Presentation, anagement, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

BACKGROUND: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.  Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. METHODS: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. RESULTS: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. CONCLUSION: In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

Current and Emerging Antiviral Agents in the Prevention and Treatment of Cytomegalovirus in Pediatric Transplant Recipients.

Despite current prophylaxis regimens, cytomegalovirus (CMV) is common in hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT) and remains a significant cause of morbidity and mortality. Newer antiviral medications are reshaping the landscape for prevention and treatment of CMV DNAemia, infection, and disease. Letermovir is approved for CMV prevention in adult HCT patients and is attractive due to the absence of marrow suppression seen with ganciclovir/valganciclovir. Letermovir should not be routinely used for CMV treatment due to its low threshold for resistance. Maribavir is approved for the treatment of refractory or resistant CMV disease in HCT and SOT recipients ≥12 years of age, though it has no current role in CMV prevention. More research is needed to fully elucidate the roles, efficacy, and safety of these newer agents in prevention and treatment of CMV in pediatric transplant recipients.

Absolute Monocyte Count as Early and Safe Marker for Antibiotic Cessation in Febrile Neutropenia Without Etiology in Pediatric Oncology Patients.

BACKGROUND: There is no practice standard regarding antibiotic duration in children with cancer and unexplained febrile neutropenia (FN). We hypothesized that absolute monocyte count (AMC) and absolute phagocyte count (APC= ANC + AMC + bands) are more sensitive, earlier, and safe markers of antibiotic cessation compared with absolute neutrophil count (ANC). METHODS: A retrospective review of FN episodes (FNEs) in pediatric oncology patients was conducted between 2009 and 2016. Included patients were afebrile for 24 hours and without an identified infectious source at antibiotic cessation. Primary endpoints, including recurrent fever, readmission, bloodstream infection, microbiologically documented infection, and adverse outcomes, were assessed 10 days after antibiotic cessation and compared among different bone marrow recovery parameters (ANC, AMC, APC). Secondary endpoints included length of FN stay, antibiotic-free days, and cost. RESULTS: Three hundred ninety-one FNEs in 235 patients were included. Three groups were compared based on ANC (cells/µL) at the time of antibiotic cessation: < 200 in 102 (26%), 200 to 500 in 111 (28%), and >500 in 178 (46%). No statistically significant differences in primary endpoints were identified among the 3 ANC groups; however, a trend toward unfavorable outcomes in the ANC ≤200 cells/µL group compared with the ANC >200 cells/µL was observed. Primary endpoints based on AMC >100 cells/µL at the time of antibiotic cessation showed statistically significant favorable outcomes compared AMC ≤100 cells/µL (80%, 88%, 90%, 89%, and 93% risk reduction in recurrent fever, readmission, new bloodstream infection, new microbiologically documented infection, and adverse events, respectively). Similar favorable results were seen when APC >300 cells/µL was used as a threshold for antibiotic cessation. The median length of stay for FN if discharged when AMC >100 cells/µL was 3 days shorter and associated with fewer unfavorable outcomes, thus resulting in fewer hospital days, fewer antibiotic days, and decreased cost. CONCLUSION: Our results suggest that AMC >100 cells/µL (regardless of ANC) or APC >300 cells/µL may be safe thresholds for empiric antibiotic cessation and result in reduced unfavorable clinical outcomes within 10 days postdischarge, reduced antibiotic days of therapy and reduced health care costs. Further prospective studies are needed to validate AMC as an accurate surrogate marker for antibiotic cessation in FNEs in children with cancer.

The impact of COVID-19 on the pediatric solid organ transplant population.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly impacted all aspects of healthcare including solid organ transplantation. In this review, we discuss the specific impact of COVID-19 on the pediatric solid organ transplant population including access to grafts for pediatric transplant candidates as well as COVID-19 disease manifestations in pediatric transplant recipients. We address the current knowledge of prevention and management of COVID-19 in pediatric transplant recipients and provide additional information regarding social distancing, infection prevention and return to school.

