Pediatrik hematopoetik kök hücre transplantasyonu yapılan hastalarda enfeksiyon sürveyansı
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Tarih
2019
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Ege Üniversitesi, Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Giriş: Hematopoetik kök hücre transplantasyonu (HKHT) çocuk ve adolesan yaş grubunda birçok malign ve non-malign hastalığın tedavisinde etkin bir tedavi seçeneği olarak kullanılmaktadır. Hematopoetik kök hücre transplantasyonu sonrası erken ve geç dönemde gelişen komplikasyonlar, hastaların prognozunu ve yaşam kalitesini etkilemektedir. Nakil sonrası gelişen enfeksiyonlar morbidite ve mortalitenin önemli bir nedenidir ve hastanede kalış süresini uzatır. Hematopoetik kök hücre transplantasyonu yapılan hastalarda bakteriyel enfeksiyon, invaziv fungal enfeksiyon (İFİ) ve sitomegalovirüs (CMV) viremisi/ reaktivasyonu sıktır. En sık görülen enfeksiyonlar, kateter ilişkili primer kan dolaşımı enfeksiyonları, pnömoni ve idrar yolu enfeksiyonudur. Altta yatan hastalık tipi, genetik polimorfizmler ve farklı kondisyon rejimleri nakil alıcılarındaki enfeksiyonların profilini etkiler. Diğer ilişkili faktörler, bu hastalarda santral venöz kateterler (SVK), komorbidite varlığı, nötropeninin yoğunluğu ve süresi, mukozit ve antimikrobiyal profilaksi kullanımı enfeksiyon komplikasyonlarının gelişimini etkileyebilir. Kanser hastalarında SVK ile ilişkili enfeksiyonların bu popülasyondaki mortalite oranlarında yedi kat artışla ilişkili olduğu bilinmektedir. Nakil sonrası gelişen enfeksiyon nedeni ile morbidite ve mortalite oranı artmaktadır. Son yıllarda destekleyici bakım önlemlerinde sağlanan gelişmeler, immunsupresyon mekanizmalarının daha iyi anlaşılması, yoğunluğu azaltılmış, hazırlık rejimlerinin, yeni antimikrobiyal ilaçların ve profilaksi stratejilerinin kullanıma girmesiyle birlikte morbidite ve mortalite azalmıştır. Hematopoetik kök hücre transplantasyonu 1992'den beri Türkiye'de yapılmasına rağmen, az sayıda çalışma ülkemizde çocuk ve ergenlerdeki kendine özgü enfeksiyon özelliklerini ve komplikasyonlarını ele almıştır. Amaç: Bu çalışmanın amacı Ege Üniversitesi Tıp Fakültesi Çocuk Hastanesi'nde Hematopoetik kök hücre nakil hastalarında retrospektif olarak enfeksiyon etkenlerini, klinik bulgularını ve prognozu belirlemektir. Kök hücre nakil komplikasyonlarının nakilden sonraki ilk 100 gün içinde mortalite ve morbidite üzerindeki etkisini değerlendirmektir. Hipotez: Hematopoetik kök hücre transplantasyonu yapılan hastalarda enfeksiyonlar erken dönem komplikasyon gelişimini etkilemektedir. İkincil hipotez Greft versus host hastalığı (GVHH) ve transplantasyon için kullanılan immunsupresif rejimler, posttransplant fırsatçı enfeksiyon sıklığında artışa neden olmaktadır. Yöntem: Eylül 2014- Aralık 2018 tarihleri arasında Ege Üniveristesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı (AD) Kemik İliği Transplantasyon Ünitesinde allojenik ve otolog HKHT yapılan ve verilerine ulaşılabilen 200 çocuk hastanın transplantasyon sonrası ilk 100 günü çalışmaya dahil edildi. Hastaların verilerine poliklinik izlem dosyalarından ve elektronik hastane kayıtlarından ulaşıldı. Transplantasyon sırasındaki hasta yaşı, kullanılan kök hücre kaynağı, donör ile ilgili bilgiler, verilen kondisyon rejiminin özellikleri, GVHH profilaksisi, donör-alıcı CMV serolojik durumu, transplantasyon öncesi-sonrası bakteriyel enfeksiyon, CMV ve fungal enfeksiyon varlığı, antifungal, antibakteriyel ve antiviral profilaksi, nötrofil engraftman günleri, posttransplant steroid kullanımı, enfeksiyon üreme yeri, enfeksiyon gelişenlerde tanının hangi yöntemle konulduğu, enfeksiyon etkeni, enfeksiyon saptandığında kan hemogram