Association between Antiviral Prophylaxis and Cytomegalovirus and Epstein-Barr Virus DNAemia in Pediatric Recipients of Allogeneic Hematopoietic Stem Cell Transplant.

BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections can have serious consequences during the period of aplasia and lymphopenia following hematopoietic stem cell transplantation (HSCT). Large pediatric cohort studies examining the effect of antiviral prophylaxis against these viruses are scarce. The present study aimed to analyse the potential effect of antiviral prophylaxis (acyclovir and famciclovir) on active post-transplant EBV and CMV infection in a pediatric cohort of allogeneic HSCT recipients. METHODS: We used data from the TREASuRE cohort, consisting of 156 patients who had a first allogeneic HSCT, enrolled in four pediatric centers in Canada between July 2013 and March 2017. Follow-up was performed from the time of transplant up to 100 days post-transplant. Adjusted hazard ratio (HR) with 95% confidence intervals (CI) for the association between antiviral prophylaxis with acyclovir and/or famciclovir and EBV and CMV DNAemia was estimated using multivariate Cox regression models. RESULTS: The post-transplant cumulative incidence of EBV and CMV DNAemia at 100 days of follow-up were, respectively, 34.5% (95% CI: 27.6-42.6) and 19.9% (95% CI: 14.5-27.1). For acyclovir, the adjusted hazard ratio (HR) for CMV and EBV DNAemia was 0.55 (95% CI: 0.24-1.26) and 1.41 (95% CI: 0.63-3.14), respectively. For famciclovir, the adjusted HR were 0.82 (95% CI: 0.30-2.29) and 0.79 (95% CI: 0.36-1.72) for CMV and EBV DNAemia, respectively. CONCLUSION: The antivirals famciclovir and acyclovir did not reduce the risk of post-transplant CMV and EBV DNAemia among HSCT recipients in our pediatric population.

Risk factors for post-transplant Epstein-Barr virus events in pediatric recipients of hematopoietic stem cell transplants.

BACKGROUND: Epstein-Barr virus (EBV) can cause severe disease following hematopoietic stem cell transplant (HSCT), including post-transplant lymphoproliferative disorder (PTLD). The objective was to analyze risk factors associated with post-transplant EBV outcomes among pediatric allogeneic HSCT recipients. METHODS: We used data from 156 pediatric allogeneic HSCT recipients enrolled in the Canadian multicenter TREASuRE study. Cox and Prentice-Williams-Petersen models were used to analyze risk factors for post-transplant EBV events including occurrence and recurrence of EBV DNAemia, increase in EBV viral load (EBV-VL), and preemptive use of rituximab, an effective therapy against PTLD. RESULTS: Females were at higher risk for increasing EBV-VL (adjusted hazard ratio (HR) = 2.83 [95% confidence intervals (CI): 1.33-6.03]) and rituximab use (HR = 3.08 [1.14-8.30]), but had the same EBV DNAemia occurrence (HR = 1.21 [0.74-1.99]) and recurrence risks (HR=1.05 [0.70-1.58]) compared to males. EBV DNAemia was associated with recipient pre-transplant EBV seropositivity (HR = 2.47 [1.17-5.21]) and with graft from an EBV-positive donor (HR = 3.53 [1.95-6.38]). Anti-thymocyte globulin (ATG) was strongly associated with all EBV outcomes, including the use of rituximab (HR = 5.33 [1.47-19.40]). Mycophenolate mofetil (MMF) significantly decreased the risk of all EBV events including the rituximab use (HR = 0.13 [0.03-0.63]). CONCLUSION: This study in pediatric allogeneic HSCT patients reveals a reduced risk of all EBV outcomes with the use of MMF. Risk factors for EBV events such as EBV-VL occurrence and recurrence include EBV positivity in the donor and recipient, and use of ATG, whereas risk factors for the most severe forms of EBV outcome (EBV-VL and the use of rituximab) include female sex and ATG use.

Factors Associated with Post-Transplant Active Epstein-Barr Virus Infection and Lymphoproliferative Disease in Hematopoietic Stem Cell Transplant Recipients: A Systematic Review and Meta-Analysis.

