Debra Boyer

Human Monoclonal Antibodies to Pseudomonas aeruginosa Alginate That Protect against Infection by Both Mucoid and Nonmucoid Strains

Two fully human mAbs specific for epitopes dependent on intact carboxylate groups on the C6 carbon of the mannuronic acid components of Pseudomonas aeruginosa alginate were found to promote phagocytic killing of both mucoid and nonmucoid strains as well as protection against both types of strains in a mouse model of acute pneumonia. The specificity of the mAbs for alginate was determined by ELISA and killing assays. Some strains of P. aeruginosa did not make detectable alginate in vitro, but in vivo protection against lethal pneumonia was obtained and shown to be due to rapid induction of expression of alginate in the murine lung. No protection against strains genetically unable to make alginate was achieved. These mAbs have potential to be passive therapeutic reagents for all strains of P. aeruginosa and the results document that alginate is a target for the proper type of protective Ab even when expressed at low levels on phenotypically nonmucoid strains.

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.

Respiratory viral infections within one year after pediatric lung transplant.

Abstract: To characterize epidemiology and risk factors for respiratory viral infections (RVI) in pediatric lung transplant recipients within the first post‐transplant year, a retrospective multicenter study of pediatric lung transplant recipients from 1988 to 2005 was conducted at 14 centers in the United States and Europe. Data were recorded for 1 year post transplant. Associations between RVI and continuous and categorical risk factors were assessed using Wilcoxons rank‐sum and χ2 tests, respectively. Associations between time to RVI and risk factors or survival were assessed by multivariable Cox proportional hazards models. Of 576 subjects, 79 subjects (14%) had 101 RVI in the first year post transplant. Subjects with RVI were younger than those without RVI (median ages 9.7, 13; P<0.01). Viruses detected included adenovirus (n=25), influenza (n=9), respiratory syncytial virus (n=21), parainfluenza virus (n=19), enterovirus (n=4), and rhinovirus (n=22). In a multivariable model for time to first RVI, etiology other than cystic fibrosis (CF), younger age, and no induction therapy were independently associated with risk of RVI. Cytomegalovirus serostatus and acute rejection were not associated with RVI. RVI was independently associated with decreased 12‐month survival (hazard ratio 2.6, 95% confidence interval 1.6–4.4). RVI commonly occurs after pediatric lung transplantation with risk factors including younger age and non‐CF diagnosis. RVI is associated with decreased 1‐year survival.

The risk, prevention, and outcome of cytomegalovirus after pediatric lung transplantation.

Background. A retrospective review of pediatric lung transplant recipients at 14 centers in North America and Europe was conducted to characterize the epidemiology and the risk factors for cytomegalovirus (CMV) and to explore the impact of preventative antiviral therapy. Methods. Data were recorded for 1 year posttransplant. Associations between CMV and continuous and categorical risk factors were assessed using Wilcoxon rank sum and chi-square tests, respectively. Associations between time to CMV and risk factors or survival were assessed by multivariable Cox proportional hazards models. Results. Within 12 months posttransplant, 172 of 577 subjects (29.8%) developed 218 CMV episodes (90 asymptomatic infection, 25 syndrome, and 103 disease). Forty-one subjects developed more than one episode of CMV. Donor or recipient CMV seropositivity was associated with increased risk of CMV episodes. Except for decreased prophylaxis in CMV D−/R− subjects, duration of prophylaxis did not vary by D/R serostatus. For CMV D+ subjects, not being on prophylaxis at the time of CMV episode increased the risk of CMV (D+/R+ hazard ratio 3.5, 95% confidence interval 1.4–8.4; D+/R− 1.9, 1.02–3.7). CMV was associated with increased mortality within the first posttransplant year among those with donor or recipient CMV seropositivity (hazard ratio 2.0: 95% confidence interval 1.1–3.6; P=0.024). Conclusions. CMV remains a serious complication after pediatric lung transplant, and the impact of prophylaxis is complex.

