Clinical Outcomes of Rapid Respiratory Virus Testing in Emergency Departments: A Systematic Review and Meta-Analysis.

Importance: Rapid tests for respiratory viruses, including multiplex panels, are increasingly available in emergency departments (EDs). Their association with patient outcomes remains unclear. Objective: To determine if ED rapid respiratory virus testing in patients with suspected acute respiratory infection (ARI) was associated with decreased antibiotic use, ancillary tests, ED length of stay, and ED return visits and hospitalization and increased influenza antiviral treatment. Data Sources: Ovid MEDLINE, Embase (Ovid), Scopus, and Web of Science from 1985 to November 14, 2022. Study Selection: Randomized clinical trials of patients of any age with ARI in an ED. The primary intervention was rapid viral testing. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were followed. Two independent reviewers (T.S. and K.W.) extracted data and assessed risk of bias using the Cochrane Risk of Bias, version 2.0. Estimates were pooled using random-effects models. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Main Outcomes and Measures: Antibiotic use and secondary outcomes were pooled separately as risk ratios (RRs) and risk difference estimates with 95% CIs. Results: Of 7157 studies identified, 11 (0.2%; n = 6068 patients) were included in pooled analyses. Routine rapid viral testing was not associated with antibiotic use (RR, 0.99; 95% CI, 0.93-1.05; high certainty) but was associated with higher use of influenza antivirals (RR, 1.33; 95% CI, 1.02-1.75; moderate certainty) and lower use of chest radiography (RR, 0.88; 95% CI, 0.79-0.98; moderate certainty) and blood tests (RR, 0.81; 95% CI, 0.69-0.97; moderate certainty). There was no association with urine testing (RR, 0.95; 95% CI, 0.77-1.17; low certainty), ED length of stay (0 hours; 95% CI, -0.17 to 0.16; moderate certainty), return visits (RR, 0.93; 95%, CI 0.79-1.08; moderate certainty) or hospitalization (RR, 1.01; 95% CI, 0.95-1.08; high certainty). Adults represented 963 participants (16%). There was no association of viral testing with antibiotic use in any prespecified subgroup by age, test method, publication date, number of viral targets, risk of bias, or industry funding. Conclusions and Relevance: The results of this systematic review and meta-analysis suggest that there are limited benefits of routine viral testing in EDs for patients with ARI. Further studies in adults, especially those with high-risk conditions, are warranted.

Bloodstream Infections in Children Hospitalized for Influenza, the Canadian Immunization Monitoring Program Active.

BACKGROUND: We aimed to estimate the proportion of children hospitalized for influenza whose illness was complicated by bloodstream infection, describe their clinical course, and identify the factors associated with bloodstream infection. METHODS: We performed active surveillance for laboratory-confirmed influenza hospitalizations among children ≤16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, from the 2010-2011 to 2020-2021 influenza seasons. Factors associated with bloodstream infection were identified using multivariable logistic regression analyses. RESULTS: Among 9179 laboratory-confirmed influenza hospital admissions, bloodstream infection occurred in 87 children (0.9%). Streptococcus pyogenes (22%), Staphylococcus aureus (18%) and Streptococcus pneumoniae (17%) were the most common bloodstream infection pathogens identified. Children with cancer [adjusted odds ratio (aOR): 2.78; 95% confidence interval (CI): 1.23-5.63], a laboratory-confirmed nonbloodstream bacterial infection (aOR: 14.1; 95% CI: 8.04-24.3) or radiographically-confirmed pneumonia (aOR: 1.87; 95% CI: 1.17-2.97) were more likely to experience a bloodstream infection, whereas children with chronic lung disorders were less likely (aOR: 0.41; 95% CI: 0.19-0.80). Disease severity markers such as intensive care unit admission (aOR: 2.11; 95% CI: 1.27-3.46), mechanical ventilation (aOR: 2.84; 95% CI: 1.63-4.80) and longer hospital length of stay (aOR: 1.02; 95% CI: 1.01-1.03) were associated with bloodstream infection. Bloodstream infection also increased the odds of death (aOR: 13.0; 95% CI: 4.84-29.1) after adjustment for age, influenza virus type and the presence of any at-risk chronic condition. CONCLUSIONS: Bloodstream infections, although infrequent, are associated with intensive care unit admission, mechanical ventilation, increased hospital length of stay and in-hospital mortality, thus requiring increased levels of care among pediatric influenza hospitalizations.