This systematic review was undertaken to identify risk factors associated with post-transplant Epstein-Barr virus (EBV) active infection and post-transplant lymphoproliferative disease (PTLD) in pediatric and adult recipients of hematopoietic stem cell transplants (HSCT). A literature search was conducted in PubMed and EMBASE to identify studies published until 30 June 2020. Descriptive information was extracted for each individual study, and data were compiled for individual risk factors, including, when possible, relative risks with 95% confidence intervals and/or p-values. Meta-analyses were planned when possible. The methodological quality and potential for bias of included studies were also evaluated. Of the 3362 titles retrieved, 77 were included (62 for EBV infection and 22 for PTLD). The overall quality of the studies was strong. Several risk factors were explored in these studies, but few statistically significant associations were identified. The use of anti-thymocyte globulin (ATG) was identified as the most important risk factor positively associated with post-transplant active EBV infection and with PTLD. The pooled relative risks obtained using the random-effect model were 5.26 (95% CI: 2.92-9.45) and 4.17 (95% CI: 2.61-6.68) for the association between ATG and post-transplant EBV infection and PTLD, respectively. Other risk factors for EBV and PTLD were found in the included studies, such as graft-versus-host disease, type of conditioning regimen or type of donor, but results are conflicting. In conclusion, the results of this systematic review indicate that ATG increases the risk of EBV infection and PTLD, but the link with all other factors is either nonexistent or much less convincing.

Transfusion-related Epstein-Barr virus (EBV) infection: A multicenter prospective cohort study among pediatric recipients of hematopoietic stem cell transplants (TREASuRE study).

BACKGROUND: Epstein-Barr virus (EBV) is carried in the blood of most adults, and transfusion-related infections have been reported. EBV is particularly deleterious in immunosuppressed transplant patients. The aim was to determine if EBV transmission occurred through leukodepleted blood product transfusion in pediatric recipients of hematopoietic stem cell transplants (HSCT). STUDY DESIGN AND METHODS: This prospective Canadian multi-center cohort study includes 156 allogeneic HSCT pediatric recipients. The association between EBV and transfusion was analyzed using Cox regressions. EBV infection, defined by a PCR+ test in the blood of seronegative recipients of an EBV-negative graft, was monitored in order to correlate the recipient EBV strain with that of the blood donors. EBV genotypes were determined by PCR amplification followed by DNA sequencing at two loci (EBNA3b and LMP1). RESULTS: No statistically significant associations were found between transfusions and EBV. One case of post-transplant EBV infection was identified among the 21 EBV-seronegative recipients receiving an EBV-negative graft. A total of 22 blood donors were retraced to determine whether the recipient's EBV strain matched that of a donor. One donor strain showed 100% sequence homology at the EBNA3b locus, but differed by one or two point mutations and by a 132-bp deletion at the LMP1 locus. The blood donor in question was alone among the 22 donors to show amplifiable virus in plasma. Blood from this donor readily produced an immortalized lymphoblastoid cell line in culture. CONCLUSION: While considered a rare event, EBV transmission through transfusion may occur in the context of severe immunosuppression.

Pediatric SJS/TEN Subdued by a Combination of Dexamethasone, Cyclosporine, and Etanercept.

We report a case of an 17-year-old male with a drug reaction in the spectrum of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), triggered by carbamazepine, who was succesfully treated with the combination of dexamethasone, cyclosporine, and etanercept. This triple therapy halted and prevented skin epidermolysis without immediate or late onset complications.

Isolated thymic Langerhans cell histiocytosis discovered on F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT).

The thymic infiltration in young patients with multisystemic Langerhans cell histiocytosis and its radiologic features are well known. However, isolated thymic disease has seldom been reported in the literature. We report the case of a 10-month-old child admitted for fever of unknown origin. Whole-body F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) was performed to identify a focus of infection. It demonstrated an unusual aspect of the thymus, which led to further investigation and revealed isolated infiltration of the thymus by Langerhans cell histiocytosis. The patient was treated accordingly and is now disease free. As evaluation of Langerhans cell histiocytosis patients with F-18 FDG PET/CT is becoming more frequent, it is important to be aware of the scintigraphical characteristics of thymic Langerhans cell histiocytosis.

Transfusion-related Epstein-Barr virus infection among stem cell transplant recipients: a retrospective cohort study in children.