ve biokimya parametreleri, transplantasyon öncesi-sonrası pik CMV DNA ve EBV DNA düzeyleri, transplantasyon sonrası ilk 100 günde mortalite gelişip gelişmediği, mortalite gelişmesi halinde ise nedeni olgu rapor formuna kaydedildi. Araştırmaya yön verecek verilerine ulaşılamayan hastalar çalışma dışı bırakıldı. Bulgular: Hastaların 115'i (%57,5) erkek, 85'i kız (%42,5) kız olup HKHT yapıldığında ortalama yaş 94,3 ay, median 85 ay (2-252) idi. İzlemde 14 hastaya greft reddi/yetmezliği nedeni ile ikinci kez kök hücre nakli uygulandı. Allojenik kök hücre nakli 187, otolog kök hücre nakli 13 hastaya uygulandı. Hazırlama rejimi dahilinde 33 hastaya TBI uygulandı. Greft versus host hastalığı profilaksisi 182 hastaya verildi. Nötrofil engraftman günü ortalama 17,5 gün, median 17 gün (9-32)'dü ve 7 hastada transplantasyon sonrasında nötrofil sayıları hep 1000/μl üzerinde seyrettiği için nötrofil engraftman gününden bahsedilemedi. 8 hasta greft reddi/ yetmezliği ve 9 hasta eksitus olması nedeniyle 17 hastada engraftman olmadı. Transplantasyon sonrası 200 hastadan 13 hasta ateşli atak geçirmedi. 187 hasta toplam 323 febril atak geçirdi. Transplantasyon sonrası 323 febril atağın 172 tanesi nedeni bilinmeyen ateş olarak saptandı. 151 bakteriyel febril atağın 66'sının gram pozitif, 85'inin gram negatif olduğu saptandı. Transplantasyon sonrası 90 hastada CMV gelişimi nedeniyle gansiklovir kullanıldı. Transplantasyon sonrası 21 hastada İFİ gelişti. Transplantasyon sonrası CMV reaktivasyonu gelişimi İFİ açısından riski arttırmamaktadır (P=0.799). Transplantasyon sonrası en sık rinovirüs olmak üzere 40 hastada viral solunum yolu enfeksiyonu saptandı. Transplantasyon sonrası en sık rotavirüs olmak üzere 44 hastada viral gastroenterit enfeksiyonu saptandı. Transplantasyon sonrası 25 hastada idrar BK virüs enfeksiyonu saptandı. Toplam 54 hastada akut GVHH gelişti. Transplantasyon sonrası aGVHH gelişenlerde bakteriyel enfeksiyon riski ve CMV gelişim riski artmaktadır (sırasıyla P=0.002, 0.014). Transplantasyon sonrası İFİ gelişimi ile aGVHH arasında istatistiksel olarak anlamlı ilişki saptanmamıştır (P=0.864). Transplantasyon sonrası steroid kullanımı olanlarda CMV reaktivasyonu daha fazla görülmesine rağmen istatistiksel olarak anlamlı saptanmamıştır (P=0.58). Transplantasyon sonrası steroid kullanımı İFİ gelişim riski arasında anlamlı ilişki saptanmamıştır. (P=0.101). Febril atak öncesi steroid kullanımı olanlarda bakteriyel enfeksiyon gelişim riski artmaktadır (P=<0.001). Kondisyon rejimleri ile bakteriyel enfeksiyon gelişimi, CMV gelişimi ve İFİ riski arasında anlamlı ilişki saptanmamıştır (sırasıyla P=0.111, 0.175, 0.138). Kök hücre kaynağının transplantasyon sonrası bakteriyel enfeksiyon gelişimi, CMV gelişimi ve İFİ gelişimi arasında istatistiksel olarak anlamlı bulunmamıştır (sırasıyla P=0.088, 0.499, 0.143). Bakteriyel enfeksiyon ile şok gelişimi istatistiksel olarak anlamlı saptanmıştır (P=0.001). Bakteriyel enfeksiyon ile yoğun bakım yatışı istatistiksel olarak anlamlı saptanmıştır (P=0.003). Transplantasyon sonrası ilk 100 günde %9 mortalite görülmüştür. Tartışma: Çocukluk çağında değişik endikasyonlarla farklı hazırlama rejimi, donör ve kök hücre kaynağı kullanılarak HKHT yapılmış heterojen bir hasta grubunda, HKHT sonrası yapılan değerlendirmede hastaların %43,5'unda bakteriyel enfeksiyon saptandı. Akut GVHH gelişen hastarda bakteriyel enfeksiyon riski ve CMV gelişim riskinin arttığı gözlendi. Nakil sonrası steroid kullanımı olanlarda bakteriyel enfeksiyon gelişimi riskinin arttığı görüldü. Bakteriyel enfeksiyon gelişen olgularda yoğun bakım yatış oranı %24,1 idi. Çocukluk çağında HKHT yapılan hastaların enfeksiyon ilişkili mortalite 13 (%6,5) saptandı.