Early stool microbiome and metabolome signatures in pediatric patients undergoing allogeneic hematopoietic cell transplantation.

BACKGROUND: The contribution of the gastrointestinal tract microbiome to outcomes after allogeneic hematopoietic cell transplantation (HCT) is increasingly recognized. Investigations of larger pediatric cohorts aimed at defining the microbiome state and associated metabolic patterns pretransplant are needed. METHODS: We sought to describe the pretransplant stool microbiome in pediatric allogenic HCT patients at four centers. We performed shotgun metagenomic sequencing and untargeted metabolic profiling on pretransplant stool samples. Samples were compared with normal age-matched controls and by clinical characteristics. We then explored associations between stool microbiome measurements and metabolite concentrations. RESULTS: We profiled stool samples from 88 pediatric allogeneic HCT patients, a median of 4 days before transplant. Pretransplant stool samples differed from healthy controls based on indices of alpha diversity and in the proportional abundance of specific taxa and bacterial genes. Relative to stool from healthy patients, samples from HCT patients had decreased proportion of Bacteroides, Ruminococcaeae, and genes involved in butyrate production, but were enriched for gammaproteobacterial species. No systematic differences in stool microbiome or metabolomic profiles by age, transplant indication, or hospital were noted. Stool metabolites demonstrated strong correlations with microbiome composition. DISCUSSION: Stool samples from pediatric allogeneic HCT patients demonstrate substantial dysbiosis early in the transplant course. As microbiome disruptions associate with adverse transplant outcomes, pediatric-specific analyses examining longitudinal microbiome and metabolome changes are imperative to identify causal associations and to inform rational design of interventions.

Immunity to varicella, measles, and mumps in patients evaluated for lung transplantation.

Vaccine-preventable viral infections are associated with increased risk of morbidity and mortality in post-transplant patients on immunosuppression regimens. Therefore, we studied rates of immunity against vaccine-preventable viruses in lung transplantation (LTx) candidates and their associations with underlying lung disease and clinical characteristics. We retrospectively studied 1025 consecutive adult patients who underwent first-time evaluation for LTx at a single center between January 2016 and October 2018. Viruses studied included varicella zoster (VZV), measles, and mumps. Young age (17-48 years old) was negatively associated with immunity for VZV (OR 4.54, p < .001), measles (OR 15.45, p < .001) and mumps (OR 3.1, p < .001), as compared to those 65+. Many LTx candidates with cystic fibrosis (CF) had undetectable virus-specific antibody titers including: 13.5% for VZV, 19.1% for measles, and 15.7% for mumps with significant odds of undetectable titers for VZV (OR 4.54, p < .001) and measles (OR 2.32, p = .010) as compared to those without CF. Therefore, a substantial number of patients undergoing LTx evaluation had undetectable virus-specific antibody titers. Our results emphasize the importance of screening for immunity to vaccine-preventable infections in this population and the need for revaccination in selected patients to boost their humoral immunity prior to transplantation.

Pediatric Febrile Neutropenia: Change in Etiology of Bacteremia, Empiric Choice of Therapy and Clinical Outcomes.

