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Cytomegalovirus infection in children after bone marrow transplantation: Risk factors, clinical aspects and outcomes
Accepted Manuscript Title: Cytomegalovirus Infection in Children after Bone Marrow Transplantation: Risk factors, Clinical aspects and Outcomes Author: Muhammad Matloob Alam Mohamed Bayoumy Areej Ali Muayad Alali Bayanah Al-enezi Ibraheem Abosoudah PII: DOI: Reference:
S2212-8328(16)30004-2 http://dx.doi.org/doi:10.1016/j.pid.2016.03.004 PID 165
To appear in: Received date: Revised date: Accepted date:
16-11-2015 29-12-2015 17-3-2016
Please cite this article as: Muhammad Matloob AlamMohamed BayoumyAreej AliMuayad AlaliBayanah Al-eneziIbraheem Abosoudah Cytomegalovirus Infection in Children after Bone Marrow Transplantation: Risk factors, Clinical aspects and Outcomes (2016), http://dx.doi.org/10.1016/j.pid.2016.03.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Original Article Cytomegalovirus Infection in Children after Bone Marrow
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Transplantation: Risk factors, Clinical aspects and Outcomes
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Muhammad Matloob Alam*, Mohamed Bayoumy, Areej Ali, Muayad Alali,
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Bayanah Al-enezi, Ibraheem Abosoudah
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Section of Pediatric Hematology / Oncology and Blood and Marrow Transplant, Department of Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
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Corresponding Author Dr. Muhammad Matloob Alam Section of Pediatric Hematology & Oncology Department of Oncology King Faisal Specialist Hospital and Research Centre P.O. Box 40047, Jeddah 21499, Saudi Arabia Phone +966 2 667 7777 x 64010 Fax +966 2 667 7777 x 64030 Email: [email protected]
Abstract words count: 250 Manuscript words count: 2992 Number of tables: 2 Number of figures: 3 Conflict of interest: None Short running title: CMV reactivation in Children after BMT
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Co- authors
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Bayanah AL-enezi, RN, BSN, MBA Bone marrow transplant coordinator, Pediatric oncology King Faisal Specialist Hospital and Research Centre [email protected]
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Mohamed Bayoumy, M.D. Chairman, Oncology Department Director, Combined Bone Marrow Transplantation Program Consultant Pediatric Hematology/Oncology/Bone Marrow Transplantation Director, Hospital Morbidly & Mortality Unit King Faisal Specialist Hospital and Research Centre [email protected]
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Muayad Alali, M.D.
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Areej Ali,RN,BSN,PGD Bone marrow transplant coordinator, Pediatric Oncology King Faisal Specialist Hospital and Research Centre [email protected]
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Section of Pediatric Hematology & Oncology Department of Oncology King Faisal Specialist Hospital and Research Centre
Dr. Ibraheem Abosoudah, MD Consultant Pediatric Hematology / Oncology and Blood and Marrow Transplant Head Section Pediatric Hematology / Oncology and Blood and Marrow Transplant King Faisal Specialist Hospital and Research Centre [email protected]
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Original Article Cytomegalovirus Infection in Children after Bone Marrow
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Transplantation: Risk factors, Clinical aspects and Outcomes
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ABSTRACTS Background and Objectives Cytomegalovirus infection remains the most common and potentially severe viral complication in patients given HSCT. The aim of this study was to determine the incidence, risk factors and
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outcomes of CMV infection in pediatric BMT unit.
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Material and Methods
This study was a retrospective analysis of clinical, laboratory and outcome data of 131 pediatric
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patients who underwent BMT.
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Results
The mean age of the study population was 6.5 ± 4 years. Out of males were 85 (64.9%). Majority
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of patients had hematological disorder/malignancy (n=101; 77%) followed by solid tumors (n=30; 23%). Most of them received allogeneic transplant (n=92; 70.2%). CMV reactivation was observed in 38 (29%) patients, out of them only (n=3; 2.3%) had clinical manifestation/organ
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involvement and most cases of CMV were resolved (n=35; 26.7%). Benign hematological
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disorder, conditioning regimen containing ATG, allogeneic BMT, GVHD prophylaxis used and development of GVHD were identifiable risk factors in all patients and lymphopenia < 300/mm3
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(p=0.047) was the only identifiable risk factors in allogeneic BMT patients associated with development CMV reactivation. Patients who had CMV reactivation had significantly higher rate of GVHD (31.6% vs 15.1%; p=0.031), however relapse rate (21% vs 25.8%) and mortality rate (22.5% vs 33.3%) in patients with CMV reactivation versus no CMV reactivation respectively, were not statistically significant. Overall survival and event free survival of patients with and without CMV antigenemia were also comparable.
Conclusions
Antigenemia-guided pre-emptive strategy with ganciclovir was very affective and CMV reactivation tended not to affect the outcome in our study cohort.
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Key
Wards:
Cytomegalovirus
reactivation/antigenemia,
Hematopoietic
Stem
cell
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Transplantation, Risk factors, GVHD, Relapse, Survival, Mortality
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INTRODUCTION Cytomegalovirus (CMV) infection remains the most common and potentially severe viral complication in patients undergoing hematopoietic stem cell transplantation (HSCT).[1] Seropositivity for CMV is an independent risk factor for mortality, even in recipients of matched
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sibling or unrelated donor transplants.
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The manifestations of CMV range from asymptomatic infection, defined as active CMV replication in the blood in the absence of clinical manifestations or organ failure abnormalities,
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to CMV disease, characterized by CMV infection with clinical symptoms or organ function abnormalities.[2] Diagnostic procedures to assess the viral load have improved greatly with the increased use of antigenemia, CMV DNA, and immediate early-messenger RNA.[3] Many
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conditions determine the risk of developing CMV reactivation or disease after bone marrow transplant with serologic status of donor and recipient, type of bone marrow transplant, presence
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of graft-versus-host disease being the most studied.[4] However, time and quality of immune reconstitution seem to be the pivotal factors. Pneumonia and gastrointestinal involvement are the
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representing a new challenge.[5]
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most frequently documented clinical pictures with late-onset CMV reactivation or disease
CMV prophylaxis or pre-emptive therapy adopted during the last few years in allogeneic HSCT
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recipients has changed the natural history of the disease, reducing the risk of CMV disease, CMV associated death, transplant-related mortality, and has prolonged the period at risk.[6]
Specific studies on children regarding post BMT CMV infection are lacking, and majority of data are derived from studies performed on adults.[1]Thus, in this single-center, retrospective study, we analyzed the medical records of 131 pediatric patients who underwent BMT to determine the incidence of CMV infection/reactivation and disease and to identify the important risk factors, clinical aspects and outcomes of CMV infection/reactivation in post BMT pediatric patients at our tertiary health care facility.
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MATERIAL AND METHODS Study Design and Setting This study was a retrospective analysis of clinical and laboratory data of post BMT pediatric patients. We included all pediatric patients consecutively underwent Bone Marrow
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Transplantation in our pediatric BMT unit over a period of 10 years from 2005 to 2014. Our hospital is a tertiary health care facility and is accredited by the international arm of the Joint
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Commission International Accreditation Survey (JCIA). There is a 20-bed, pediatric hematology/oncology ward along with a 5-bed BMT unit within the hematology/oncology ward.
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Total of 131 pediatric patients underwent BMT in the last 10 years duration and average BMT was 13 per year.
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Patient population and definition
Patients from one month to 15 years of age, who were admitted to the pediatric BMT unit for
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transplantation from 2005 to 2014, were included in this study. Post BMT patients with CMV reactivation was identified and compared with the rest of post BMT patients to identify the risk factors, any difference in clinical manifestations and their outcomes. For definition of CMV
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reactivation and viremia or infection, investigations and management in this study American
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Society for Blood and Marrow Transplantation (2009) Guidelines for Preventing Infectious
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Complications among Hematopoietic Cell Transplantation Recipients were accepted.[4]
CMV Infection prophylaxis:
Preemptive Therapy (< 100 days post-HCT): Administer to all HCT recipients (all ages) with evidence of CMV infection in blood by antigenemia, PCR more than 500 copies/ml for CMV DNA or detection of CMV mRNA. Ganciclovir, 5mg/kg/dose, intravenously (i.v.) Induction: Twice daily for 7-14 days tell CMV PCR titer is less than 500 copies/ml for two consecutive readings then start maintenance with Valgancyclovir Once daily dose (mg) = 7 x body surface area x creatinine clearance for another 7 to 14 days . Note: Continue screening for CMV reactivation weekly and re-treat if screening tests become positive after discontinuation of therapy 7 Page 7 of 25
Data collection All patients who had diagnosis codes for both neoplastic disease (International Classification of Diseases, 9th revision, clinical modification [ICD-9-CM] code 140-239), nonmalignant disease and bone marrow transplantation, and 15 years or younger was identified by using health information management system and internal BMT registry which records all the MBT patients
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were included in this analysis. For those patients who had more than one BMT, each BMT was
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counted and analyzed as separate case.