Introduction: Hematopoietic stem cell transplantation (HSCT) is an effective treatment for the treatment of many malignant and non-malignant diseases in children and adolescents. Early and late complications after hematopoietic stem cell transplantation affect the prognosis of the disease and life quality of the patients. Post-transplant infections are an important cause of morbidity and mortality and prolong hospital stay. Bacterial infection, invasive fungal infection (IFI) and cytomegalovirus (CMV) viremia /reactivation are common in patients undergoing hematopoietic stem cell transplantation. The most common infections are catheter-related primary bloodstream infections, pneumonia and urinary tract infection. Type of underlying disease, genetic polymorphisms and different conditioning regimens affect the profile of infections in theese patients. Other related factors, such as central venous catheters (CVC), presence of comorbidity, intensity and duration of neutropenia, use of mucositis and antimicrobial prophylaxis may affect the occurence of infection complications. It is known that CVC-related infections in cancer patients are associated with a sevenfold increase in mortality in this population. Morbidity and mortality rates increase due to infection after transplantation. Recent advances in supportive care, improved understanding of the mechanisms of immunosuppression, reduced intensity preparation regimens used with new antimicrobial drugs and prophylaxis strategies reduced morbidity and mortality. Hematopoietic stem cell transplantation is carried out in Turkey since 1992. However, few studies have examined the specific infection characteristics and complications in children and adolescents in our country. Objective: The aim of this retrospective study is to determine the infectious agents, clinical findings and prognosis of hematopoietic stem cell transplant patients in Children's Hospital of Ege University Faculty of Medicine and to evaluate the effect of stem cell transplantation complications on mortality and morbidity within the first 100 days after transplantation. Hypothesis: In patients undergoing hematopoietic stem cell transplantation, infections affect the development of early complications. Secondary hypothesis, graft versus host disease (GVHD) and immunosuppressive regimens used for transplantation increase the frequency of posttransplant opportunistic infections. Methods: The first 100 days after transplantation of 200 allogeneic and autologous HSCT patients in the Bone Marrow Transplantation Unit of Ege University Faculty of Medicine, Department of Pediatrics (AD) between September 2014 and December 2018 were included in the study. The data was gathered from clinic follow-up files and electronic hospital records. Patient age during transplantation, stem cell source used, information about the donor, properties of the given conditioning regimen, GVHD prophylaxis, donor-recipient CMV serological status, pre and post-transplant bacterial infection, presence of CMV and fungal infection, antifungal, antibacterial and antiviral prophylaxis, neutrophil engraftment days, posttransplant steroid use; when infection was detected, infection site, diagnosis, method used for diagnose of infection, casue of infection, blood hemogram and biochemical parameters, pre-transplant post-transplant peak CMV DNA and EBV DNA levels, mortality in the first 100 days after transplantation, and in case of mortality, the cause were recorded in the case report form. We excluded patients that vital data could not be reached. Results: 115 (57.5%) of the patients were male and 85 (42.5%) were female. Mean age was 94.3 months and median 85 months (2-252). During follow-up, 14 patients underwent a second stem cell transplantation due to graft rejection / failure. Allogeneic stem cell transplantation was performed in 187 patients and autologous stem cell transplantation was performed in 13 patients. TBI was applied to 33 patients within the preparation regimen. GVHD prophylaxis was given to 182 patients. Neutrophil engraftment day was 17.5 days, median 17 days (9-32). Neutrophil engraftment day could not be mentioned in 7 patients since neutrophil counts were always 1000 / μl after transplantation. There was no engraftment in 17 patients due to graft rejection / failure and 8 patients died. After transplantation, 13 patients out of 200 had no febrile attacks. 