BACKGROUND: Blood safety warrants strict screening measures to minimize the risk of transmitting blood-borne pathogens. However, transfusion-transmitted infections for which testing is not currently performed continue to be a concern. Among these untested agents is Epstein-Barr virus (EBV) which, in the transplant setting, is associated with lymphoproliferative disease, a potentially fatal cancer. The aim of this study was to analyze the incidence of posttransplant EBV infection and its association with administration of blood products in children receiving a hematopoietic stem cell (HSC) graft. STUDY DESIGN AND METHODS: This retrospective cohort study sought to review charts of pediatric recipients of HSC grafts to collect information on the presence of EBV antibodies in the recipients' pretransplant sera and in HSC donor sera, incidence of posttransplant EBV infection, and patients' transfusion history. Cumulative incidence of posttransplant EBV infection was estimated by Kaplan-Meier methods according to pretransplant serology. The association between blood products and EBV infection was measured by Cox regression models. RESULTS: The pretransplant EBV seroprevalence was 77.9% for recipients and 61.8% for graft donors. Virtually, all recipients received blood products during the peritransplant period. Among seronegative recipients, the 30- and 60-day cumulative incidences of posttransplant EBV infection were 4.6 (95% confidence interval [CI], 1.2-17.3) and 13.4% (95% CI, 5.8%-29.4%), respectively. The 60-day cumulative incidence was 8.3% (95% CI, 2.2%-29.4%) when restricting the analysis to seronegative recipients of cord blood grafts. Importantly, there was a clear positive trend associating EBV infection to transfusion volume. CONCLUSION: This study suggests an association between transfusions and posttransplant EBV infection in HSC transplant recipients.

Deep cutaneous fungal infections in immunocompromised children.

BACKGROUND: Life-threatening infections from ubiquitous fungi are becoming more prevalent in adults and children because of the increased use of immunosuppressive agents and broad-spectrum anti-infective drugs. Extremely low birth weight premature neonates and patients with a disrupted epidermal barrier are also at increased risk. Lethality is high, particularly with delayed diagnosis. As cutaneous lesions are often the first manifestation of such infections, early recognition of suspicious lesions is crucial to decrease associated morbidity and mortality. The clinical features of deep cutaneous fungal infection (DCFI) in immunocompromised children deserve special attention. OBJECTIVES: This study aimed to characterize our pediatric patients with DCFI, the causative fungi, and the associated risk factors. METHODS: A medical record review was conducted of pediatric patients with DCFI treated at out institution using data retrieved from the hospital's pathology and microbiology database (1980-2008). RESULTS: In all, 26 patients with DCFI were identified (9 girls and 17 boys) ranging in age from 1 day to 18 years (mean age: 8 years), the majority of whom had a hematologic disorder. All patients were immunocompromised, 90% were receiving broad-spectrum antibiotics, and 50% had severe neutropenia (absolute neutrophilic count < or = 500 x 10(6)/L). Necrotic ulcers (42%) and papules (34%) represented the most frequent lesion morphology. Fungal species were identified by culture in 20 (87%) of 23 patients tested and were observed histopathologically in 20 of 23 patients tested. Aspergillus was identified in 12 (44%) patients and Candida in 9 (33%). The other species included Fusarium (one), Exserohilum rostratum (one), Alternaria (one), Zygomycetes (two), and Blatomycetes (one). All but two patients received systemic antifungal therapy; wide surgical excision was performed in 13. Infection resolved in 20 (77%), whereas 6 (23%) died of disseminated infection. LIMITATIONS: This study was limited by the small number of cases and the retrospective nature of the collected data. DISCUSSION: DCFI should rank high in the differential diagnosis of any suspicious skin lesions in immunocompromised children. Early biopsies should be performed for histopathology and microbiological analysis, as lethality is high if appropriate treatment is delayed.

Fatal cases of Staphylococcus aureus pleural empyema in infants.