The primary outcome of this analysis were to identify the risk factors for CMV
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reactivation/infection and outcomes (GVHD, survival rate and mortality). Relevant covariates data were collected including demographic features, age, gender, primary diagnosis, phase of chemotherapy (if applicable), clinical features at presentation, duration of symptoms, initial
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laboratory work up including CMV status and radiological finding (if applicable) and microbiological data, management and outcomes. Underlying disease (acute Leukemia, chronic
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leukemia, solid tumors and nonmalignant diseases), type of donors, transplant type, conditioning regimen etc. Pre-transplant CMV status of all recipients and donors along with post BMT assessment, investigations and prophylaxis and management of CMV were also be recorded. All
(2009)
Guidelines
for
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Transplantation
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patients were treated as inpatients following the American Society for Blood and Marrow Preventing
Infectious
Complications
among
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Hematopoietic Cell Transplantation.[4] Statistical analysis
For analysis, SPSS version 20.0 (IBM, Chicago, USA) was used. Summary statistics was used to describe the cohort. The frequency of CMV antigenemia was measured during the posttransplantation period of 100 days. Frequencies were computed for qualitative variables and mean and standard deviation were used for quantitative variables. Independent risk factors associated with development of CMV reactivation/infection were identified by comparing patients with CMV reactivation/infection and patients without CMV reactivation/infection (patients at risk group). A p-value of 0.05 was considered significant at the univariate level.
Ethical approval/ Considerations The study was started after getting approval from the Institutional Review Board (IRB) of our hospital. 8 Page 8 of 25
RESULT
One hundred and thirty one pediatric patients admitted for BMT during this study period were included in the final analysis. The mean age of the study population at the time of transplant was 6.5 ± 4 years. Out of males were 85 (64.9%) and females were 46 (35.1%). Table 1 provides a
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summary of patient’s demographics.
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Majority of patients had hematological nonmalignant disorder (n=51, 38.2%) including betathalassemia (n=13; 9.9%), sickel cell anemia (n=8; 6.1%), aplastic anemia (n=8; 6.1%), fanconi
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anemia (n=4; 3.1%), followed by hematological malignancy (n=50; 38.2%); out of them ALL (n=11; 8.4%), AML (n=20; 15.3%), lymphoma (n=8; 6.1%) then solid tumors (n=30;22.8%)
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including neuroblastoma (n=26; 19.8%) and medulloblastoma (n=3; 2.3%).
Pre-transplatation CMV serology was positive for all recipients and donors except one donor had
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negative CMV serology. Most of the patients received allogeneic transplant (n=92; 70.2%) and remaining (n=39; 29.8%) were underwent autologous transplant. Source of donor in all
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allogeneic cases were full matched related donor. No difference in ANC engraftment was
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observed between patients with and without CMV reactivation (median 19 days vs. 20 days), however in platelets engraftment minor difference was observed (median 23 days vs. 20 days)
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but statistically not significant. Acute graft-versus-host disease (GVHD) was observed in 26 (19.8%) and chronic GVHD was observed in 9 (6.9%) cases.
CMV reactivation was observed in 38 patients (29%) cases within 100 day of post BMT. Out of them majority were asymptomatic (n=35; 26.7%) and remaining (n=3; 2.3%) had clinical manifestation/organ involvement (retinitis/pneumonia/colitis/hepatitis and skin manifestation). Most of CMV cases were resolved (n=35; 26.7%). A total 3 patients who had history of CMV reactivation were died (2 patients were CMV positive and one was negative for CMV at the time of expiry).
Transplantation-related factors that could influenced the onset of viral reactivation were also assessed (Table. 2). Primary diagnosis as a group benign hematological disorder [p= 0.014; OR 4.2 (CI, 1.14-16.69)], conditioning regimen containing ATG [P=0.037 OR 2.6 (CI, 1.04-6.62], 9 Page 9 of 25
allogeneic BMT [p=0.025; OR 2.7 (CI, 1.03-4.96) ], GVHD prophylaxis used [p<0.005; OR 5.4 (CI, 2.24-13.12)], and development of GVHD [p=0.031; OR 2.6 (CI, 1.07-6.34)] in all patients. However in allogeneic BMT patients only lymphopenia < 300/mm3 [p=0.047; OR 2.5 (CI, 0.996.28)] was identified as risk factor associated with development CMV reactivation in post BMT
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pediatric patients.
All cases we developed antigenamia within 100 days of post transplantation except one and 9
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cases had antigenemia of above 5000 copies/ml for CMV DNA. Median days at onset of antigenemia after BMT was 40 (Range: 5-111) days and median duration of antigenemia was 14
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(Range: 7-431) days. Median days at onset of antigenemia after BMT was 45.5 vs 41 days and duration of antigenemia was 14 vs 20 days for patients who had CMV viral load <5000 and >
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5000 copies/ml of CMV DNA respectively. (Figure 1) The attack rate for CMV disease in patients who developed CMV infection was 7.9% (3/38) and all of them was belong to high CMV viral load (> 5000 copies/ml for CMV DNA) group. Antigenemia-guided pre-emptive
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strategy with GCV was used for all patients. In most case (35/38; 92.1%), the level of antigenemia declined within 2 weeks as a result of the continuation of GCV therapy, but only
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three out of 38 patients were subsequently developed CMV disease.
There was no difference in engraftment failure in patients who had CMV reactivation and no
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CMV reactivation 18.5% vs 16% [p=0.75; OR 1.2 (CI, 0.437-3.157)] was observed, however patients who had CMV reactivation had significantly higher rate of GVHD as compared to patients without CMV reactivation (12/38 = 31.6%) vs 14/93= 15.1%) [p=0.031; OR 2.6 (CI, 1.07-6.34)]. Other outcome variables including relapse rate (8/38=21% vs 24/93=25.8%) [(OR: 0.8; 95% CI: (0.31-1.91)] and mortality rate 9/40=22.5% vs 31/93=33.3% [(OR: 0.7; 95% CI: 0.29-1.63)] in patients with CMV reactivation versus no CMV reactivation respectively, however result was not statistically significant. (Figure 2)
Overall survival time was 35.5 (+/-2.8) months with mean duration of follow up 68.5 (+/- 4.4) months and EFS is 31.6 (+/- 2.6) months with mean duration of follow up 72 (+/- 4.4) months. Overall survival was 33.5 +/- 5.5 months and 36.3 +/- 3.3 and event free survival was 31.2 +/5.2 and 31.9 +/- 3.1 months for patients with and without CMV anigenemia, respectively. 10 Page 10 of 25
DISCUSSION The incidence of CMV reactivation in our study population was 29% overall and in allogeneic transplantation it was 34.8%. Nichols et al reported a high incidence of rising antigenemia while patients were receiving pre-emptive therapy, which was caused by the immunosuppressed status
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of the host, not by resistance to antiviral agents. (7) The incidence reported by them (39%) was slightly higher than our observation but substantially higher than the 13% of cases with rising
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antigenemia observed among the patients in another study. (8) However the incidence of CMV disease in our patients was 2.3%, which was substantially lower than the reports recently
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published by M Yanada et al (7.5%) and other results of pre-emptive therapy for other groups. (7-11)
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CMV reactivation or disease have typically been reported within the first 100 days after transplant, both in allogeneic and autologous BMT recipients (12-15), similar to our study
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population as nearly all cases (37/38) we observed CMV reactivation within first 100 days after transplant, except one case where CMV activation was observed at +111 days after
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transplantation. However, recent observations showed that CMV prophylaxis or pre-emptive therapy has changed the natural history of the disease and has prolonged the period of risk, likely
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by inhibiting the development of CMV-specific T-cell lymphocyte response.