Antibiotic use in children hospitalised for influenza, 2010-2021: the Canadian Immunization Monitoring Program Active (IMPACT).

PURPOSE: To determine characteristics associated with inappropriate antibiotic use amongst children hospitalised for influenza. METHODS: We performed active surveillance for laboratory-confirmed influenza hospitalizations amongst children ≤ 16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, from September 2010 to August 2021. Antibiotic use was presumed appropriate if any of the following indications were met: age < 1 month, immunocompromised, hemoglobinopathy, laboratory-confirmed bacterial infection, radiographically confirmed pneumonia, admission to an intensive care unit and mechanical ventilation. Regression analyses were used to identify baseline and clinical characteristics associated with antibiotic use amongst patients without an appropriate indication. RESULTS: Amongst 8971 children, 6424 (71.6%) received any antibiotics during their hospitalisation. Amongst the 4429 children without an appropriate indication, 2366 (53.2%) received antibiotics. Antibiotic use amongst children without appropriate indication differed between study centres, ranging from 33.2% to 66.1% (interquartile range [IQR] 50.6-56.3%); it did not change significantly over time (p-value for trend = 0.28). In multivariable analyses, older age (adjusted odds ratio [aOR] 0.97, 95% confidence interval [CI] 0.96-0.99), presence of any high-risk condition (aOR 0.80, 95% CI 0.70-0.92), influenza virus type B (aOR 0.8, 95% CI 0.70-0.91) and croup (aOR 0.64, 95% CI 0.49-0.83) were associated with less, whilst fever ≥ 38.5 °C (aOR 1.82, 95% CI 1.42-2.35) and hospitalisation duration (aOR 1.12, 95% CI 1.09-1.15) were associated with more inappropriate antibiotic use. CONCLUSIONS: Over two-third of children hospitalised for influenza received antibiotics, including over half of those without an appropriate indication for antibiotic treatment. Differences amongst study centres suggest the importance of contextual determinants of antibiotic use.

Decrease in vancomycin MICs and prevalence of hGISA in MRSA and MSSA isolates from a German pediatric tertiary care center.

PURPOSE: Resistance of Staphylococcus aureus to vancomycin includes a general increase of minimal inhibitory concentrations (MIC) within the susceptible range over time (Vancomycin MIC Creep) and the presence of a subset of the bacterial population that expresses resistance (heterogeneous glycopeptide-intermediate S. aureus; hGISA). Increased MICs have been associated with adverse clinical outcomes. However, the vancomycin MIC creep is not a uniform trend suggesting the importance of regional surveys. METHODS: We performed a retrospective analysis at a German pediatric tertiary care hospital. Isolates from 2002 to 2017 were selected which were newly identified methicillin-resistant S. aureus (MRSA) or samples from invasive methicillin-susceptible S. aureus (MSSA) or MRSA infections. Vancomycin and oxacillin MICs as well as GISA/hGISA were measured using MIC test strips and resistance was evaluated over time. RESULTS: A total of 540 samples were tested, 200 from the early (2002-2009) and 340 from the later period (2010-2017). All samples were vancomycin susceptible, but the MIC was higher for the earlier samples as compared to the later ones (1.11 vs 0.99; p < 0.001). 14% of the samples were hGISA, GISA strains were not detected. Again, vancomycin resistance decreased over time with 28 vs. 6% hGISA (p < 0.001). There was no significant difference between MRSA and MSSA samples with respect to vancomycin MIC and hGISA prevalence. CONCLUSION: This study shows a decreasing trend for both MIC values and presence of hGISA strains highlighting the importance of monitoring local susceptibilities. Vancomycin remains a first-line treatment option for suspected severe infection with Gram-positive cocci and proven infection with MRSA.