Community-associated infections and especially pleural empyema due to Staphylococcus aureus are increasing worldwide. The virulence of staphylococcal strains is notably determined by different toxin expressing-genes, such as the Panton-Valentine leukocidin (PVL) gene found in S. aureus isolates obtained from pediatric necrotizing pneumonia samples. We describe 2 similar cases of infants with severe respiratory distress and death after an upper respiratory tract infection, having occurred in the same urban area during the same winter time. Necropsies performed between November 2006 and March 2007 revealed bronchopneumonia and an important pleural empyema, justifying the review of clinical charts and laboratory exams. A methicillin-sensitive S. aureus (MSSA) isolate carrying the PVL gene was identified in both cases. We have subsequently cared for an additional case in the same time interval with sudden death and similar pathological findings. No positive microbiological results were obtained, a negative finding possibly related to a 5-day antibiotics regimen. This report describes the pathological features of these cases and stresses the need to recognize PVL-positive S. aureus infections in young children. Finally, we believe that all lethal infections due to PVL-positive S. aureus, independently of the methicillin resistance profile, deserve a mandatory report to the provincial public health authorities.

Prevention of CMV disease in pediatric kidney transplant recipients: evaluation of pp67 NASBA-based pre-emptive ganciclovir therapy combined with CMV hyperimmune globulin prophylaxis in high-risk patients.

A new prevention strategy for CMV infection was evaluated in our pediatric kidney transplant unit. This approach comprises a pre-emptive therapy, based upon the monitoring of CMV pp67 mRNA in whole blood by the qualitative NASBA, combined with prophylactic CMV-IG in high risk (R-/D+) children. Thirty-one kidney transplant children were followed for six months with serial measurements of CMV pp67 mRNA in the blood. The R-/D+ patients were given prophylactic CMV-IG for the first 16 wk after transplantation. I.v. ganciclovir was administered upon CMV detection by NASBA and was discontinued after two consecutive negative results. CMV infection, detected by NASBA, developed in 11 (35%) recipients: one (33%) of the R+/D- patients and 10 (72%) of the R-/D+ patients. CMV disease developed in 9.6% of the patients (3/31), exclusively in the R-/D+ group. These three patients presented concurrently with CMV viremia and disease. It is noteworthy that two of the three patients could not receive a complete course of CMV-IG, and one of the latter two subjects had been treated for acute rejection 15 days before CMV infection. Ganciclovir was given for the 11 cases of primary infection, and for three cases of relapsed CMV infection. pp67 NASBA-based pre-emptive ganciclovir therapy, combined with prophylactic CMV-IG in high-risk patients leads to a lower rate of CMV disease, as long as a complete course of CMV-IG has been administered and ganciclovir is given during the period of treatment for acute rejection in high-risk populations.

Systemic capillary leak syndrome presenting as recurrent shock.

OBJECTIVE: To report a case of systemic capillary leak syndrome (SCLS) in a child. DESIGN: Case report. SETTING: Pediatric intensive care unit. PATIENT: A 6-yr-old girl was admitted twice to the pediatric intensive care unit, at a 10-month interval, in severe shock with important edema. RESULTS: The patient presented with acute symptoms of abdominal pain, vomiting, and syncope in the hour preceding the shock. During both episodes necessary management included aggressive intravenous fluid rehydration, mechanical ventilation, and use of inotropes/vasopressors. Suspicion of a lower limb fasciitis necessitated surgical exploration, but pathology reports were negative on both occasions revealing only subcutaneous tissue edema. The patient recovered within 24 hrs on both episodes. Investigation ruled out cardiogenic shock and septic shock due to bacterial etiology. On the first episode, a nasopharyngeal aspirate was positive for influenza A (H3N2) by both viral immunofluorescence and culture. The presumed diagnosis was toxic shock syndrome associated with influenza virus. On the second episode, all bacterial and virology cultures remained negative. Hypovolemic shock was suspected, but there was no history of dehydration, bleeding, or gastrointestinal losses (persistent vomiting or diarrhea). Noninfectious causes of hypovolemic shock with edema were ruled out, leading us to believe that she suffered from SCLS. CONCLUSIONS: Although well described in the adult literature, there have been few reports of SCLS in pediatric patients. SCLS should be considered in the differential diagnosis of recurrent hypovolemic shock without identifiable cause. The only therapeutic intervention is to obtain vascular access when initial manifestations occur and give aggressive fluid reanimation.

Infectious risk in pediatric organ transplant recipients: is it increased with the new immunosuppressive agents?