BACKGROUND: The optimal choice of initial antibiotic therapy for patients with high-risk febrile neutropenia (FN) in children is unclear and varies by the institution on the basis of local antibiograms and epidemiology of specific pathogens. The authors evaluated the appropriateness of antibiotics for the empiric treatment of FN in pediatric patients with cancer in our institution on the basis of changes in the epidemiology of organisms isolated from blood cultures (BCx). METHODS: The authors conducted a retrospective medical record review of pediatric patients who received any oncology care (including patients with cancer and patients who had stem cell transplant) at University of Chicago Medicine Comer Children's Hospitals (March 2009 to December 2016) with a diagnosis of FN who had at least 1 BCx obtained. They reviewed pathogens isolated from BCx and determined whether they were pathogens or contaminants using the Infectious Diseases Society of America (IDSA) guidelines and the team's decision to treat. They investigated the microbiologic spectrum and susceptibility patterns of pathogens causing bacteremia in pediatric FN and whether the empiric therapy chosen may have affected clinical outcomes. RESULTS: A total of 667 FN episodes were identified in 268 patients. BCx were negative in 497 (74.5%) and were determined to be contaminants in 27 (4%). In 143 episodes (21.5%), the BCx were positive for a pathogenic species. Polymicrobial bacteremia was identified in 25 episodes; a total of 176 pathogens were isolated. The majority of pathogens (95/176, 54%) were Gram-positive (GP), whereas 64 of 162 (36%) were Gram-negative (GN), 5 were fungal, and 4 were mycobacterial. The most common GP pathogens were viridans group streptococci (VGS) (n=34, 19.3%), coagulase-negative staphylococci (n=25, 14%), and methicillin-susceptible Staphylococcus aureus (n=12, 6.8%). Of aerobic GN bacilli, 15 (8.5%) were AmpC producers and 3 (1.7%) carried extended-spectrum beta-lactamases. There was no increase in the prevalence of multidrug-resistant GN isolates during the study period. Patients with VGS and multidrug-resistant GN bacteremia were more likely to be admitted to the pediatric intensive care unit [odds ratio (OR), 3.24; P=0.017; and OR, 2.8; P=0.07, respectively]. There were trends toward a higher prevalence of GP pathogens causing bacteremia and the emergence of VGS with decreased penicillin sensitivity. The prevalence of bacteremia with VGS was higher in acute myelogenous leukemia and neuroblastoma (OR, 2.3; P<0.01) than in patients with other solid tumors. CONCLUSIONS: Empiric antibiotic treatment should be tailored to patients' risk for VGS and multidrug-resistant organisms. Individual hospitals should monitor the pathogens causing FN among patients with cancer to guide choice of empiric therapy.

Association Between Depth of Neutropenia and Clinical Outcomes in Febrile Pediatric Cancer and/or Patients Undergoing Hematopoietic Stem-cell Transplantation.

BACKGROUND: Infectious Diseases Society of America guidelines defines febrile neutropenia (FN) patients as high risk, if they have an absolute neutrophil count (ANC) ≤100 cells/µL anticipated to last >7 days. However, data evaluating the clinical significance of the depth and duration of neutropenia are limited. METHODS: We conducted a retrospective cohort study of pediatric oncology patients presenting with FN to examine whether the effects of the depth and duration of neutropenia prior to presentation were predictive of blood stream infection (BSI), invasive fungal disease (IFD), pediatric intensive care unit (PICU) admission or length of stay. RESULTS: A total of 585 FN episodes (FNEs) were identified in 265 patients. ANC at the time of presentation was <100 in 411 (70%), 100-500 in 119 (20%), and >500 cells/µL with subsequent decline to <500 cells/µL in the next 48 hours in 55 (10%) of FNEs. In the group with ANC > 500 with subsequent decline in 48 hours, rates of IFD and BSI were higher when compared with ANC < 100 cells/µL [odds ratio (OR) = 5.9, 95% confidence interval (CI): 0.7-29.6] and (OR = 2.35, 95% CI: 01.02-5.4), and patients in this group were more likely to be admitted to the PICU (OR= 5.1, 95% CI: 1.134-19.46). No difference in outcomes was identified when the groups of ANC < 100 and ANC of 100-500 cells/µL were compared. Neutropenia >7 days prior to FNE was an independent risk factor for BSI (OR = 2.88, 95% CI: 1.55-5.35 and increased length of stay. CONCLUSIONS: Clinicians should not be reassured when patients present with FN and initial ANC >500 cells/mL after recent chemotherapy if continued decline is expected as patients in this group are at high risk of IFD, BSI and PICU admission.

Sterility Cultures Following Pancreatectomy with Islet Autotransplantation in the Pediatric Population: Do They Matter?