187 patients had 323 febrile attacks. After transplantation, 172 of 323 febrile attacks were defined as fever of unknown origin. Of the 151 bacterial febrile attacks, 66 were gram positive and 85 were gram negative. Ganciclovir was used in 90 patients due to CMV development after transplantation. After transplantation, IFI developed in 21 patients. The development of CMV reactivation after transplantation does not increase the risk for IFI (P = 0.799). After transplantation, viral respiratory infection was detected in 40 patients, the most common agent was rhinovirus. Viral gastroenteritis infection was detected in 44 patients, most commonly agent was rotavirus. Urine BK virus infection was detected in 25 patients after transplantation. Acute GVHD developed in 54 patients. The risk of bacterial infection and CMV development increases in patients with aGVHD after transplantation (P = 0.002, 0.014, respectively). There was no statistically significant relationship between IFI development after transplantation and aGVHD (P = 0.864). Although CMV reactivation was more common in patients with steroid use after transplantation, it was not statistically significant (P = 0.58). There was no significant relationship between the risk of IFI development after steroid use after transplantation. (P = 0.101). The risk of developing bacterial infection increases in patients with steroid use before febrile attacks (P = <0.001). There was no significant relationship between conditioning regimens and bacterial infection, CMV development and IFI risk (P = 0.111, 0.175, 0.138, respectively). Bacterial infection after transplantation of stem cell source was not statistically significant between CMV development and IFI development (P = 0.088, 0.499, 0.143, respectively). Bacterial infection and shock development were statistically significant (P = 0.001). Bacterial infection and ICU stay were statistically significant (P = 0.003). 9% mortality was observed in the first 100 days after transplantation. Discussion: Bacterial infection was detected 43.5% of heterogeneous group of patients who underwent HSCT using different preparation regimen, donor and stem cell source with different indications in childhood when we evaluated after HSCT. The risk of bacterial infection and CMV development increased in patients with acute GVHD. The risk of developing bacterial infections was increased in patients with steroid use after transplantation. Intensive care hospitalization rate was 24.1% in cases of bacterial infection. Infection-related mortality was found in 13 (6.5%) patients who underwent HSCT in childhood.
Introduction: Hematopoietic stem cell transplantation (HSCT) is an effective treatment for the treatment of many malignant and non-malignant diseases in children and adolescents. Early and late complications after hematopoietic stem cell transplantation affect the prognosis of the disease and life quality of the patients. Post-transplant infections are an important cause of morbidity and mortality and prolong hospital stay. Bacterial infection, invasive fungal infection (IFI) and cytomegalovirus (CMV) viremia /reactivation are common in patients undergoing hematopoietic stem cell transplantation. The most common infections are catheter-related primary bloodstream infections, pneumonia and urinary tract infection. Type of underlying disease, genetic polymorphisms and different conditioning regimens affect the profile of infections in theese patients. Other related factors, such as central venous catheters (CVC), presence of comorbidity, intensity and duration of neutropenia, use of mucositis and antimicrobial prophylaxis may affect the occurence of infection complications. It is known that CVC-related infections in cancer patients are associated with a sevenfold increase in mortality in this population. Morbidity and mortality rates increase due to infection after transplantation. Recent advances in supportive care, improved understanding of the mechanisms of immunosuppression, reduced intensity preparation regimens used with new antimicrobial drugs and prophylaxis strategies reduced morbidity and mortality. Hematopoietic stem cell transplantation is carried out in Turkey since 1992. However, few studies have examined the specific infection characteristics and complications in children and adolescents in our country. Objective: The aim of this retrospective study is to determine the infectious agents, clinical findings and prognosis of hematopoietic stem cell transplant patients in Children's Hospital of Ege University Faculty of Medicine and to evaluate the effect of stem cell transplantation complications on mortality and morbidity within the first 100 days after transplantation. Hypothesis: In patients undergoing hematopoietic stem cell transplantation, infections affect the development of early complications. Secondary hypothesis, graft versus host disease (GVHD) and immunosuppressive regimens used for transplantation increase the frequency of posttransplant opportunistic infections. Methods: The first 100 days after transplantation of 200 allogeneic and autologous HSCT patients in the Bone Marrow Transplantation Unit of Ege University