Churg-Strauss syndrome in children: A clinical and pathologic review

Churg-Strauss syndrome is a vasculitis accompanied by asthma and eosinophilia. It is generally considered a disease of adults; occurrence in children has been reported infrequently. Here we report 2 pediatric patients with Churg-Strauss syndrome manifesting with prominent pulmonary involvement. One, a 16-year-old with a previous history of asthma, presented with pleuritic chest pain and a peripheral pulmonary nodule complicated by an eosinophilic pleural effusion. The other patient presented at age 6 with cough, weight loss, and radiographic infiltrates. Lung biopsies revealed elements characteristic of Churg-Strauss syndrome, including eosinophilic microabscesses and vasculitis. Three- and 5-year follow-up showed continued symptoms in both patients despite medical therapy. Both patients illustrate many of the typical features of Churg-Strauss syndrome. We report these cases to expand the scant knowledge about Churg-Strauss syndrome in pediatric patients and to heighten awareness that this serious disease may affect the pediatric population. The relevant literature on Churg-Strauss syndrome, with specific reference to childhood cases, is reviewed.

Variability in standard care for cytomegalovirus prevention and detection in pediatric lung transplantation: survey of eight pediatric lung transplant programs.

Abstract:  Cytomegalovirus (CMV) infection after pediatric lung transplantation is a significant risk factor for morbidity and mortality in the first year after transplantation. Multiple strategies have been reported for CMV prevention among adult lung transplant programs. In contrast, little information has been reported regarding protocols for prevention and detection of CMV from pediatric programs. We conducted a survey to better understand the range of practice patterns for CMV prevention and detection at pediatric lung transplant centers. A self‐administered questionnaire was distributed to 11 pediatric lung transplant centers identified through the International Pediatric Lung Transplant Collaborative in September 2002. A member of the lung transplant team from each institution was asked to provide the methods of CMV prevention and surveillance. Eight of 11 centers surveyed responded to the questionnaire accounting for 45.6% (26 of 57) and 100% (three of three) of the pediatric lung transplants performed in the US and UK in 2001, respectively. All centers used prophylactic therapy against CMV with either ganciclovir or valganciclovir with duration ranging from 3.5 wk to indefinitely. Most centers (six of eight) prescribed a prophylactic regimen based on donor and recipient CMV serostatus. Half (four of eight) of the centers report using CMV hyperimmune globulin in addition to an antiviral agent. Method for CMV detection varied widely, including use of conventional viral culture (n = 1), antigenemia (n = 7), and polymerase chain reaction (n = 2). A wide range of strategies is used to prevent and detect CMV in pediatric lung transplant recipients with little empiric evidence demonstrating the optimal approach. A retrospective analysis among these centers is being conducted to evaluate the efficacy of these approaches.

Variability in immunization guidelines in children before and after lung transplantation

Abstract:  Lung transplant candidates and recipients are at high risk of infections from vaccine‐preventable diseases. However, well‐established guidelines neither exist for pre‐ and post‐transplant vaccination nor do monitoring guidelines for pediatric lung transplant recipients. To ascertain the current vaccination and monitoring practices of pediatric lung transplant centers, a self‐administered questionnaire was distributed to the 18 pediatric lung transplant centers within the International Pediatric Lung Transplant Collaborative in April 2006. Sixteen of 18 centers (89%) surveyed responded. Pretransplant, national vaccination guidelines are followed. Eleven centers reported following standardized vaccination guidelines post‐transplant. Vaccines were more commonly provided by the primary‐care physician pretransplant (69%) rather than post‐transplant (38%). Post‐transplant, 50% of the centers recommend live vaccines for household contacts but not for the transplant recipient. Pretransplant monitoring of response to prior vaccination was performed inconsistently except for varicella (88%). Only 44% of the transplant centers measure for response to vaccination post‐transplant, mostly hepatitis B. Current vaccination practices of pediatric lung transplant centers are heterogeneous. The lung transplant community would be well served by studies designed to evaluate the efficacy of vaccinations in this population.