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Pneumonia and gastrointestinal involvement are the most frequently described clinical pictures caused by CMV after BMT. Other documented conditions include hepatitis, retinitis, encephalitis, hemorrhagic cystitis, unexplained fever, endothelial damage, and thrombotic microangiopathy. (16-17) Frequency of CMV disease (2.3%), CMV pneumonia (0.8%), Colitis (0.8%) and hepatitis (0.8%) was less in our study. All three cases that developed CMV disease in our study were successfully treatment with standard therapy and resolved their CMV without fetal out. Another study reported the frequency of CMV pneumonia (1.7%) and gastroenteritis (5%), but they observed that CMV pneumonia was associated with a higher mortality rate in contrast, to CMV gastroenteritis. Our patient with CMV colitis did not demonstrate positive antigenemia prior to disease onset and same observation was reported by another study (7), suggesting that CMV surveillance using the antigenemia assay might be of limited value in cases of gastroenteritis. 11 Page 11 of 25
The frequency of development of CMV disease in our study was significantly higher in group of patients with high titer of CMV reactivations (n=9/38, 23.7%; CMV load, > 5000 copies/mL) compared to another group with low titer of CMV reactivation (n=29/38, 76.3%; CMV load, < 5000 copies/mL) as all patients who developed CMV diseases belonged to high reactivation
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group thus these patients should be monitored closely and carefully.
Several risk factors have been identified for CMV reactivation and disease after HSCT, including
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pre transplant serostatus, GVHD, transplant from an unrelated or HLA mismatched donor, the use of TBI or ATG in the conditioning regimen, T-cell-depleted transplant, and advanced
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age.(18-25) In particular, GVHD and donor type are considered to be strong indicators, as well as pretransplant serostatus. Our study demonstrated that benign hematologic disease as a group,
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conditioning regimen containing ATG, allogeneic, GVHD prophylaxis used, and development of GVHD, lymphopenia < 300/mm3 and bone marrow as a source of stem cell had a significant
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influence on CMV antigenemia and disease, but that age and gender did not.
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The development of graft-versus-host disease (GVHD) after transplant is another important risk factor for CMV reactivation or disease. In a time-dependent multivariate analysis, acute (19) and
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chronic (26-27) GVHD significantly increased the risk of CMV infection and patients with CMV infection show an increased risk of acute and chronic GVHD (28). Notably, 31.6 % (12/38)
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patients developed rising antigenemia in our study had acute GVHD and 12/26 (46.2%) patient with acute GVHD had history of CMV reactivation suggesting significant associations between two and that the immunological status of the host may be of importance. It has been shown (27) that the cumulative probability of first positivization or recurrence of antigenemia increased during the first year after allogeneic BMT from 45.4% on day 100 to 64.8% on day 180, and to 71.2% on day 365, especially in the presence of chronic GVHD. Presence of GVHD and administration of pre-emptive therapy have also been demonstrated to be major risk factors for late CMV reactivation (29), but administration of antiviral prophylaxis during the first 3 months after transplantation also has a significant impact on frequency, timing, and outcome of CMV infection that occur later than in patients receiving pre-emptive therapy. (30)
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Despite recent advances in the development of antiviral agents and diagnostic techniques, CMV disease remains a common cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. (31) The available management strategies can be divided into prevention of a primary infection or recurrence of CMV (prophylaxis) or prevention of development of disease
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when a reactivation has occurred (preemptive therapy). (32)
Antigenemia-guided pre-emptive strategy with GCV was used for all patients in our study. Most
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of patients were successfully treated with standard dose of ganciclovir and the level of antigenemia declined within 2 weeks as a result of the continuation of GCV therapy, except 3
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patients required foscarnet (two patient because of gancyclovir induced neutropenia and one patient who did not respond to gancyclovir). Only three out of 38 patients subsequently
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developed CMV disease. Such cases should therefore be treated with caution even after antigenemia has improved.
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High-dose acyclovir prophylaxis administered in seropositive patients or in negative subjects receiving graft from a positive donor, from 5 days before engraftment to 100 days after
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transplant, reduces the risk of CMV infection and invasive disease, as well as mortality (33),
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with very low toxicity. Ganciclovir has also been used as CMV prophylaxis but no survival advantage was demonstrated and severe neutropenia was observed in all studies and was
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potentially linked to greater risks of fungal or bacterial infections, perhaps because of ganciclovir-induced neutropenia. (34-35)
Pre-emptive therapy in BMT refers to identification of at risk recipients by using timely CMV detection with polymerase chain reaction techniques or pp65 antigenemia, followed by immediate implementation of antiviral treatment on viral detection. Both ganciclovir and foscarnet are used as pre-emptive therapy, with similar efficacy, but different toxicity profiles: mainly neutropenia with ganciclovir and impaired renal function and electrolyte abnormalities with foscarnet. (36) Two major problems have emerged as a result of early intervention with GCV: late CMV disease and secondary infection with bacteria and fungus. Excessive suppression of CMV replication delays recovery of CMV-specific T-cell immunity, (37) so that viral reactivation occasionally occurs after discontinuation of antiviral therapy. (38-40)
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Additionally, GCV use is associated with bone marrow toxicity, (41) and neutropenia may increase the risk for bacterial and fungal infection.
Although randomized clinical trials have not yet been performed, some studies have shown the efficacy of cidofovir as second-line therapy in patients with CMV disease whose traditional
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antiviral treatments have failed or in low-risk patients after low-intensity conditioning regimens (42). Few data about efficacy or toxicity of these drugs are available in children, with a clear
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need of tailored studies to identify the correct dose and schedule of administration, and the
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toxicity profile of these drugs in children, without continuing to make inferences from adults.
More recent developments in preparative regimens and manipulations of the grafts led to
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important changes in the epidemiology of CMV infection after transplantation. Developments of new methods that allow for the reconstitution of CMV-specific immune responses such as adoptive T-cell therapy might help prevent late CMV disease and thus help to further improve
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transplant outcomes on a long-term basis. (43)
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CONCLUSION
In conclusion, advances in the control of CMV infection after HSCT have had a great impact on the improvement in transplant outcomes. Our study showed the effectiveness of antigenemiaguided pre-emptive strategy with ganciclovir and that the prognosis for those who developed
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antigenemia was not significantly poorer than was the prognosis for those who did not, while development of CMV disease tended not to affect the outcome. However higher titer of
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reactivation is associated with development of CMV disease and there is significant association between development of CMV antigenemia and disease and acute GVHD, indicating an urgent
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need for the establishment of an optimum pre-emptive strategy based on the severity of acute
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GVHD.
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CONFLICTS OF INTEREST The authors of this study have no relevant conflicts of interest to disclose.
Acknowledgments
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& Research Center, Jeddah for their contributions, and all the patients.
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The authors thanks all the pediatric HSC transplantation team of King Faisal Specialist Hospital
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REFERENCES: 1. ElioCastagnola, Barbara Cappelli, Daniela Erba. Cytomegalovirus Infection AfterBoneMarrow Transplantation in Children. Human Immunology 65, 416-422 (2004).
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2. Ljungman P, Griffiths P, Paya C: Definitions of CMV infection and disease in transplant recipients. Clin Infect Dis 34:1094, 2002. 3. Drew WL. Laboratory diagnosis of cytomegalovirus infection and disease in immunocompromised patients. CurrOpin Infect Dis. 2007;20:408-411.
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5. Hebart H, Einsele H, at al. Clinical Aspects of CMV Infection after Stem Cell Transplantation. Human Immunology 65, 432-436 (2004)
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6. Fries BC, Riddell SR, Kim HW, et al. Cytomegalovirus disease before hematopoietic cell transplantation as a risk for complications after transplantation. Biol Blood Marrow Transplant. 2005;11:136-148.
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7. Nichols WG, Corey L, Gooley T et al. Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes. Blood 2001; 97: 867–874.