BACKGROUND: Pancreatectomy with islet autotransplantation (IAT) is a treatment option for children with debilitating chronic pancreatitis. Sterility cultures from preservation solutions are often positive, yet their impact has not been well studied in children. METHODS: A retrospective review of all patients who underwent IAT from 2015 to 2018 at a single institution was performed. Sterility culture data were obtained from both the pancreas transport and islet transplant media. All patients received prophylactic perioperative meropenem and vancomycin for 72 h per our protocol. If cultures resulted positive, antibiotics were extended for a total of 7 days. Primary outcomes were postoperative fever and 30-day infectious complications. RESULTS: Forty-one patients underwent IAT during the study period. Seventeen (41.5 %) patients had negative cultures of both the transport and transplant media, while 24 (58.5 %) patients had a positive culture from either sample. Of these patients, 13 (31.7 %) were positive in both, 10 (24.4 %) were positive in only the transport media, and 1 (2.4 %) was positive in only the transplant media. Patients with positive transplant media were similar with regard to age, gender, etiology, and disease duration compared to those with negative transplant media (all p > 0.05), but the positive group was more likely to have a pancreatic stent in place at the time of surgery (38.5 % vs. 4.2 %, p = 0.01). The overall postoperative infectious complication rate was 31.2 % (n = 13). No difference was detected between the transplant positive and negative culture groups in postoperative fever or 30-day infectious complications (p > 0.05 for each). CONCLUSION: An existing pancreatic stent at the time of pancreatectomy with IAT is a risk factor for positive sterility cultures. However, positive islet transplant media culture was not associated with increased risk of post-IAT infection or morbidity in the setting of an empiric antibiotic protocol. Future work is necessary to study the optimal perioperative antibiotic regimen in pediatric IAT.

Usefulness of gene expression profiling of bronchoalveolar lavage cells in acute lung allograft rejection.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Because effective therapies are lacking, early identification and mitigation of risk factors is a pragmatic approach to improve outcomes. Acute cellular rejection (ACR) is the most pervasive risk factor for CLAD, but diagnosis requires transbronchial biopsy, which carries risks. We hypothesized that gene expression in the bronchoalveolar lavage (BAL) cell pellet (CP) could replace biopsy and inform on mechanisms of CLAD. METHODS: We performed RNA sequencing on BAL CPs from 219 lung transplant recipients with A-grade ACR (n = 61), lymphocytic bronchiolitis (n = 58), infection (n = 41), or no rejection/infection (n = 59). Differential gene expression was based on absolute fold difference >2.0 and Benjamini-adjusted p-value ≤0.05. We used the Database for Annotation, Visualization and Integrated Discovery Bioinformatics Resource for pathway analyses. For classifier modeling, samples were randomly split into training (n = 154) and testing sets (n = 65). A logistic regression model using recursive feature elimination and 5-fold cross-validation was trained to optimize area under the curve (AUC). RESULTS: Differential gene expression identified 72 genes. Enriched pathways included T-cell receptor signaling, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction. A 4-gene model (AUC = 0.72) and classification threshold defined in the training set exhibited fair performance in the testing set; accuracy was 76%, specificity 82%, and sensitivity 60%. In addition, classification as ACR was associated with worse CLAD-free survival (hazard ratio = 2.42; 95% confidence interval = 1.29-4.53). CONCLUSIONS: BAL CP gene expression during ACR is enriched for immune response pathways and shows promise as a diagnostic tool for ACR, especially ACR that is a precursor of CLAD.

Training in transplant infectious diseases: A survey of infectious diseases and transplant infectious diseases fellows in the United States and Canada.