Outcomes of immunocompromised children hospitalized for Influenza, 2010-2021, the Canadian Immunization Monitoring Program Active (IMPACT).

OBJECTIVES: To evaluate immunocompromising conditions and subgroups of immunocompromise as risk factors for severe outcomes among children admitted for influenza. METHODS: We performed active surveillance for laboratory-confirmed influenza hospitalizations among children ≤16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, during 2010-2021. Logistic regression analyses were used to compare outcomes between immunocompromised and non-immunocompromised children, and for different subgroups of immunocompromise. The primary outcome was intensive care unit (ICU) admission; the secondary outcomes were mechanical ventilation and death. RESULTS: Among 8982 children, 892 (9.9%) were immunocompromised; these patients were older (median, 5.6 (IQR, 3.1-10.0) vs. 2.4 (1-6) years; p < 0.001) than non-immunocompromised children, had a similar frequency of comorbidities, excluding immunocompromise and/or malignancy (38% (340/892) vs. 40% (3272/8090); p 0.2), but fewer respiratory symptoms, such as respiratory distress (20% (177/892) vs. 42% (3424/8090), p < 0.001). In multivariable analyses, immunocompromise (adjusted odds ratio (aOR), 0.19; 95% CI, 0.14-0.25) and its subcategories immunodeficiency (aOR, 0.16; 95% CI, 0.10-0.23), immunosuppression (aOR, 0.17; 95% CI, 0.12-0.23), chemotherapy (aOR, 0.07; 95% CI, 0.03-0.13), and solid organ transplantation (aOR, 0.17; 95% CI, 0.06-0.37) were associated with decreased probability of ICU admission in children admitted for influenza. Immunocompromise was also associated with a decreased probability of mechanical ventilation (aOR, 0.26; 95% CI, 0.16-0.38) or death (aOR, 0.22; 95% CI, 0.03-0.72). CONCLUSION: Immunocompromised children are overrepresented among hospitalizations for influenza, but have a decreased probability of ICU admission, mechanical ventilation, and mortality following admission. Admission bias precludes generalizability beyond the hospital setting.

Risk factors for severe PCR-positive SARS-CoV-2 infection in hospitalised children.

OBJECTIVE: To identify risk factors for severe disease in children hospitalised for SARS-CoV-2 infection. DESIGN: Multicentre retrospective cohort study. SETTING: 18 hospitals in Canada, Iran and Costa Rica from 1 February 2020 to 31 May 2021. PATIENTS: Children<18 years of age hospitalised for symptomatic PCR-positive SARS-CoV-2 infection, including PCR-positive multisystem inflammatory syndrome in children (MIS-C). MAIN OUTCOME MEASURE: Severity on the WHO COVID-19 Clinical Progression Scale was used for ordinal logistic regression analyses. RESULTS: We identified 403 hospitalisations. Median age was 3.78 years (IQR 0.53-10.77). At least one comorbidity was present in 46.4% (187/403) and multiple comorbidities in 18.6% (75/403). Eighty-one children (20.1%) met WHO criteria for PCR-positive MIS-C. Progression to WHO clinical scale score ≥6 occurred in 25.3% (102/403). In multivariable ordinal logistic regression analyses adjusted for age, chest imaging findings, laboratory-confirmed bacterial and/or viral coinfection, and MIS-C diagnosis, presence of a single (adjusted OR (aOR) 1.90, 95% CI 1.13 to 3.20) or multiple chronic comorbidities (aOR 2.12, 95% CI 1.19 to 3.79), obesity (aOR 3.42, 95% CI 1.76 to 6.66) and chromosomal disorders (aOR 4.47, 95% CI 1.25 to 16.01) were independent risk factors for severity. Age was not an independent risk factor, but different age-specific comorbidities were associated with more severe disease in age-stratified adjusted analyses: cardiac (aOR 2.90, 95% CI 1.11 to 7.56) and non-asthma pulmonary disorders (aOR 3.07, 95% CI 1.26 to 7.49) in children<12 years old and obesity (aOR 3.69, 1.45-9.40) in adolescents≥12 years old. Among infants<1 year old, neurological (aOR 10.72, 95% CI 1.01 to 113.35) and cardiac disorders (aOR 10.13, 95% CI 1.69 to 60.54) were independent predictors of severe disease. CONCLUSION: We identified risk factors for disease severity among children hospitalised for PCR-positive SARS-CoV-2 infection. Comorbidities predisposing children to more severe disease may vary by age. These findings can potentially guide vaccination programmes and treatment approaches in children.