The risk of infection in pediatric organ transplant recipients is determined by several factors, including age, the types of organ transplanted and the immunosuppressive treatment which has dramatically changed over the past 10 yr. Little information has been reported regarding the infectious complications related to the current immunosuppressive protocols used in these children. This paper reviews (i) the immunosuppressive agents, focusing on their mechanisms of action and on the new regimens, (ii) the infections related to excessive immunosuppression and also anti-infectious properties or infectious adverse reactions associated with specific immunosuppressive agents. With the new immunosuppressive protocols, the advances in immunologic monitoring, microbiological diagnosis, anti-infectious prophylactic and preemptive treatments, strategies to minimize the risk of infection related to the immunosuppressive therapy are proposed.

Is routine chest radiography necessary for the initial evaluation of fever in neutropenic children with cancer?

BACKGROUND: The yield of routine chest radiography (CXR) as part of the initial management of febrile neutropenic pediatric oncology patients is questionable. PROCEDURE: We retrospectively analyzed the clinical records of neutropenic (absolute neutrophil count < or = 0.5 x 10(9)/L) children with cancer, admitted with oral temperature > or = 38 degrees C to our institution, between January 2001 and October 2002. Following admission, patients received tobramycin plus (piperacillin or ticarcillin-clavulanic acid). Admission routine CXRs were reviewed. Clinical and radiological features were compared with the discharge diagnosis. Age, underlying disease, and the presence of pulmonary symptoms or signs were studied as possible predictors of CXR findings related to pneumonia. RESULTS: In total, 88 patients experienced 170 episodes of fever. A routine admission CXR was obtained for 157 of the episodes. Radiologists found 20 (12.7%) abnormal CXR (6 with a segmental or lobar consolidation considered as a pneumonia). In addition, two patients with abnormal admission CXR developed lobar consolidation on a repeat film, later in their hospital course. There were no differences in age and type of underlying disease between children with or without pneumonia. Respiratory symptoms were initially present in 58 cases. Seven (12%) had pneumonia. Among the 99 asymptomatic cases only one (1%) patient had a pneumonia (P = 0.0041). This child had a positive blood culture for P. aeruginosa at the time of admission. None of the children had initial therapy modified on the basis of radiologic findings. CONCLUSION: In this study, pneumonia is an unusual cause of fever (5%), especially in the absence of respiratory signs or symptoms (1%). Admission CXR should be reserved for the neutropenic pediatric oncology patient presenting with fever and abnormal respiratory findings.

Inhibition of EBV-induced lymphoproliferation by CD4(+) T cells specific for an MHC class II promiscuous epitope.

Posttransplant lymphoproliferative disorder (PTLD) and B cell lymphomas induced by EBV continue to be a major life-threatening complication in transplant patients. The establishment and enhancement of T cell immunity to EBV before transplantation and immunosuppressive therapy could help diminish these complications, but the lack of an effective vaccine has limited this prophylactic approach. We describe here the identification of a peptide epitope from the EBV EBNA2 Ag that is capable of inducing in vitro CD4(+) T cell responses that inhibit the EBV-mediated B lymphocyte proliferation associated with PTLD. Most significantly, T cell responses to the EBNA2 epitope were found to be restricted by numerous MHC class II alleles (DR1, DR7, DR16, DR52, DQ2, and DQ7), indicating that this peptide is highly promiscuous and would be recognized by a large proportion (>50%) of the general population. These results are relevant for the design of a simple, inexpensive and widely applicable peptide-based vaccine to prevent PTLD in solid organ transplant patients.

Challenges in the development of effective peptide vaccines for cancer.

The ability of the immune system to recognize malignant cells has opened the door to development of tumor vaccines to treat or prevent various types of cancer. In the era of molecular biology, the tumor antigens recognized by the immune system have been identified, allowing the generation of subunit vaccines that may improve safety and efficacy compared with more crude vaccines such as irradiated tumor cells and tumor cell lysates. Synthetic peptides corresponding to defined antigenic epitopes for tumor-reactive lymphocytes represent one of the new types of vaccines currently being developed to treat or prevent various types of malignant disorders. The design of peptide-based vaccines to stimulate antitumor T-cell responses has many attractive features such as ease of manufacturing and characterization (ie, quality control), as well as an excellent safety profile in past clinical studies. However, ambiguous results from initial clinical trials indicate that these vaccines are far from optimal and that considerable efforts for their optimization lie ahead. We attempt to address the 8 most important challenges we currently face for developing peptide-based vaccines that would effectively induce immune responses leading to antitumor effects.