Faculty of Medicine, Department of Pediatrics (AD) between September 2014 and December 2018 were included in the study. The data was gathered from clinic follow-up files and electronic hospital records. Patient age during transplantation, stem cell source used, information about the donor, properties of the given conditioning regimen, GVHD prophylaxis, donor-recipient CMV serological status, pre and post-transplant bacterial infection, presence of CMV and fungal infection, antifungal, antibacterial and antiviral prophylaxis, neutrophil engraftment days, posttransplant steroid use; when infection was detected, infection site, diagnosis, method used for diagnose of infection, casue of infection, blood hemogram and biochemical parameters, pre-transplant post-transplant peak CMV DNA and EBV DNA levels, mortality in the first 100 days after transplantation, and in case of mortality, the cause were recorded in the case report form. We excluded patients that vital data could not be reached. Results: 115 (57.5%) of the patients were male and 85 (42.5%) were female. Mean age was 94.3 months and median 85 months (2-252). During follow-up, 14 patients underwent a second stem cell transplantation due to graft rejection / failure. Allogeneic stem cell transplantation was performed in 187 patients and autologous stem cell transplantation was performed in 13 patients. TBI was applied to 33 patients within the preparation regimen. GVHD prophylaxis was given to 182 patients. Neutrophil engraftment day was 17.5 days, median 17 days (9-32). Neutrophil engraftment day could not be mentioned in 7 patients since neutrophil counts were always 1000 / μl after transplantation. There was no engraftment in 17 patients due to graft rejection / failure and 8 patients died. After transplantation, 13 patients out of 200 had no febrile attacks. 187 patients had 323 febrile attacks. After transplantation, 172 of 323 febrile attacks were defined as fever of unknown origin. Of the 151 bacterial febrile attacks, 66 were gram positive and 85 were gram negative. Ganciclovir was used in 90 patients due to CMV development after transplantation. After transplantation, IFI developed in 21 patients. The development of CMV reactivation after transplantation does not increase the risk for IFI (P = 0.799). After transplantation, viral respiratory infection was detected in 40 patients, the most common agent was rhinovirus. Viral gastroenteritis infection was detected in 44 patients, most commonly agent was rotavirus. Urine BK virus infection was detected in 25 patients after transplantation. Acute GVHD developed in 54 patients. The risk of bacterial infection and CMV development increases in patients with aGVHD after transplantation (P = 0.002, 0.014, respectively). There was no statistically significant relationship between IFI development after transplantation and aGVHD (P = 0.864). Although CMV reactivation was more common in patients with steroid use after transplantation, it was not statistically significant (P = 0.58). There was no significant relationship between the risk of IFI development after steroid use after transplantation. (P = 0.101). The risk of developing bacterial infection increases in patients with steroid use before febrile attacks (P = <0.001). There was no significant relationship between conditioning regimens and bacterial infection, CMV development and IFI risk (P = 0.111, 0.175, 0.138, respectively). Bacterial infection after transplantation of stem cell source was not statistically significant between CMV development and IFI development (P = 0.088, 0.499, 0.143, respectively). Bacterial infection and shock development were statistically significant (P = 0.001). Bacterial infection and ICU stay were statistically significant (P = 0.003). 9% mortality was observed in the first 100 days after transplantation. Discussion: Bacterial infection was detected 43.5% of heterogeneous group of patients who underwent HSCT using different preparation regimen, donor and stem cell source with different indications in childhood when we evaluated after HSCT. The risk of bacterial infection and CMV development increased in patients with acute GVHD. The risk of developing bacterial infections was increased in patients with steroid use after transplantation. Intensive care hospitalization rate was 24.1% in cases of bacterial infection. Infection-related mortality was found in 13 (6.5%) patients who underwent HSCT in childhood.
Açıklama
Anahtar Kelimeler
Hematopoetik Kök Hücre Transplantasyonu, Bakteriyel Enfeksiyon, CMV Viremisi, CMV Reaktivasyonu, İnvaziv Fungal Enfeksiyon, Greft Versus Host Hastalığı, Mortalite, Hematopoietic Stem Cell Transplantation, Bacterial İnfection, CMV Viremia, CMV Reactivation, Invasive Fungal İnfection, Graft Versus Host Disease, Mortality