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8. Cytomegalovirus antigenemia and outcome of patients treated with preemptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation 9. Boeckh M, Gooley TA, Myerson D et al. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996; 88: 4063–4071. 10. Ljungman P, Lore K, Aschan J et al. Use of a semiquantitative PCR for cytomegalovirus DNA as a basis for pre-emptive antiviral therapy in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1996; 17: 583–587. 11. Einsele H, Hebart H, Kauffmann-Schneider C et al. Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant 2000; 25: 757–763. 12. Boeckh MJ, Ljungman P. Cytomegalovirus infection after hemopoietic stem cell transplantation. In Bowden RA, Ljungman P, Paya VP (eds): Transplant Infections. Lippincott-Williams & Wilkins, Philadelphia, 2002.
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14. Craddock C, Szydlo RM, Dazzi F, Olavarria E, Cwynarski K, Yong A, Brookes P, de la Fuente J, Kanfer E, Apperley JF, Goldman JM: Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis. Br J Haematol 112:228, 2001.
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16. Ljungman P, Griffiths P, Paya C: Definitions of CMV infection and disease in transplant recipients. Clin Infect Dis 34:1094, 2002.
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17. Takatsuka H, Wakae T, Mori A, Okada M, Fujimori Y, Takemoto Y, Okamoto T, Kanamaru A, Kakishita E: Endothelial damage caused by cytomegalovirus and human herpesvirus-6. Bone Marrow Transplant 31:475, 2003.
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18. Per Ljungman. Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients. Hematol Oncol Clin North Am. 2011 February; 25(1): 151–169. doi:10.1016/j.hoc.2010.11.011.
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19. Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986; 153: 478–488.
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20. Enright H, Haake R, Weisdorf D et al. Cytomegalovirus pneumonia after bone marrow transplantation. Risk factors and response to therapy. Transplantation 1993; 55: 1339– 1346. 21. Forman SJ, Zaia JA. Treatment and prevention of cytomegalovirus pneumonia after bone marrow transplantation: where do we stand? Blood 1994; 83: 2392–2398. 22. Bacigalupo A, Tedone E, Isaza A et al. CMV-antigenemia after allogeneic bone marrow transplantation: correlation of CMV-antigen positive cell numbers with transplant-related mortality. Bone Marrow Transplant 1995; 16: 155–161. 23. Takenaka K, Gondo H, Tanimoto K et al. Increased incidence of cytomegalovirus (CMV) infection and CMV-associated disease after allogeneic bone marrow transplantation from unrelated donors. The Fukuoka Bone Marrow Transplantation Group. Bone Marrow Transplant 1997; 19: 241–248. 24. Ljungman P, Aschan J, Lewensohn-Fuchs I et al. Results of different strategies for reducing cytomegalovirus-associated mortality in allogeneic stem cell transplant recipients. Transplantation 1998; 66: 1330–1334. 18 Page 18 of 25
25. Osarogiagbon RU, Defor TE, Weisdorf MA et al. CMV antigenemia following bone marrow transplantation: risk factors and outcomes. Biol Blood Marrow Transplant 2000; 6: 280–288.
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26. Osarogiagbon RU, Defor TE, Weisdorf MA, Erice A, Weisdorf DJ: CMV antigenemia following bone marrow transplantation: risk factors and outcomes. Biol Blood Marrow Transplant 6:280, 2000.
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27. Machado CM, Menezes RX, Macedo MCA, Mendes AVA, Villas Boas LS, Castelli JB, Dulley FL, Pannuti CS: Extended antigenemia surveillance and late cytomegalovirus infection after allogeneic BMT. Bone Marrow Transplant 28:1053, 2001.
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28. Matthes-Martin S, Aberle SW, Peters C, Holter W, Popow-Kraupp T, Potschger U, Fritsch G, Ladenstein R, Rosenmayer A, Dieckmann K, Gadner H: CMV-viraemia during allogenic bone marrow transplantation in paediatric patients: association with survival and graft-versushost disease. Bone Marrow Transplant 21(Suppl 2):S53, 1998.
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29. Einsele H, Hebart H, Kauffmann-Schneider C, Sinzger C, Jahn G, Bader P, Klingebiel T, Dietz K, Loffler J, Bokemeyer C, Muller CA, Kanz L: Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant 25:757, 2002.
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30. Nguyen Q, Champlin R, Giralt S, Rolston K, Raad I, Jacobson K, Ippoliti C, Hecht D, Tarrand J, Luna M, Whimbey E: Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients. Clin Infect Dis 28:618, 1999.
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31. M Yanada1, K Yamamoto. Cytomegalovirus antigenemia and outcome of patients treated with preemptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplantation (2003) 32, 801–807 32. P LjungmanBone .CMV infections after hematopoietic stem cell transplantation.Bone Marrow Transplantation (2008) 42, S70–S72; doi:10.1038/bmt.2008.120 33. Prentice HG, Gluckman E, Powles RL, Ljungman P, Milpied NJ, Camara R, Mandelli F, Kho P, Kennedy L, Bell AR: Long-term survival in allogeneic bone marrow transplant recipients following acyclovir prophylaxis for CMV infection. The European Acyclovir for CMV Prophylaxis Study Group. Bone Marrow Transplant 19:129,1997. 34. Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA: Cytomegalovirus pp65 antigenemia- guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized doubleblind study. Blood 88:4063,1996. 35. Salzberger B, Bowden RA, Hackman RC, Davis C, Boeckh M: Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood 90: 2502, 1997. 19 Page 19 of 25
36. Reusser P, Einsele H, Lee J, Volin L, Rovira M, Engelhard D, Finke J, Cordonnier C, Link H, Ljungman P: Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Blood 99:1159, 2002.
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37. Li CR, Greenberg PD, Gilbert MJ et al. Recovery of HLArestricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994; 83: 1971–1979.
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38. Boeckh M, Gooley TA, Myerson D et al. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996; 88: 4063–4071. 39. Nguyen Q, Champlin R, Giralt S et al. Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients. Clin Infect Dis 1999; 28: 618–623.
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40. Machado CM, Menezes RX, Macedo MC et al. Extended antigenemia surveillance and late cytomegalovirus infection after allogeneic BMT. Bone Marrow Transplant 2001; 28: 1053–1059.
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41. Salzberger B, Bowden RA, Hackman RC et al. Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood 1997; 90: 2502–2508.
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42. Ljungman P, Deliliers GL, Platzbecker U, Matthes-Martin S, Bacigalupo A, Einsele H, at el. Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients. The Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood 97:388, 2001. 43. Clinical Aspects of CMV Infection After Stem Cell Transplantation, Holger Hebart and Hermann Einsele, Human Immunology 65, 432_436 (2004)
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Figure
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Figure 1. Relation of CMV titer in copies/ml for CMV DNA (y-axis) with duration of antigenemia in days (x-axis)
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Table
No. of patients
Age, mean (years)
ATG used Yes Yes Yes Yes Yes
6.5 ± 4 years 64.9% 35.1% 38.2% 38.2% 22.8% 70.2% 29.8% 29% 2.3% 21.4% 19.8% 6.9% 83.2% 24.4% 30.5%
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85 46 51 50 30 92 39 38 3 28 26 9 109 32 40
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CMV antigenemia CMV Disease Conditioning Regimen Acute GVHD Chronic GVHD Engraftment Relapse Mortality
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Type of SCT
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Diagnosis
Male Female Benign Hematology Malignant Hematology Solid Tumors Allogeneic Autologous
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Sex
Percentages (%)
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Characteristic
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Table 1. Summary of patient’s demographics
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Abbreviations: GVHD: Graft Versus Host Disease, SCT: Stem Cell Transplant, CMV: Cytomegalovirus
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Diagnosis
30 51
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131
SCT recipients with reactivation of CMV infection No. (%)of patients 38
SCT recipients with no reactivation of CMV infection No. (%)of patients 93
4 (13.3%)
26 (86.7%)
20 (39.2%)
31 (60.8%)
0.014
4.2 (1.1416.69)
36 (72%)
0.128
2.5 (0.75-8.56)
33 (84.6%) 60 (65.2%)
0.025
2.7 (1.03-4.96)
0.824
1.2 (0.48-2.67)
0.836
1.1 (0.46-2.68)
0.488
1.3 (0.59-3.15)
0.886
1.1 (0.42-2.86)
0.049
2.5 (0.99-6.04)
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RISK FACTORS (All Patients)
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CHARACTERISTIC
Total no of patients
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Table 2. Characteristics of Stem Cell Transplant (SCT) Recipients
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Malignant 50 14 (28%) Hematology Autologous†† 39 6 (15.4%) Type of SCT Allogeneic 92 32 (34.8%) RISK FACTORS FOR ALLOGENEIC TRANSPLANTATION Allo-BMT patients 92 32 < 5 yr †† 47 17 (53.1%) Age >5 yr 45 15 (46.9%) Male †† 56 20 (62.5%) Sex Female 36 12 (37.5%) Benign Hematology 51 20 (62.5%) Diagnosis Malignant 41 12 (37.5%) Hematology†† 28 10 (31.2%) Conditioning ATG used Regimen ATG Not Used†† 64 22 (68.8%) 48 12 (37.5%) Lymphopenia Present < 300/mm3 Absent†† 44 20 (62.5%)
60 30 (50%) 30 (50%) 36 (60%) 24 (40%) 31 (51.7%) 29 (43.7%) 18 (30%) 42 (70%) 36 (60%) 24 (40%)
Univariate Analysis
OR (Confidence Interval) †
P values
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12 (31.5%) 26 (68.5%) 8 (21.1%) 30 (78.9%) 9 (23.7%) 29 (76.3%)
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26 105 32 99 40 91
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OUTCOMES (All Patients) Yes GVHD No Yes Relapse No Yes Mortality No
14 (15.1%) 79 (84.9%) 24 (25.8%) 69 (74.2%) 31(33.3%) 62 (66.7%)
0.031
2.6 (1.07-6.34)
0.33
0.8 (0.31-1.91)
0.27
0.7 (0.29-1.63)
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Abbreviations: OR: Odd Ratio, CI: 95% Confidence Interval, SCT: Stem Cell Transplant, CMV: Cytomegalovirus, GVHD: Graft Versus Host Disease †The odds ratio reflects the risk of risk factor of CMV reactivation and adverse outcome in patients with CMV reactivation as compared to patients without CMV reactivation for each variable. ††This is the reference group for the categorical predictor variable. Note: For each variable of outcomes (GVHD, Relapse and Mortality), not having the specific risk was used as the reference group.