Feasibility and Diagnostic Accuracy of Saliva-Based SARS-CoV-2 Screening in Educational Settings and Children Aged <12 Years.

Children have been disproportionately affected during the COVID-19 pandemic. We aimed to assess a saliva-based algorithm for SARS-CoV-2 testing to be used in schools and childcare institutions under pandemic conditions. A weekly SARS-CoV-2 sentinel study in primary schools, kindergartens, and childcare facilities was conducted over a 12-week-period. In a sub-study covering 7 weeks, 1895 paired oropharyngeal and saliva samples were processed for SARS-CoV-2 rRT-PCR testing in both asymptomatic children (n = 1243) and staff (n = 652). Forty-nine additional concurrent swab and saliva samples were collected from SARS-CoV-2 infected patients (patient cohort). The Salivette® system was used for saliva collection and assessed for feasibility and diagnostic performance. For children, a mean of 1.18 mL saliva could be obtained. Based on results from both cohorts, the Salivette® testing algorithm demonstrated the specificity of 100% (95% CI 99.7-100) and sensitivity of 94.9% (95% CI 81.4-99.1) with oropharyngeal swabs as reference. Agreement between sampling systems was 100% for moderate to high viral load situations (defined as Ct-values <33 from oropharyngeal swabs). Comparative analysis of Ct-values derived from saliva vs. oropharyngeal swabs demonstrated a significant difference (mean 4.23; 95% CI 2.48-6.00). In conclusion, the Salivette® system proved to be an easy-to-use, safe and feasible saliva collection method and a more pleasant alternative to oropharyngeal swabs for SARS-CoV-2 testing in children aged 3 years and above.

Weekly SARS-CoV-2 Sentinel Surveillance in Primary Schools, Kindergartens, and Nurseries, Germany, June‒November 2020.

We investigated severe acute respiratory syndrome coronavirus 2 infections in primary schools, kindergartens, and nurseries in Germany. Of 3,169 oropharyngeal swab specimens, only 2 were positive by real-time reverse transcription PCR. Asymptomatic children attending these institutions do not appear to be driving the pandemic when appropriate infection control measures are used.

Blood culture sampling rate in hospitalised children as a quality indicator for diagnostic stewardship.

PURPOSE: Recommendations regarding the optimal number of blood cultures in children are not available. The aim of this article is to describe the correlation between blood culture (BC) rates and laboratory-confirmed bloodstream infection (LCBSI) rates, on different paediatric wards of a tertiary-care centre in Germany. METHODS: We conducted a retrospective cohort study in a paediatric university hospital, from 1st January to 31st December 2018. All blood cultures collected from neonatal (NICU) and paediatric intensive-care units (PICU), haematology/oncology, and general paediatric wards were included. There were no exclusion criteria. BC taken/1000 patients-days (BC rates/BCR) and LCBSI/1000 patient-days at risk (LCBSI rates) were calculated for each unit. RESULTS: A total of 6040 patients were admitted to the hospital with 3114 of them into wards studied. Of the 3072 BCs collected, 200 (6.5%) were positive. Collection of BCs was performed in 51/77 (66.2%) of admitted patients on NICU, in 151/399 (37.8%) of PICU patients, in 163/755 (21.6%) of haematology/oncology patients, and in 281/1883 (14.9%) of children on general paediatric wards. Gram-positive bacteria were the most commonly detected organisms in blood cultures from all wards with exception of NICU. The BCR in NICU, PICU, haematology/oncology wards, and general wards were 61.6, 196.2, 358.4, and 52.3, respectively. Excluding commensal pathogens and possible contaminations, the LCBSI rates in the same units were 2.4, 5.6, 4.4, and 1.0, respectively. CONCLUSION: We found different BCR values according the ward studied, being higher in patients with high risk of bloodstream infection such as haematology/oncology patients.

