Melinda Solomon

Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children

Pollock‐BarZiv SM, Finkelstein Y, Manlhiot C, Dipchand AI, Hebert D, Ng VL, Solomon M, McCrindle BW, Grant D. Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children.
Pediatr Transplantation 2010: 14:968–975.

Inconclusive Diagnosis of Cystic Fibrosis After Newborn Screening

OBJECTIVES: To prospectively study infants with an inconclusive diagnosis of cystic fibrosis (CF) identified by newborn screening (NBS; “CF screen positive, inconclusive diagnosis” [CFSPID]) for disease manifestations. METHODS: Infants with CFSPID and CF based on NBS from 8 CF centers were prospectively evaluated and monitored. Genotype, phenotype, repeat sweat test, serum trypsinogen, and microbiology data were compared between subjects with CF and CFSPID and between subjects with CFSPID who did (CFSPID→CF) and did not (CFSPID→CFSPID) fulfill the criteria for CF during the first 3 years of life. RESULTS: Eighty-two subjects with CFSPID and 80 subjects with CF were enrolled. The ratio of CFSPID to CF ranged from 1:1.4 to 1:2.9 in different centers. CFTR mutation rates did not differ between groups; 96% of subjects with CFSPID and 93% of subjects with CF had 2 mutations. Subjects with CFSPID had significantly lower NBS immunoreactive trypsinogen (median [interquartile range]:77 [61–106] vs 144 [105–199] μg/L; P < .0001) than did subjects with CF. Pseudomonas aeruginosa and Stenotrophomonas maltophilia were isolated in 12% and 5%, respectively, of subjects with CFSPID. CF was diagnosed in 9 of 82 (11%) subjects with CFSPID (genotype and abnormal sweat chloride = 3; genotype alone = 4; abnormal sweat chloride only = 2). Sweat chloride was abnormal in CFSPID→CF patients at a mean (SD) age of 21.3 (13.8) months. CFSPID→CF patients had significantly higher serial sweat chloride (P < .0001) and serum trypsinogen (P = .009) levels than did CFSPID→CFSPID patients. CONCLUSIONS: A proportion of infants with CFSPID will be diagnosed with CF within the first 3 years. These findings underscore the need for clinical monitoring, repeat sweat testing at age 2 to 3 years, and extensive genotyping.

Prevalence of Hepatopulmonary Syndrome in Children

OBJECTIVE. The hepatopulmonary syndrome is defined as a triad of liver disease, hypoxemia, and intrapulmonary vascular dilation. The reported prevalence of hepatopulmonary syndrome in adults with cirrhosis ranges from 4% to 29%; however, the prevalence of hepatopulmonary syndrome and its outcome in children is unknown. The objective of this study was to describe prospectively the prevalence of intrapulmonary vascular dilation and hepatopulmonary syndrome in children with liver disease. METHODS. Pulse oximetry was undertaken in children with liver disease, and those with oxygen saturation ≤97%, those with cirrhosis, and those with clinically severe portal hypertension from other causes underwent contrast-enhanced echocardiography for detection of intrapulmonary vascular dilations. Patients with intrapulmonary vascular dilation underwent arterial blood gas analysis and technetium-99m–labeled macroaggregated albumin scan. RESULTS. Oxygen saturation was measured in 301 children and was ≤97% in 8. These 8 and an additional 18 patients with cirrhosis or portal hypertension underwent contrast-enhanced echocardiography. Seven (27%) patients had intrapulmonary vascular dilation detected by contrast-enhanced echocardiography; 2 of these patients had abnormal arterial blood gas analysis and thus met diagnostic criteria for hepatopulmonary syndrome (representing 8% of patients with cirrhosis or severe portal hypertension). Both patients with hepatopulmonary syndrome had abnormal pulse oximetry. Technetium-99m–labeled macroaggregated albumin scans for 6 patients showed a median 6.5% (range: 4%–12%) tracer uptake outside the lungs. CONCLUSIONS. Hepatopulmonary syndrome occurs in an important minority of children with cirrhosis or severe portal hypertension. Additional studies should be undertaken to determine the importance of intrapulmonary vascular dilation without hepatopulmonary syndrome and the impact of hepatopulmonary syndrome on the outcomes of affected children.

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.

Pneumocystis jiroveci pneumonia following rituximab treatment in Wegener's granulomatosis

Wegeners granulomatosis (WG) is a devastating small‐vessel vasculitis in children. Standard treatment consists of immunosuppressive medications with cyclophosphamide potentially associated with significant infectious side effects, including Pneumocystis jiroveci pneumonia (PCP). Recently, rituximab, a monoclonal antibody against B cells, has successfully been used in refractory disease.

Role of respiratory viruses in pulmonary exacerbations in children with cystic fibrosis

Abstract Background The role of respiratory viruses in cystic fibrosis (CF) exacerbations is incompletely understood. Methods Cross-sectional study of CF children with a pulmonary exacerbation. Mid-turbinate swabs were tested by a direct immunofluorescent antibody assay and a multiplex PCR panel (ResPlex II v2.0, Qiagen). Resplex II was also applied to sputum or throat swab samples. Pulmonary function tests and quality of life and severity scores were recorded. Sputum cell counts, bacterial density and cytokines were measured. Results 26/43 (60.5%) subjects tested positive for at least one respiratory virus by any diagnostic method applied to any sample type. Virus-positive patients were younger (p =0.047), more likely to be male (p =0.029), and had higher CF clinical severity (p =0.041) and lower quality of life (physical) scores (p =0.023) but similar IL-8, neutrophil percentage and elastase levels. Conclusions Compared to non-viral exacerbations, viral-related exacerbations were associated with worse severity and quality of life scores but similar pulmonary inflammation.