BACKGROUND: Infectious diseases (ID) specialists with experience in managing infections in transplant recipients and other immunocompromised hosts are increasingly needed as these fields expand. METHODS: To evaluate experiences and identify trainee-described needs in transplant infectious diseases (TID) training, the American Society of Transplantation, Infectious Diseases Community of Practice (AST IDCOP) surveyed ID fellows across the United States and TID fellows in the United States and Canada and received responses from 203 ID fellows and 13 TID fellows. RESULTS: Among ID fellows, the amount of TID training during ID fellowship was rated between less than ideal and adequate. Reasons cited included limited frequency of didactic activities and limited exposure to transplant patients during training. In particular, ID fellows at low-volume transplantation centers expressed interest in more TID training time, away training opportunities, and specific TID didactics. Educational resources of high interest among trainees were case-based interactive websites, mobile phone applications with TID guidelines, and a centralized collection of relevant articles. Pediatric ID fellows reported lower satisfaction scores with TID training, while TID fellows were overall satisfied or more than satisfied with their training experience. CONCLUSION: Findings from this survey will inform local and national TID educational initiatives.

Anellovirus loads are associated with outcomes in pediatric lung transplantation.

Anelloviruses are DNA viruses ubiquitously present in human blood. Due to their elevated levels in immunosuppressed patients, anellovirus levels have been proposed as a marker of immune status. We hypothesized that low anellovirus levels, reflecting relative immunocompetence, would be associated with adverse outcomes in pediatric lung transplantation. We assayed blood samples from 57 patients in a multicenter study for alpha- and betatorquevirus, two anellovirus genera. The primary short-term outcome of interest was acute rejection, and longer-term outcomes were analyzed individually and as "composite" (death, chronic rejection, or retransplant within 2 years). Patients with low alphatorquevirus levels at 2 weeks post-transplantation were more likely to develop acute rejection within 3 months after transplant (P = .013). Low betatorquevirus levels at 6 weeks and 6 months after transplant were associated with death (P = .047) and the composite outcome (P = .017), respectively. There was an association between low anellovirus levels and adverse outcomes in pediatric lung transplantation. Alphatorquevirus levels were associated with short-term outcomes (ie, acute rejection), while betatorquevirus levels were associated with longer-term outcomes (ie, death, or composite outcome within 2 years). These observations suggest that anelloviruses may serve as useful biomarkers of immune status and predictors of adverse outcomes.

Airway plaque presenting after alteration of immunosuppression in a pediatric patient remote from heart transplantation.

Success after solid organ transplantation is dependent on the proper balance of immunosuppression to prevent rejection of the allograft while limiting the risk of developing infections and malignancy. We present a 9-year-old girl, remote from transplant, who presented with airway plaque after a change in immunosuppression to include the mTOR inhibitor sirolimus. Differential diagnosis included direct medication side effect, infection, and neoplasia.

Cytomegalovirus risk, prevention, and management in pediatric solid organ transplantation.

Cytomegalovirus (CMV) is an important cause of morbidity and mortality in children who have received organ transplants. Patients have been reported to be at differential risk for CMV disease based on the serostatus of the donor and recipient with highest risk reported for CMV seronegative recipients who receive an organ from a CMV seropositive donor. Prophylaxis with ganciclovir and/or oral valganciclovir is reasonable to attempt to prevent CMV infections. A hybrid strategy bridging prophylaxis and pre-emptive therapy appears to be emerging as an additional method to prevent CMV disease. However, there is no agreement on the optimal schedule of testing, duration and dosing of antiviral medications or the role of immunoglobulin therapy. This manuscript will review the most recent literature and recommendations for the prophylaxis and treatment of CMV infections and disease in pediatric transplant recipients. Multicenter, randomized, clinical studies involving several pediatric transplant centers are needed to determine the best strategies to prevent and treat CMV infections in these patients.

The novel 2009 H1N1 influenza virus pandemic: unique considerations for programs in cardiothoracic transplantation.

The emergence of the novel 2009 H1N1 influenza virus highlights unique aspects of transplant care that will require heightened vigilance in coming months. Recognition of the syndrome, aggressive diagnosis and early treatment should be paired with active preventative measures to stem the impact of infection in the transplant population. This special advisory addresses issues relevant to cardiothoracic transplant candidates, selection of donors, recipient management and those patients with mechanical circulatory support devices.