Comparison of antibiotic and acyclovir usage before and after the implementation of an on-site FilmArray meningitis/encephalitis panel in an academic tertiary pediatric hospital: a retrospective observational study.

BACKGROUND: Prompt initiation of empiric therapy is common practice in case of suspected meningitis or encephalitis. However, in children the most common pathogens are viruses that usually do not require and are not covered by the applied anti-infective treatment. Novel multiplex PCR (mPCR) panels provide rapid on-site diagnostic testing for a variety of pathogens. This study compared empiric antibiotic and acyclovir usage before and after the introduction of an on-site FilmArray Meningitis/Encephalitis Panel (FA ME Panel). METHODS: We retrospectively compared data for empiric antibiotic and acyclovir usage between pediatric patients with suspected central nervous system (CNS) infection receiving mPCR testing and a matched historical control group. Patients were matched by age and suspected CNS infection. We included all patients for whom empiric antibiotics and/or acyclovir were prescribed. RESULTS: Each study group consisted of 46 patients with 29 (63.0%) infants and 17 (37.0%) older children. A viral pathogen was diagnosed in 5/46 (10.9%) patients in the control group (all enteroviruses) and in 14/46 (30.4%) patients in the mPCR group (enterovirus n = 9; human herpesvirus 6 (HHV-6) n = 5), (p = 0.038)). Length of Therapy (LoT) and Days of Therapy (DoT) for antibiotics were significantly lower for infants (4.0 vs. 3.0, p = 0.038 and 8.0 vs. 6.0, p = 0.015, respectively). Acyclovir therapy was significantly shorter for both, infants and older children (3.0 vs. 1.0 day, p < 0.001 for both age groups). CONCLUSION: The findings of our study suggest that the introduction of a FA ME Panel into clinical routine procedures is associated with a significantly reduced LoT and DoT of empiric anti-infective treatment in children with suspected meningoencephalitis. The largest effect was observed in infants.

Patterns of antimicrobial consumption in neonatal and pediatric intensive care units in Germany and Brazil.

Antibiotic consumption (AC) is a key component of antimicrobial stewardship programs to recognize local patterns of antibiotic use. Our aim was to measure AC in neonatal units, including neonatal (NICU)/paediatric (PICU) intensive care units in different countries. We conducted a multicenter, retrospective, cohort study in three NICUs, one neonatal ward, and three PICUs with a total of 84 beds. Global and individual AC in days of therapy (DOT) and DOT per 1000 patient-days were assessed. During the study period, 2567 patients were admitted, corresponding to 4961 patient-days in neonatal units and 9243 patient-days in PICUs. Multidrug-resistant Gram-negative bacteria and methicillin-resistant Staphylococcus aureus were more frequent in Brazil than in Germany. Average AC was 386.5 and 1335.5 DOT/1000PD in German and Brazilian neonatal units, respectively. Aminopenicillins plus 3rd generation cephalosporins were the most commonly prescribed antibiotics in German neonatal units, while aminopenicillins plus aminoglycosides were the class most commonly used in Brazilian NICU. Average AC was 888.1 and 1440.7 DOT/1000PD in German and Brazilian PICUs, respectively. Antipseudomonal penicillins were most commonly used in the German PICU, and glycopeptides were the most frequently prescribed in Brazilian PICUs. Carbapenems represented 2.3-14% of total DOTs in German neonatal units and 4% in the Brazilian NICU and 13.0% in the German PICU and 6-12.2% in Brazilian PICUs. We concluded that different patterns of most commonly prescribed antibiotics were observed in neonatal units and PICUs in these two countries, probably related to different local patterns of antibiotic resistance, with a higher antibiotic consumption in Brazilian study units.

CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.

BACKGROUND: Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. METHODS: To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. RESULTS: Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. CONCLUSION: Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

Epstein-Barr Virus-Associated γδ T-Cell Lymphoproliferative Disorder Associated With Hypomorphic IL2RG Mutation.

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is an EBV-associated lymphoproliferative disease characterized by repeated or sustainable infectious mononucleosis (IM)-like symptoms. EBV is usually detected in B cells in patients who have IM or Burkitt's lymphoma and even in patients with X-linked lymphoproliferative syndrome, which is confirmed to have vulnerability to EBV infection. In contrast, EBV infects T cells (CD4+ T, CD8+ T, and γδT) or NK cells mono- or oligoclonally in CAEBV patients. It is known that the CAEBV phenotypes differ depending on which cells are infected with EBV. CAEBV is postulated to be associated with a genetic immunological abnormality, although its cause remains undefined. Here we describe a case of EBV-related γδT-cell proliferation with underlying hypomorphic IL2RG mutation. The immunological phenotype consisted of γδT-cell proliferation in the peripheral blood. A presence of EBV-infected B cells and γδT cells mimicked γδT-cell-type CAEBV. Although the patient had normal expression of CD132 (common γ chain), the phosphorylation of STAT was partially defective, indicating impaired activation of the downstream signal of the JAK/STAT pathway. Although the patient was not diagnosed as having CAEBV, this observation shows that CAEBV might be associated with immunological abnormality.

Whole genome sequencing suggests transmission of Corynebacterium diphtheriae-caused cutaneous diphtheria in two siblings, Germany, 2018.

In September 2018, a child who had returned from Somalia to Germany presented with cutaneous diphtheria by toxigenic Corynebacterium diphtheriae biovar mitis. The child's sibling had superinfected insect bites harbouring also toxigenic C. diphtheriae. Next generation sequencing (NGS) revealed the same strain in both patients suggesting very recent human-to-human transmission. Epidemiological and NGS data suggest that the two cutaneous diphtheria cases constitute the first outbreak by toxigenic C. diphtheriae in Germany since the 1980s.

Epstein-Barr Virus+ Smooth Muscle Tumors as Manifestation of Primary Immunodeficiency Disorders.

Epstein-Barr virus positive (EBV+) smooth muscle tumors (SMTs) constitute a very rare oncological entity. They usually develop in the context of secondary immunodeficiency caused by human immunodeficiency virus infection or immunosuppressive treatment after solid organ transplantation. However, in a small fraction of predominantly pediatric patients, EBV+ SMTs may occur in patients with primary immunodeficiency disorders (PIDs), such as GATA2 and CARMIL2 deficiency. In secondary immunodeficiencies and when the underlying condition can not be cured, the treatment of EBV+ SMTs is based on surgery in combination with antiretroviral and reduced or altered immunosuppressive pharmacotherapy, respectively. Importantly, without definitive reconstitution of cellular immunity, long-term survival is poor. This is particularly relevant for patients with EBV+ SMTs on the basis of PIDs. Recently, allogeneic hematopoietic stem cell transplantation resulted in cure of immunodeficiency and EBV+ SMTs in a GATA2-deficient patient. We propose that in the absence of secondary immunodeficiency disorders patients presenting with EBV+ SMTs should be thoroughly evaluated for PIDs. Allogeneic hematopoietic stem cell transplantation should be taken into consideration, ideally in the setting of a prospective clinical trial.

Classical Hodgkin lymphoma-type PTLD after solid organ transplantation in children: a report on 17 patients treated according to subsequent GPOH-HD treatment schedules.