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S2212-8328(16)30004-2 http://dx.doi.org/doi:10.1016/j.pid.2016.03.004 PID 165
To appear in: Received date: Revised date: Accepted date:
16-11-2015 29-12-2015 17-3-2016
Please cite this article as: Muhammad Matloob AlamMohamed BayoumyAreej AliMuayad AlaliBayanah Al-eneziIbraheem Abosoudah Cytomegalovirus Infection in Children after Bone Marrow Transplantation: Risk factors, Clinical aspects and Outcomes (2016), http://dx.doi.org/10.1016/j.pid.2016.03.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Original Article Cytomegalovirus Infection in Children after Bone Marrow
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Transplantation: Risk factors, Clinical aspects and Outcomes
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______________________________________________________________________________
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Muhammad Matloob Alam*, Mohamed Bayoumy, Areej Ali, Muayad Alali,
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Bayanah Al-enezi, Ibraheem Abosoudah
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Section of Pediatric Hematology / Oncology and Blood and Marrow Transplant, Department of Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
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Corresponding Author Dr. Muhammad Matloob Alam Section of Pediatric Hematology & Oncology Department of Oncology King Faisal Specialist Hospital and Research Centre P.O. Box 40047, Jeddah 21499, Saudi Arabia Phone +966 2 667 7777 x 64010 Fax +966 2 667 7777 x 64030 Email: [email protected]
Abstract words count: 250 Manuscript words count: 2992 Number of tables: 2 Number of figures: 3 Conflict of interest: None Short running title: CMV reactivation in Children after BMT
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Co- authors
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Bayanah AL-enezi, RN, BSN, MBA Bone marrow transplant coordinator, Pediatric oncology King Faisal Specialist Hospital and Research Centre [email protected]
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Mohamed Bayoumy, M.D. Chairman, Oncology Department Director, Combined Bone Marrow Transplantation Program Consultant Pediatric Hematology/Oncology/Bone Marrow Transplantation Director, Hospital Morbidly & Mortality Unit King Faisal Specialist Hospital and Research Centre [email protected]
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Muayad Alali, M.D.
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Areej Ali,RN,BSN,PGD Bone marrow transplant coordinator, Pediatric Oncology King Faisal Specialist Hospital and Research Centre [email protected]
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Section of Pediatric Hematology & Oncology Department of Oncology King Faisal Specialist Hospital and Research Centre
Dr. Ibraheem Abosoudah, MD Consultant Pediatric Hematology / Oncology and Blood and Marrow Transplant Head Section Pediatric Hematology / Oncology and Blood and Marrow Transplant King Faisal Specialist Hospital and Research Centre [email protected]
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Original Article Cytomegalovirus Infection in Children after Bone Marrow
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Transplantation: Risk factors, Clinical aspects and Outcomes
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______________________________________________________________________________
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ABSTRACTS Background and Objectives Cytomegalovirus infection remains the most common and potentially severe viral complication in patients given HSCT. The aim of this study was to determine the incidence, risk factors and
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outcomes of CMV infection in pediatric BMT unit.
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Material and Methods
This study was a retrospective analysis of clinical, laboratory and outcome data of 131 pediatric
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patients who underwent BMT.
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Results
The mean age of the study population was 6.5 ± 4 years. Out of males were 85 (64.9%). Majority
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of patients had hematological disorder/malignancy (n=101; 77%) followed by solid tumors (n=30; 23%). Most of them received allogeneic transplant (n=92; 70.2%). CMV reactivation was observed in 38 (29%) patients, out of them only (n=3; 2.3%) had clinical manifestation/organ
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involvement and most cases of CMV were resolved (n=35; 26.7%). Benign hematological
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disorder, conditioning regimen containing ATG, allogeneic BMT, GVHD prophylaxis used and development of GVHD were identifiable risk factors in all patients and lymphopenia < 300/mm3
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(p=0.047) was the only identifiable risk factors in allogeneic BMT patients associated with development CMV reactivation. Patients who had CMV reactivation had significantly higher rate of GVHD (31.6% vs 15.1%; p=0.031), however relapse rate (21% vs 25.8%) and mortality rate (22.5% vs 33.3%) in patients with CMV reactivation versus no CMV reactivation respectively, were not statistically significant. Overall survival and event free survival of patients with and without CMV antigenemia were also comparable.
Conclusions
Antigenemia-guided pre-emptive strategy with ganciclovir was very affective and CMV reactivation tended not to affect the outcome in our study cohort.
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Key
Wards:
Cytomegalovirus
reactivation/antigenemia,
Hematopoietic
Stem
cell
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Transplantation, Risk factors, GVHD, Relapse, Survival, Mortality
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INTRODUCTION Cytomegalovirus (CMV) infection remains the most common and potentially severe viral complication in patients undergoing hematopoietic stem cell transplantation (HSCT).[1] Seropositivity for CMV is an independent risk factor for mortality, even in recipients of matched
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sibling or unrelated donor transplants.
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The manifestations of CMV range from asymptomatic infection, defined as active CMV replication in the blood in the absence of clinical manifestations or organ failure abnormalities,
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to CMV disease, characterized by CMV infection with clinical symptoms or organ function abnormalities.[2] Diagnostic procedures to assess the viral load have improved greatly with the increased use of antigenemia, CMV DNA, and immediate early-messenger RNA.[3] Many
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conditions determine the risk of developing CMV reactivation or disease after bone marrow transplant with serologic status of donor and recipient, type of bone marrow transplant, presence
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of graft-versus-host disease being the most studied.[4] However, time and quality of immune reconstitution seem to be the pivotal factors. Pneumonia and gastrointestinal involvement are the
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representing a new challenge.[5]
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most frequently documented clinical pictures with late-onset CMV reactivation or disease
CMV prophylaxis or pre-emptive therapy adopted during the last few years in allogeneic HSCT
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recipients has changed the natural history of the disease, reducing the risk of CMV disease, CMV associated death, transplant-related mortality, and has prolonged the period at risk.[6]
Specific studies on children regarding post BMT CMV infection are lacking, and majority of data are derived from studies performed on adults.[1]Thus, in this single-center, retrospective study, we analyzed the medical records of 131 pediatric patients who underwent BMT to determine the incidence of CMV infection/reactivation and disease and to identify the important risk factors, clinical aspects and outcomes of CMV infection/reactivation in post BMT pediatric patients at our tertiary health care facility.