Fungal infections in pediatric lung transplant recipients: colonization and invasive disease.

BACKGROUND: The purpose of this study was to evaluate the epidemiology and investigate the impact of colonization and pulmonary fungal infections (PFIs). METHODS: In this investigation we performed a retrospective analysis of 55 pediatric lung transplant recipients from 2002 to 2007 at a single institution. Associations between risk factors and time to post-transplant colonization, PFI, and other outcomes were assessed using Cox proportional hazard models. RESULTS: Although 29 patients had positive pre-transplant colonization, 33 (60%) were colonized post-transplant and 20% (11 subjects) developed proven or probable PFI. In a multivariate model, post-transplant fungal colonization was associated with older age (hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.1 to 7.6), cytomegalovirus (CMV) prophylaxis (HR 5.6, 95% CI 1.3 to 24.6) and respiratory viral infection prior to fungal colonization (HR 2.9, 95% CI 1.0 to 8.3). CONCLUSION: Neither fungal colonization nor PFI was associated with the development of chronic allograft rejection or death.

Increased mortality after pulmonary fungal infection within the first year after pediatric lung transplantation.

BACKGROUND: Risk factors, morbidity and mortality from pulmonary fungal infections (PFIs) within the first year after pediatric lung transplant have not previously been characterized. METHODS: A retrospective, multicenter study from 1988 to 2005 was conducted with institutional approval from the 12 participating centers in North America and Europe. Data were recorded for the first post-transplant year. The log-rank test assessed for the association between PFI and survival. Associations between time to PFI and risk factors were assessed by Cox proportional hazards models. RESULTS: Of the 555 subjects transplanted, 58 (10.5%) had 62 proven (Candida, Aspergillus or other) or probable (Aspergillus or other) PFIs within the first year post-transplant. The mean age for PFI subjects was 14.0 years vs 11.4 years for non-PFI subjects (p < 0.01). Candida and Aspergillus species were recovered equally for proven disease. Comparing subjects with PFI (n = 58) vs those without (n = 404), pre-transplant colonization was associated with PFI (hazard ratio [HR] 2.0; 95% CI 0.95 to 4.3, p = 0.067). Cytomegalovirus (CMV) mismatch, tacrolimus-based regimen and age >15 years were associated with PFI (p < 0.05). PFI was associated with any prior rejection higher than Grade A2 (HR 2.1; 95% CI 1.2 to 3.6). Cystic fibrosis, induction therapy, transplant era and type of transplant were not associated with PFI. PFI was independently associated with decreased 12-month survival (HR 3.9, 95% CI 2.2 to 6.8). CONCLUSIONS: Risk factors for PFI include Grade A2 rejection, repeated acute rejection, CMV-positive donor, tacrolimus-based regimen and pre-transplant colonization.

Safety and efficacy of prolonged cytomegalovirus prophylaxis with intravenous ganciclovir in pediatric and young adult lung transplant recipients.

CMV infection causes morbidity and mortality after transplantation. Despite a wide range of prevention strategies among pediatric lung transplant programs, the optimal duration of prophylactic therapy against CMV infection in pediatric lung transplantation is unknown. To assess the feasibility, safety, and short-term efficacy of extending intravenous ganciclovir administration from six wk duration to 12 wk duration in pediatric lung transplant recipients. An open-label pilot study was performed in primary pediatric lung transplant recipients with donor and/or recipient CMV seropositivity. Intravenous ganciclovir was given for 12 wk post-transplantation. Subjects were tracked for protocol completion. Toxicities monitored included renal dysfunction, myelosuppression, gastrointestinal and neurological complications, as well as infection related to indwelling catheter placement. Serial CMV levels were measured to determine short-term efficacy of the intervention. Nine of nine subjects enrolled completed the pilot study. Subjects' ages ranged from six to 18 yr. Indications for lung transplantation included cystic fibrosis (n = 7), idiopathic pulmonary hypertension (n = 1), and complex congenital heart disease with pulmonary hypertension (n = 1). Seven subjects underwent deceased donor bilateral lung transplantation and two subjects underwent heart-lung transplantation. No subjects had protocol-defined drug toxicity. No episodes of neutropenia, thrombocytopenia, or renal toxicity occurred. Five subjects had catheter-related infections (three after week 12 of ganciclovir). Seven of nine subjects had CMV detected by PCR (four prior to ganciclovir completion) with only one subject having a positive viral culture for CMV viremia (prior to ganciclovir completion). No subjects had UL-97 mutation for ganciclovir resistance detected. The use of prolonged prophylactic administration of ganciclovir for 12 wk duration is a feasible, safe, and effective treatment to prevent CMV viremia based on viral culture in at risk pediatric lung transplant recipients. Further clinical studies are underway to determine optimal CMV prevention strategies.