Post-transplant lymphoproliferative disease (PTLD) is a severe complication after solid organ transplantation (SOT). Classical Hodgkin lymphoma-type (HL-) PTLD is a rare subtype, and systematic data on treatment and prognosis are lacking. We report on 17 pediatric patients with classical HL-PTLD. HL-PTLD developed late at a median of 8.1 years after SOT. It was commonly EBV-positive (16/17) and expressed both CD30 (all tumors) and CD20 (8/17 tumors). Patients were treated with chemotherapy +/- involved field radiotherapy (IF-RT) according to the respective GPOH-HD protocol tailored by stage and LDH. Overall survival at 2 and 5 years was 86% with 81% of patients surviving event-free. Six patients had additional rituximab treatment; in two it was given as upfront monotherapy and in four was given concurrently with their chemotherapy. Rituximab monotherapy did not lead to long-term remission. In conclusion, treatment of HL-PTLD with classical HL chemotherapy is effective and tolerable. New treatment modalities such as CD30-targeted or EBV-specific agents may diminish toxicity.

Posttransplant lymphoproliferative disease after pediatric solid organ transplantation.

Patients after solid organ transplantation (SOT) carry a substantially increased risk to develop malignant lymphomas. This is in part due to the immunosuppression required to maintain the function of the organ graft. Depending on the transplanted organ, up to 15% of pediatric transplant recipients acquire posttransplant lymphoproliferative disease (PTLD), and eventually 20% of those succumb to the disease. Early diagnosis of PTLD is often hampered by the unspecific symptoms and the difficult differential diagnosis, which includes atypical infections as well as graft rejection. Treatment of PTLD is limited by the high vulnerability towards antineoplastic chemotherapy in transplanted children. However, new treatment strategies and especially the introduction of the monoclonal anti-CD20 antibody rituximab have dramatically improved outcomes of PTLD. This review discusses risk factors for the development of PTLD in children, summarizes current approaches to therapy, and gives an outlook on developing new treatment modalities like targeted therapy with virus-specific T cells. Finally, monitoring strategies are evaluated.

Characteristics of early and late PTLD development in pediatric solid organ transplant recipients.

BACKGROUND: Posttransplantation lymphoproliferative disorders (PTLD) present a major cause of mortality and morbidity after solid organ transplantation. The purpose of this study was to identify the factors associated with the development of early- and late-onset PTLD in pediatric solid organ transplant recipients. METHODS: We examined the medical history, laboratory parameters, and pathology of 127 children with PTLD who were registered in the German multicenter pediatric PTLD registry. Data were collected retrospectively from 1991 to 2003 and prospectively from 2004 onward. We compared early (<1 year) and late (>1 year) PTLD using survival analysis. RESULTS: The median time to PTLD was 3.00 (95% confidence interval, 2.12-3.26) years. Forty-two patients developed PTLD within the first year after transplantation (early PTLD) and 85 patients developed PTLD after 1 year (late PTLD). Early PTLD development was associated with younger age (P=0.0016), extranodal disease (P=0.019), graft organ involvement (P=0.0065), and immunosuppressive regimens including tacrolimus (P=0.001) or mycophenolate (P=0.0025). Most early PTLD patients experienced graft rejection before PTLD diagnosis (P=0.0081). Early PTLD was often of B-cell lymphoma histology (P=0.024) and tended to be Epstein-Barr virus positive (P=0.052). In contrast, Burkitt's lymphoma (P=0.0047) and Hodgkin's disease (P=0.016) were only observed in late PTLDs, which are more likely to present with nodal disease (P=0.019). Overall survival and event-free survival were not significantly different between early and late PTLD. CONCLUSION: Early and late childhood PTLD have distinct characteristics. Whereas early PTLD appears mainly as an Epstein-Barr virus-driven disease especially favored by insufficient immunosurveillance, late PTLD often resembles tumors with distinct pathogenetic alterations and nodal appearance.