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MATERIAL AND METHODS Study Design and Setting This study was a retrospective analysis of clinical and laboratory data of post BMT pediatric patients. We included all pediatric patients consecutively underwent Bone Marrow
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Transplantation in our pediatric BMT unit over a period of 10 years from 2005 to 2014. Our hospital is a tertiary health care facility and is accredited by the international arm of the Joint
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Commission International Accreditation Survey (JCIA). There is a 20-bed, pediatric hematology/oncology ward along with a 5-bed BMT unit within the hematology/oncology ward.
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Total of 131 pediatric patients underwent BMT in the last 10 years duration and average BMT was 13 per year.
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Patient population and definition
Patients from one month to 15 years of age, who were admitted to the pediatric BMT unit for
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transplantation from 2005 to 2014, were included in this study. Post BMT patients with CMV reactivation was identified and compared with the rest of post BMT patients to identify the risk factors, any difference in clinical manifestations and their outcomes. For definition of CMV
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reactivation and viremia or infection, investigations and management in this study American
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Society for Blood and Marrow Transplantation (2009) Guidelines for Preventing Infectious
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Complications among Hematopoietic Cell Transplantation Recipients were accepted.[4]
CMV Infection prophylaxis:
Preemptive Therapy (< 100 days post-HCT): Administer to all HCT recipients (all ages) with evidence of CMV infection in blood by antigenemia, PCR more than 500 copies/ml for CMV DNA or detection of CMV mRNA. Ganciclovir, 5mg/kg/dose, intravenously (i.v.) Induction: Twice daily for 7-14 days tell CMV PCR titer is less than 500 copies/ml for two consecutive readings then start maintenance with Valgancyclovir Once daily dose (mg) = 7 x body surface area x creatinine clearance for another 7 to 14 days . Note: Continue screening for CMV reactivation weekly and re-treat if screening tests become positive after discontinuation of therapy 7 Page 7 of 25
Data collection All patients who had diagnosis codes for both neoplastic disease (International Classification of Diseases, 9th revision, clinical modification [ICD-9-CM] code 140-239), nonmalignant disease and bone marrow transplantation, and 15 years or younger was identified by using health information management system and internal BMT registry which records all the MBT patients
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were included in this analysis. For those patients who had more than one BMT, each BMT was
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counted and analyzed as separate case.
The primary outcome of this analysis were to identify the risk factors for CMV
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reactivation/infection and outcomes (GVHD, survival rate and mortality). Relevant covariates data were collected including demographic features, age, gender, primary diagnosis, phase of chemotherapy (if applicable), clinical features at presentation, duration of symptoms, initial
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laboratory work up including CMV status and radiological finding (if applicable) and microbiological data, management and outcomes. Underlying disease (acute Leukemia, chronic
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leukemia, solid tumors and nonmalignant diseases), type of donors, transplant type, conditioning regimen etc. Pre-transplant CMV status of all recipients and donors along with post BMT assessment, investigations and prophylaxis and management of CMV were also be recorded. All
(2009)
Guidelines
for
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Transplantation
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patients were treated as inpatients following the American Society for Blood and Marrow Preventing
Infectious
Complications
among
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Hematopoietic Cell Transplantation.[4] Statistical analysis
For analysis, SPSS version 20.0 (IBM, Chicago, USA) was used. Summary statistics was used to describe the cohort. The frequency of CMV antigenemia was measured during the posttransplantation period of 100 days. Frequencies were computed for qualitative variables and mean and standard deviation were used for quantitative variables. Independent risk factors associated with development of CMV reactivation/infection were identified by comparing patients with CMV reactivation/infection and patients without CMV reactivation/infection (patients at risk group). A p-value of 0.05 was considered significant at the univariate level.
Ethical approval/ Considerations The study was started after getting approval from the Institutional Review Board (IRB) of our hospital. 8 Page 8 of 25
RESULT
One hundred and thirty one pediatric patients admitted for BMT during this study period were included in the final analysis. The mean age of the study population at the time of transplant was 6.5 ± 4 years. Out of males were 85 (64.9%) and females were 46 (35.1%). Table 1 provides a
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summary of patient’s demographics.
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Majority of patients had hematological nonmalignant disorder (n=51, 38.2%) including betathalassemia (n=13; 9.9%), sickel cell anemia (n=8; 6.1%), aplastic anemia (n=8; 6.1%), fanconi
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anemia (n=4; 3.1%), followed by hematological malignancy (n=50; 38.2%); out of them ALL (n=11; 8.4%), AML (n=20; 15.3%), lymphoma (n=8; 6.1%) then solid tumors (n=30;22.8%)
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including neuroblastoma (n=26; 19.8%) and medulloblastoma (n=3; 2.3%).
Pre-transplatation CMV serology was positive for all recipients and donors except one donor had
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negative CMV serology. Most of the patients received allogeneic transplant (n=92; 70.2%) and remaining (n=39; 29.8%) were underwent autologous transplant. Source of donor in all
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allogeneic cases were full matched related donor. No difference in ANC engraftment was
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observed between patients with and without CMV reactivation (median 19 days vs. 20 days), however in platelets engraftment minor difference was observed (median 23 days vs. 20 days)
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but statistically not significant. Acute graft-versus-host disease (GVHD) was observed in 26 (19.8%) and chronic GVHD was observed in 9 (6.9%) cases.
CMV reactivation was observed in 38 patients (29%) cases within 100 day of post BMT. Out of them majority were asymptomatic (n=35; 26.7%) and remaining (n=3; 2.3%) had clinical manifestation/organ involvement (retinitis/pneumonia/colitis/hepatitis and skin manifestation). Most of CMV cases were resolved (n=35; 26.7%). A total 3 patients who had history of CMV reactivation were died (2 patients were CMV positive and one was negative for CMV at the time of expiry).
Transplantation-related factors that could influenced the onset of viral reactivation were also assessed (Table. 2). Primary diagnosis as a group benign hematological disorder [p= 0.014; OR 4.2 (CI, 1.14-16.69)], conditioning regimen containing ATG [P=0.037 OR 2.6 (CI, 1.04-6.62], 9 Page 9 of 25
allogeneic BMT [p=0.025; OR 2.7 (CI, 1.03-4.96) ], GVHD prophylaxis used [p<0.005; OR 5.4 (CI, 2.24-13.12)], and development of GVHD [p=0.031; OR 2.6 (CI, 1.07-6.34)] in all patients. However in allogeneic BMT patients only lymphopenia < 300/mm3 [p=0.047; OR 2.5 (CI, 0.996.28)] was identified as risk factor associated with development CMV reactivation in post BMT
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pediatric patients.
All cases we developed antigenamia within 100 days of post transplantation except one and 9
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cases had antigenemia of above 5000 copies/ml for CMV DNA. Median days at onset of antigenemia after BMT was 40 (Range: 5-111) days and median duration of antigenemia was 14
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(Range: 7-431) days. Median days at onset of antigenemia after BMT was 45.5 vs 41 days and duration of antigenemia was 14 vs 20 days for patients who had CMV viral load <5000 and >
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5000 copies/ml of CMV DNA respectively. (Figure 1) The attack rate for CMV disease in patients who developed CMV infection was 7.9% (3/38) and all of them was belong to high CMV viral load (> 5000 copies/ml for CMV DNA) group. Antigenemia-guided pre-emptive
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strategy with GCV was used for all patients. In most case (35/38; 92.1%), the level of antigenemia declined within 2 weeks as a result of the continuation of GCV therapy, but only
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three out of 38 patients were subsequently developed CMV disease.
