediatric Stem Cell Transplantation Departments, Ege University Faculty of Medicine between August 1998 and January 2017. Patients were classified according to 2015 IUIS primary immunodeficiencies classification. Patients were classified in three main groups such as SCID (severe combined immunodeficiency disease), non-SCID combined immunodeficiencies (CID) and other primary immunodeficiencies (other-PID). SCID patients were grouped as T-B-NK+, T-B+ NK+, and T-B+NK- according to their immune phenotypes. T+ combined immunodeficiencies (leaky SCID), DOCK8 deficiency, CD40 deficiency, CD40L deficiency, Artemis deficiency, MHC class 2 deficiency, ZAP70 deficiency, Omenn syndrome, Purine nucleoside phosphorylase deficiency and Wiskott-Aldrich syndrome constituted non-SCID combined immunodeficiency group. Chronic granulomatous disease, Chediak Higashi syndrome, Griscelli syndrome, Interferon-gamma receptor 1 complete defect, IL10 receptor defect and common variable immunodeficiency subjects were grouped as other-PIDs. Information about the demographic features, diagnosis, follow-up period, treatment strategies, transplantation procedures, complications and outcome of HSCT were collected from medical files. Statistical analysis was performed with IBM SPSS statistics 23 program. Results : Median age on admission and age at diagnosis age was lower in SCID group and there was a statistically significant difference among disease groups (p=0.03 and p=0.04, respectively). The most common complaint was the recurrent respiratory infections. Growth failure was more prevalent in the SCID group (p=0.048) and the recurrent abscess was mostly observed in the other PID group (p=0.001). Initial laboratory findings, such as leucocyte, absolute neutrophil and lymphocyte counts, IgG, IgM, IgA levels, and lymphocyte subsets were lower in SCID group (p<0.005). Mycobacterial infections were more common in the other- PID group and CMV infection was commonly seen in CID group (p=0.001). Age at HSCT, and the follow-up period between diagnosis and transplantation was shorter in SCID patients (p<0.001). Eleven SCID patients did not received conditioning regimen, 37 patients had myeloablative, 4 had non-myeloablative protocol, and 5 had RIC (Reduced Intensity Conditioning) conditioning protocol. Median time to neutrophil engrafment was 16 days in 41 patients (71.9%), and it was 24 days in 32 patients (55.4%) for the thrombocyte engrafment. Five out of 8 patients with BCGrelated complication after transplantation were in SCID group (p=0.018). Considering 1st, 2nd and 12th month chimerism values according to the disease groups, 1st and 12th month chimerism ratios were found to be statistically lower in SCID group (p<0.05). There was no statistically significant difference between the ratios of CD3+ T cells, CD19+B cells, CD3-CD16+/56+ natural killer cells (NK) checked on 1, 2 and 12 months after HSCT (p>0.05). The median age of diagnosis age in SCID group (p=0.008), the median age of transplantation (p=0.007), the median interval between the diagnosis and transplantation (p=0.036) were found to be shorter in surviving SCID patients than deceased ones. A statistically significant difference was found between the alive and deceased patients in terms of chronic lung disease before transplantation (p=0.024), malnutrition (p=0.008). Lung infections were the most common cause of death after HSCT. Overall survival was 89.5% in MSD group, 75% in MRD group, and 58.3% in MUD group; all of MMRD transplants were all lost. Conclusion: In terms of the ongoing utility of HSCT, it will remain the mainstay of correcting severe PIDs in Turkey. Despite significant pre-HSCT morbidity from the underlying PID in our patients (malnutrition, chronic lung disease, CMV infection), the outcome of our patients is satisfactory. Efforts to educate primary care physicians on early diagnosis and efoorts to implement newborn screening in our country might result in better survival rates in PID patients.