Mucoepidermoid carcinoma of bronchus in a pediatric patient: 18 F-FDG PET findings

In children, primary neoplasms of the tracheobronchial tree and lungs are rare; most are malignant. Of the primary malignant pulmonary neoplasms arising in childhood, mucoepidermoid carcinoma accounts for approximately 10%. Due to its well-confined local growth within the airway, mucoepidermoid carcinoma commonly produces respiratory symptoms from progressive tracheal or bronchial obstruction. Mucoepidermoid tumor has minimal metastatic potential in children, and local resection alone is the current treatment of choice. Early detection, diagnosis, and surgical resection of mucoepidermoid tumor are especially important in pediatric patients since the bulk of the remaining pulmonary parenchyma can be preserved, thereby decreasing the thoracic deformity and pulmonary functional morbidity. Radiographic and CT imaging findings of bronchial mucoepidermoid carcinoma in children have been described in several case reports. However, to the best of our knowledge, imaging findings of 2-(18F)-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET) of mucoepidermoid carcinoma of the bronchus in pediatric patients have not been well established. We report a mucoepidermoid carcinoma arising from the right upper lobe bronchus in a 15-year-old girl with an emphasis on the 18F-FDG PET findings.

Cytomegalovirus immunoglobulin decreases the risk of cytomegalovirus infection but not disease after pediatric lung transplantation.

BACKGROUND Cytomegalovirus (CMV) has been associated with morbidity, including chronic allograft rejection, in transplant recipients. Data from adult centers suggests that CMV hyperimmune globulin (CMVIG) and ganciclovir together are superior in preventing CMV viremia than ganciclovir alone. METHODS A retrospective review of pediatric lung transplant recipients at 14 sites in North America and Europe was conducted to evaluate the effect of adding cytomegalovirus immunoglobulin (CMVIG) prophylaxis to at least 3 weeks of intravenous ganciclovir therapy in pediatric lung transplant recipients. Data were recorded for the first year after transplantation. Associations between time to CMV and risk factors, including CMVIG use, were assessed by multivariable Cox proportional hazards models. RESULTS Of 599 patients whose records were reviewed, 329 received at least 3 weeks of ganciclovir, with 62 (19%) receiving CMVIG. CMVIG was administered more frequently with CMV donor-positive/recipient-negative serostatus (p < 0.05). In multivariable models, patients who did not receive CMVIG as part of their prophylaxis were 3 times more likely to develop CMV infection (hazard ratio, 3.4; 95% confidence interval, 1.2-9.5) independent of CMV serostatus. However, CMVIG administration was not associated with decreased risk of episodes of CMV disease. Receipt of CMVIG was not associated with decreased risks of post-transplant morbidities (acute rejection, respiratory viral infection or early bronchiolitis obliterans) or morbidity within the first year after pediatric lung transplantation. CONCLUSION The use of CMVIG in addition to antiviral prophylaxis in pediatric lung transplantation requires further evaluation.

Balancing education and service in graduate medical education: data from pediatric trainees and program directors.

Purpose To measure pediatric program directors’ (PDs’) and trainees’ perceptions of and expectations for the balance of service and education in their training programs. Method In fall 2011, an electronic survey was sent to PDs and trainees at Boston Children’s Hospital. Respondents described perceptions and expectations for service and education and rated the education and service inherent to 12 vignettes. Wilcoxon rank sum tests measured the agreement between PD and trainee perceptions and ratings of service and education assigned to each vignette. Results Responses were received from 28/39 PDs (78%) and 223/430 trainees (52%). Seventy-five (34%) trainees responded that their education had been compromised by excessive service obligations; only 1 (4%) PD agreed (P < .0001). Although 132 (59%) trainees reported that service obligations usually/sometimes predominated over clinical education, only 3 (11%) PDs agreed (P < .0001). One hundred trainees (45%) thought rotations never/rarely/sometimes provided a balance between education and clinical demands compared with 2 PDs (7%) (P < .0001). Both groups agreed that service can, without formal teaching, be considered educational. Trainees scored 6 vignettes as having greater educational value (P ⩽ .01) and 10 as having lower service content (P ⩽ .04) than PDs did. Conclusions Trainees and medical educators hold mismatched impressions of their training programs’ balance of service and education. Trainees are more likely to report an overabundance of service. These data may impact the interpretation of Accreditation Council for Graduate Medical Education survey results and should be incorporated into dialogue about future curricular design initiatives.