There was no difference in engraftment failure in patients who had CMV reactivation and no
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CMV reactivation 18.5% vs 16% [p=0.75; OR 1.2 (CI, 0.437-3.157)] was observed, however patients who had CMV reactivation had significantly higher rate of GVHD as compared to patients without CMV reactivation (12/38 = 31.6%) vs 14/93= 15.1%) [p=0.031; OR 2.6 (CI, 1.07-6.34)]. Other outcome variables including relapse rate (8/38=21% vs 24/93=25.8%) [(OR: 0.8; 95% CI: (0.31-1.91)] and mortality rate 9/40=22.5% vs 31/93=33.3% [(OR: 0.7; 95% CI: 0.29-1.63)] in patients with CMV reactivation versus no CMV reactivation respectively, however result was not statistically significant. (Figure 2)
Overall survival time was 35.5 (+/-2.8) months with mean duration of follow up 68.5 (+/- 4.4) months and EFS is 31.6 (+/- 2.6) months with mean duration of follow up 72 (+/- 4.4) months. Overall survival was 33.5 +/- 5.5 months and 36.3 +/- 3.3 and event free survival was 31.2 +/5.2 and 31.9 +/- 3.1 months for patients with and without CMV anigenemia, respectively. 10 Page 10 of 25
DISCUSSION The incidence of CMV reactivation in our study population was 29% overall and in allogeneic transplantation it was 34.8%. Nichols et al reported a high incidence of rising antigenemia while patients were receiving pre-emptive therapy, which was caused by the immunosuppressed status
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of the host, not by resistance to antiviral agents. (7) The incidence reported by them (39%) was slightly higher than our observation but substantially higher than the 13% of cases with rising
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antigenemia observed among the patients in another study. (8) However the incidence of CMV disease in our patients was 2.3%, which was substantially lower than the reports recently
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published by M Yanada et al (7.5%) and other results of pre-emptive therapy for other groups. (7-11)
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CMV reactivation or disease have typically been reported within the first 100 days after transplant, both in allogeneic and autologous BMT recipients (12-15), similar to our study
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population as nearly all cases (37/38) we observed CMV reactivation within first 100 days after transplant, except one case where CMV activation was observed at +111 days after
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transplantation. However, recent observations showed that CMV prophylaxis or pre-emptive therapy has changed the natural history of the disease and has prolonged the period of risk, likely
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by inhibiting the development of CMV-specific T-cell lymphocyte response.
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Pneumonia and gastrointestinal involvement are the most frequently described clinical pictures caused by CMV after BMT. Other documented conditions include hepatitis, retinitis, encephalitis, hemorrhagic cystitis, unexplained fever, endothelial damage, and thrombotic microangiopathy. (16-17) Frequency of CMV disease (2.3%), CMV pneumonia (0.8%), Colitis (0.8%) and hepatitis (0.8%) was less in our study. All three cases that developed CMV disease in our study were successfully treatment with standard therapy and resolved their CMV without fetal out. Another study reported the frequency of CMV pneumonia (1.7%) and gastroenteritis (5%), but they observed that CMV pneumonia was associated with a higher mortality rate in contrast, to CMV gastroenteritis. Our patient with CMV colitis did not demonstrate positive antigenemia prior to disease onset and same observation was reported by another study (7), suggesting that CMV surveillance using the antigenemia assay might be of limited value in cases of gastroenteritis. 11 Page 11 of 25
The frequency of development of CMV disease in our study was significantly higher in group of patients with high titer of CMV reactivations (n=9/38, 23.7%; CMV load, > 5000 copies/mL) compared to another group with low titer of CMV reactivation (n=29/38, 76.3%; CMV load, < 5000 copies/mL) as all patients who developed CMV diseases belonged to high reactivation
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group thus these patients should be monitored closely and carefully.
Several risk factors have been identified for CMV reactivation and disease after HSCT, including
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pre transplant serostatus, GVHD, transplant from an unrelated or HLA mismatched donor, the use of TBI or ATG in the conditioning regimen, T-cell-depleted transplant, and advanced
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age.(18-25) In particular, GVHD and donor type are considered to be strong indicators, as well as pretransplant serostatus. Our study demonstrated that benign hematologic disease as a group,
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conditioning regimen containing ATG, allogeneic, GVHD prophylaxis used, and development of GVHD, lymphopenia < 300/mm3 and bone marrow as a source of stem cell had a significant
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influence on CMV antigenemia and disease, but that age and gender did not.
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The development of graft-versus-host disease (GVHD) after transplant is another important risk factor for CMV reactivation or disease. In a time-dependent multivariate analysis, acute (19) and
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chronic (26-27) GVHD significantly increased the risk of CMV infection and patients with CMV infection show an increased risk of acute and chronic GVHD (28). Notably, 31.6 % (12/38)
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patients developed rising antigenemia in our study had acute GVHD and 12/26 (46.2%) patient with acute GVHD had history of CMV reactivation suggesting significant associations between two and that the immunological status of the host may be of importance. It has been shown (27) that the cumulative probability of first positivization or recurrence of antigenemia increased during the first year after allogeneic BMT from 45.4% on day 100 to 64.8% on day 180, and to 71.2% on day 365, especially in the presence of chronic GVHD. Presence of GVHD and administration of pre-emptive therapy have also been demonstrated to be major risk factors for late CMV reactivation (29), but administration of antiviral prophylaxis during the first 3 months after transplantation also has a significant impact on frequency, timing, and outcome of CMV infection that occur later than in patients receiving pre-emptive therapy. (30)
12 Page 12 of 25
Despite recent advances in the development of antiviral agents and diagnostic techniques, CMV disease remains a common cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. (31) The available management strategies can be divided into prevention of a primary infection or recurrence of CMV (prophylaxis) or prevention of development of disease
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when a reactivation has occurred (preemptive therapy). (32)
Antigenemia-guided pre-emptive strategy with GCV was used for all patients in our study. Most
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of patients were successfully treated with standard dose of ganciclovir and the level of antigenemia declined within 2 weeks as a result of the continuation of GCV therapy, except 3
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patients required foscarnet (two patient because of gancyclovir induced neutropenia and one patient who did not respond to gancyclovir). Only three out of 38 patients subsequently
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developed CMV disease. Such cases should therefore be treated with caution even after antigenemia has improved.
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High-dose acyclovir prophylaxis administered in seropositive patients or in negative subjects receiving graft from a positive donor, from 5 days before engraftment to 100 days after
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transplant, reduces the risk of CMV infection and invasive disease, as well as mortality (33),
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with very low toxicity. Ganciclovir has also been used as CMV prophylaxis but no survival advantage was demonstrated and severe neutropenia was observed in all studies and was
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potentially linked to greater risks of fungal or bacterial infections, perhaps because of ganciclovir-induced neutropenia. (34-35)
Pre-emptive therapy in BMT refers to identification of at risk recipients by using timely CMV detection with polymerase chain reaction techniques or pp65 antigenemia, followed by immediate implementation of antiviral treatment on viral detection. Both ganciclovir and foscarnet are used as pre-emptive therapy, with similar efficacy, but different toxicity profiles: mainly neutropenia with ganciclovir and impaired renal function and electrolyte abnormalities with foscarnet. (36) Two major problems have emerged as a result of early intervention with GCV: late CMV disease and secondary infection with bacteria and fungus. Excessive suppression of CMV replication delays recovery of CMV-specific T-cell immunity, (37) so that viral reactivation occasionally occurs after discontinuation of antiviral therapy. (38-40)
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Additionally, GCV use is associated with bone marrow toxicity, (41) and neutropenia may increase the risk for bacterial and fungal infection.
Although randomized clinical trials have not yet been performed, some studies have shown the efficacy of cidofovir as second-line therapy in patients with CMV disease whose traditional
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antiviral treatments have failed or in low-risk patients after low-intensity conditioning regimens (42). Few data about efficacy or toxicity of these drugs are available in children, with a clear
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need of tailored studies to identify the correct dose and schedule of administration, and the
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toxicity profile of these drugs in children, without continuing to make inferences from adults.
More recent developments in preparative regimens and manipulations of the grafts led to
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important changes in the epidemiology of CMV infection after transplantation. Developments of new methods that allow for the reconstitution of CMV-specific immune responses such as adoptive T-cell therapy might help prevent late CMV disease and thus help to further improve
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transplant outcomes on a long-term basis. (43)
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CONCLUSION
In conclusion, advances in the control of CMV infection after HSCT have had a great impact on the improvement in transplant outcomes. Our study showed the effectiveness of antigenemiaguided pre-emptive strategy with ganciclovir and that the prognosis for those who developed
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antigenemia was not significantly poorer than was the prognosis for those who did not, while development of CMV disease tended not to affect the outcome. However higher titer of
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reactivation is associated with development of CMV disease and there is significant association between development of CMV antigenemia and disease and acute GVHD, indicating an urgent
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need for the establishment of an optimum pre-emptive strategy based on the severity of acute
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GVHD.