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.

Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language?

Background The American and European cystic fibrosis (CF) guidelines recommend different diagnostic criteria. This study assessed diagnostic concordance between these recommendations. Methods Subjects with single organ manifestations suggestive of CF (chronic sinopulmonary disease (RESP), chronic/recurrent pancreatitis (PANC) or obstructive azoospermia (AZOOSP)) were prospectively evaluated by sweat test, nasal potential difference and genotyping. Concordance in diagnostic outcomes between the two algorithms was measured using observed agreement and κ statistics. Results A total of 208 subjects were evaluated. Observed agreement was 84.8% and level of agreement was excellent (κ=0.87) between the American and European recommendations. The RESP phenotype was associated with the highest degree of concordance (observed agreement ≥90%, κ=0.92) compared with the PANC (observed agreement 86%, κ=0.65) and AZOOSP (observed agreement 80%, κ=0.87) phenotypes. Incorporation of nasal potential difference into the American algorithm failed to improve the overall degree of concordance (good agreement level; κ=0.75); the level of agreement was unchanged in RESP and PANC subjects, but reduced in AZOOSP subjects (from excellent to good). Extensive genotyping had limited clinical utility in the diagnosis of CF in both algorithms. Conclusions Despite inconsistencies between the American and European diagnostic recommendations, concordance in diagnostic outcomes among subjects presenting with single organ manifestations of CF was good to excellent. These diagnostic guidelines provide guidance and promote rigorous evaluation for the diagnosis of CF but neither guideline should be regarded as dogma.

Does extensive genotyping and nasal potential difference testing clarify the diagnosis of cystic fibrosis among patients with single-organ manifestations of cystic fibrosis?

Background The phenotypic spectrum of cystic fibrosis (CF) has expanded to include patients affected by single-organ diseases. Extensive genotyping and nasal potential difference (NPD) testing have been proposed to assist in the diagnosis of CF when sweat testing is inconclusive. However, the diagnostic yield of extensive genotyping and NPD and the concordance between NPD and the sweat test have not been carefully evaluated. Methods We evaluated the diagnostic outcomes of genotyping (with 122 mutations included as disease causing), sweat testing and NPD in a prospectively ascertained cohort of undiagnosed patients who presented with chronic sino-pulmonary disease (RESP), chronic/recurrent pancreatitis (PANC) or obstructive azoospermia (AZOOSP). Results 202 patients (68 RESP, 42 PANC and 92 AZOOSP) were evaluated; 17.3%, 22.8% and 59.9% had abnormal, borderline and normal sweat chloride results, respectively. Only 17 (8.4%) patients were diagnosable as having CF by genotyping. Compared to sweat testing, NPD identified more patients as having CF (33.2%) with fewer borderline results (18.8%). The level of agreement according to kappa statistics (and the observed percentage of agreement) between sweat chloride and NPD in RESP, PANC and AZOOSP subjects was ‘moderate’ (65% observed agreement), ‘poor’ (33% observed agreement) and ‘fair’ (28% observed agreement), respectively. The degree of agreement only improved marginally when subjects with borderline sweat chloride results were excluded from the analysis. Conclusions The diagnosis of CF or its exclusion is not always straightforward and may remain elusive even with comprehensive evaluation, particularly among individuals who present at an older age with single-organ manifestations suggestive of CF.

Seven-valent pneumococcal conjugate vaccine in pediatric solid organ transplant recipients: a prospective study of safety and immunogenicity.

Objectives: To determine the safety and immunogenicity of the conjugate pneumococcal vaccine (PCV7) in pediatric solid organ transplant recipients. Patients and Methods: Pediatric solid organ transplant recipients were prospectively enrolled at ≥4 months following transplantation. Eligible pneumococcal vaccine-naive subjects received 3 doses of PCV7 at 8 week intervals, followed 8 weeks later by a dose of the 23-valent vaccine (PV23). Serology was done at baseline, 8 weeks following doses 2 and 3 of PCV7 and 8–12 weeks after PV23. Repeated measures analyses were done using SAS 9. Results: Eighty-one recipients commenced immunization at a median age of 7.8 (0.6–17.5) years and a median time from transplantation to immunization of 1.3 (0.3–6.0) years. There were 31 heart, 18 liver, 5 lung, and 27 kidney recipients. Reported adverse events following vaccine doses included local reactions (PCV7: PV23 = 19%:16%) and fever (PCV7: PV23 = 3.8%:4.9%) and there were no serious reactions. Two doses of PCV7 induced ≥2 fold increases in geometric mean concentrations (GMCs) in all organ groups. Cardiac and lung recipients demonstrated additional benefit from a third dose of PCV7. The cardiac recipients showed most benefit from boosting with PV23 with significant increases in GMCs (P ≤ 0.008). The time of initiation of the vaccine strategy posttransplantation predicted seroprotection. Conclusion: PCV7 was safe and immunogenic in solid organ recipients. Three doses of this vaccine appear beneficial for selected organ groups. PV23 when administered at ≥1 year posttransplantation was useful in boosting antibody responses in patient groups demonstrating lower rates of responsiveness.