Quantitative analysis of procalcitonin after pediatric cardiothoracic surgery.

Procalcitonin appears to be an early and sensitive marker of bacterial infection in a variety of clinical settings. The use of levels of procalcitonin to predict infection in children undergoing cardiac surgery, however, may be complicated by the systemic inflammatory response that normally accompanies cardiopulmonary bypass. The aim of our study was to estimate peri-operative concentrations of procalcitonin in non-infected children undergoing cardiac surgery. Samples of serum for assay of procalcitonin were obtained in 53 patients at baseline, 24, 48, and 72 hours following cardiac surgery. Concentrations were assessed using an immunoluminetric technique. Median concentrations were lowest at baseline at less than 0.5 nanograms per millilitre, increased at 24 hours to 1.8 nanograms per millilitre, maximized at 48 hours at 2.1 nanograms per millilitre, and decreased at 72 hours to 1.3 nanograms per millilitre, but did not return to baseline levels. Ratios of concentrations between 24, 48 and 72 hours after surgery as compared to baseline were 6.15, with 95 percent confidence intervals between 4.60 and 8.23, 6.49, with 95 percent confidence intervals from 4.55 to 9.27, and 4.26, with 95 percent confidence intervals between 2.78 and 6.51, respectively, with a p value less than 0.001. In 8 patients, who had no evidence of infection, concentrations during the period from 24 to 72 hours were well above the median for the group. We conclude that concentrations of procalcitonin in the serum increase significantly in children following cardiac surgery, with a peak at 48 hours, and do not return to baseline within 72 hours of surgery. A proportion of patients, in the absence of infection, had exaggerated elevations post-operatively.

Cytomegalovirus viremia associated with death or retransplantation in pediatric lung-transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection is a frequent complication of lung transplantation. However, there is limited information regarding the incidence and sequelae of CMV infections in pediatric lung-transplant recipients. On the basis of case series suggesting that CMV infection was associated with excess morbidity and mortality in lung-transplant recipients, we hypothesize that CMV viremia increases the risk of bronchiolitis obliterans (BOS) or death and retransplantation in the first year following transplantation. METHODS: A case-cohort study of pediatric primary lung-transplant recipients was performed. Univariate analysis was used to assess whether CMV viremia was associated with BOS or death and retransplantation within 1 year after transplantation. Patients at high risk for CMV infection received ganciclovir prophylaxis for 42 days posttransplantation. RESULTS: From July 1990 to November 2000, 194 pediatric patients received primary lung transplants. Twenty-three percent of patients developed CMV viremia. Eighty percent of CMV viremia episodes occurred before 120 days posttransplant. A first episode of CMV viremia was associated with retransplantation or death between days 90 and 365 (RR=4.1, 95% confidence interval [CI] 1.1-14.5) and was not associated with BOS (RR=1.3, 95% CI 0.5-3.3). CONCLUSIONS: CMV viremia in the first year after pediatric primary lung transplantation is associated with increased risk of death or retransplantation between 90 and 365 days posttransplant, when CMV prophylaxis has stopped. A phase II pilot trial is warranted to assess safety and short-term efficacy of increasing the duration of CMV prophylaxis from 42 to 120 days.