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CONFLICTS OF INTEREST The authors of this study have no relevant conflicts of interest to disclose.
Acknowledgments
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& Research Center, Jeddah for their contributions, and all the patients.
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The authors thanks all the pediatric HSC transplantation team of King Faisal Specialist Hospital
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2. Ljungman P, Griffiths P, Paya C: Definitions of CMV infection and disease in transplant recipients. Clin Infect Dis 34:1094, 2002. 3. Drew WL. Laboratory diagnosis of cytomegalovirus infection and disease in immunocompromised patients. CurrOpin Infect Dis. 2007;20:408-411.
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17. Takatsuka H, Wakae T, Mori A, Okada M, Fujimori Y, Takemoto Y, Okamoto T, Kanamaru A, Kakishita E: Endothelial damage caused by cytomegalovirus and human herpesvirus-6. Bone Marrow Transplant 31:475, 2003.
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19. Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986; 153: 478–488.
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20. Enright H, Haake R, Weisdorf D et al. Cytomegalovirus pneumonia after bone marrow transplantation. Risk factors and response to therapy. Transplantation 1993; 55: 1339– 1346. 21. Forman SJ, Zaia JA. Treatment and prevention of cytomegalovirus pneumonia after bone marrow transplantation: where do we stand? Blood 1994; 83: 2392–2398. 22. Bacigalupo A, Tedone E, Isaza A et al. CMV-antigenemia after allogeneic bone marrow transplantation: correlation of CMV-antigen positive cell numbers with transplant-related mortality. Bone Marrow Transplant 1995; 16: 155–161. 23. Takenaka K, Gondo H, Tanimoto K et al. Increased incidence of cytomegalovirus (CMV) infection and CMV-associated disease after allogeneic bone marrow transplantation from unrelated donors. The Fukuoka Bone Marrow Transplantation Group. Bone Marrow Transplant 1997; 19: 241–248. 24. Ljungman P, Aschan J, Lewensohn-Fuchs I et al. Results of different strategies for reducing cytomegalovirus-associated mortality in allogeneic stem cell transplant recipients. Transplantation 1998; 66: 1330–1334. 18 Page 18 of 25
25. Osarogiagbon RU, Defor TE, Weisdorf MA et al. CMV antigenemia following bone marrow transplantation: risk factors and outcomes. Biol Blood Marrow Transplant 2000; 6: 280–288.
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27. Machado CM, Menezes RX, Macedo MCA, Mendes AVA, Villas Boas LS, Castelli JB, Dulley FL, Pannuti CS: Extended antigenemia surveillance and late cytomegalovirus infection after allogeneic BMT. Bone Marrow Transplant 28:1053, 2001.
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28. Matthes-Martin S, Aberle SW, Peters C, Holter W, Popow-Kraupp T, Potschger U, Fritsch G, Ladenstein R, Rosenmayer A, Dieckmann K, Gadner H: CMV-viraemia during allogenic bone marrow transplantation in paediatric patients: association with survival and graft-versushost disease. Bone Marrow Transplant 21(Suppl 2):S53, 1998.
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29. Einsele H, Hebart H, Kauffmann-Schneider C, Sinzger C, Jahn G, Bader P, Klingebiel T, Dietz K, Loffler J, Bokemeyer C, Muller CA, Kanz L: Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant 25:757, 2002.
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36. Reusser P, Einsele H, Lee J, Volin L, Rovira M, Engelhard D, Finke J, Cordonnier C, Link H, Ljungman P: Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Blood 99:1159, 2002.
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38. Boeckh M, Gooley TA, Myerson D et al. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996; 88: 4063–4071. 39. Nguyen Q, Champlin R, Giralt S et al. Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients. Clin Infect Dis 1999; 28: 618–623.
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41. Salzberger B, Bowden RA, Hackman RC et al. Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood 1997; 90: 2502–2508.
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42. Ljungman P, Deliliers GL, Platzbecker U, Matthes-Martin S, Bacigalupo A, Einsele H, at el. Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients. The Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood 97:388, 2001. 43. Clinical Aspects of CMV Infection After Stem Cell Transplantation, Holger Hebart and Hermann Einsele, Human Immunology 65, 432_436 (2004)
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Figure
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Figure 1. Relation of CMV titer in copies/ml for CMV DNA (y-axis) with duration of antigenemia in days (x-axis)
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Table
No. of patients
Age, mean (years)
ATG used Yes Yes Yes Yes Yes
6.5 ± 4 years 64.9% 35.1% 38.2% 38.2% 22.8% 70.2% 29.8% 29% 2.3% 21.4% 19.8% 6.9% 83.2% 24.4% 30.5%
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85 46 51 50 30 92 39 38 3 28 26 9 109 32 40
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CMV antigenemia CMV Disease Conditioning Regimen Acute GVHD Chronic GVHD Engraftment Relapse Mortality
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Type of SCT
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Diagnosis
Male Female Benign Hematology Malignant Hematology Solid Tumors Allogeneic Autologous
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Sex
Percentages (%)
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Characteristic
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Table 1. Summary of patient’s demographics
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Abbreviations: GVHD: Graft Versus Host Disease, SCT: Stem Cell Transplant, CMV: Cytomegalovirus
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Diagnosis
30 51
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131
SCT recipients with reactivation of CMV infection No. (%)of patients 38
SCT recipients with no reactivation of CMV infection No. (%)of patients 93
4 (13.3%)
26 (86.7%)
20 (39.2%)
31 (60.8%)
0.014
4.2 (1.1416.69)
36 (72%)
0.128
2.5 (0.75-8.56)
33 (84.6%) 60 (65.2%)
0.025
2.7 (1.03-4.96)
0.824
1.2 (0.48-2.67)
0.836
1.1 (0.46-2.68)
0.488
1.3 (0.59-3.15)
0.886
1.1 (0.42-2.86)
0.049
2.5 (0.99-6.04)
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RISK FACTORS (All Patients)
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CHARACTERISTIC
Total no of patients
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Table 2. Characteristics of Stem Cell Transplant (SCT) Recipients
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Malignant 50 14 (28%) Hematology Autologous†† 39 6 (15.4%) Type of SCT Allogeneic 92 32 (34.8%) RISK FACTORS FOR ALLOGENEIC TRANSPLANTATION Allo-BMT patients 92 32 < 5 yr †† 47 17 (53.1%) Age >5 yr 45 15 (46.9%) Male †† 56 20 (62.5%) Sex Female 36 12 (37.5%) Benign Hematology 51 20 (62.5%) Diagnosis Malignant 41 12 (37.5%) Hematology†† 28 10 (31.2%) Conditioning ATG used Regimen ATG Not Used†† 64 22 (68.8%) 48 12 (37.5%) Lymphopenia Present < 300/mm3 Absent†† 44 20 (62.5%)
60 30 (50%) 30 (50%) 36 (60%) 24 (40%) 31 (51.7%) 29 (43.7%) 18 (30%) 42 (70%) 36 (60%) 24 (40%)
Univariate Analysis
OR (Confidence Interval) †
P values
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12 (31.5%) 26 (68.5%) 8 (21.1%) 30 (78.9%) 9 (23.7%) 29 (76.3%)
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26 105 32 99 40 91
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OUTCOMES (All Patients) Yes GVHD No Yes Relapse No Yes Mortality No
14 (15.1%) 79 (84.9%) 24 (25.8%) 69 (74.2%) 31(33.3%) 62 (66.7%)
0.031
2.6 (1.07-6.34)
0.33
0.8 (0.31-1.91)
0.27
0.7 (0.29-1.63)
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Abbreviations: OR: Odd Ratio, CI: 95% Confidence Interval, SCT: Stem Cell Transplant, CMV: Cytomegalovirus, GVHD: Graft Versus Host Disease †The odds ratio reflects the risk of risk factor of CMV reactivation and adverse outcome in patients with CMV reactivation as compared to patients without CMV reactivation for each variable. ††This is the reference group for the categorical predictor variable. Note: For each variable of outcomes (GVHD, Relapse and Mortality), not having the specific risk was used as the reference group.
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