Albert Faro

Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation

BACKGROUND Ivacaftor is used to treat patients with CF and a G551D gating mutation; the KONNECTION study assessed the efficacy and safety of ivacaftor in patients with CF and a non-G551D gating mutation. METHODS Patients with CF ≥6-years- old with non-G551D gating mutations received ivacaftor 150mg q12h or placebo for 8weeks in this 2-part, double-blind crossover study (Part 1) with a 16-week open-label extension (Part 2). The primary efficacy outcome was absolute change in FEV1 through 8 and 24weeks of ivacaftor treatment; secondary outcomes were changes in BMI, sweat chloride, and CFQ-R and safety through 8 and 24weeks of treatment. RESULTS Eight weeks of ivacaftor resulted in significant improvements in percent predicted FEV1, BMI, sweat chloride, and CFQ-R scores that were maintained through 24weeks. Ivacaftor was generally well tolerated. CONCLUSIONS Ivacaftor was efficacious in a group of patients with CF who had selected non-G551D gating mutations.

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.

Extracorporeal membrane oxygenation in pediatric lung transplantation.

OBJECTIVE Effectiveness of preoperative and postoperative extracorporeal membrane oxygenation support in pediatric lung transplantation was studied. METHODS Institutional database of pediatric lung transplants from 1990 to 2008 was reviewed. RESULTS Three hundred forty-four patients underwent lung transplants in the study period. Thirty-three of 344 patients (9.6%) required perioperative extracorporeal membrane oxygenation support. Fifteen patients (median, age 1.3 years; range, 0.2-18 years) required 16 pretransplant extracorporeal membrane oxygenation runs. Indications were respiratory failure (8/16, 50%), severe pulmonary hypertension (5/16, 31%), and cardiopulmonary collapse (3/16, 19%). Four of these patients (27%) also required postoperative support. Six (40%) were weaned before lung transplant. Six (40%) survived to hospital discharge. Survival to discharge was higher among patients weaned before lung transplant (4/6, 66% vs 2/9, 22%). Twenty-two patients (median age, 9.4 years; range, 0.2-21 years) underwent 24 extracorporeal membrane oxygenation runs after lung transplant. Indications for postoperative support were primary graft dysfunction (18/24, 75%), pneumonia (4/24, 16%), and others (2/24, 9%). Median time between lung transplant and institution of extracorporeal membrane oxygenation was 32 hours (range, 0-1084 hours); median duration of support was 141 hours (range, 48-505 hours). Five of these patients (23%) survived to hospital discharge. Among nonsurvivors, causes of death were intractable respiratory failure (12/17, 70%) and infectious complications (4/17, 24%). CONCLUSIONS Need for perioperative extracorporeal membrane oxygenation support is associated with significant morbidity and mortality among pediatric patients receiving lung transplants. A subset of patients who can be weaned from support preoperatively have greater likelihood of survival.

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.

American Society of Transplantation executive summary on pediatric lung transplantation.

Lung transplantation in children poses distinctly different challenges from those seen in the adult population. This consensus statement reviews the experience in the field of pediatric lung transplantation and highlights areas that deserve further investigation.

Lung Transplantation in Infants and Toddlers from 1990 to 2004 at St. Louis Children's Hospital

In a retrospective, single‐center cohort study, outcomes of infants and toddlers undergoing lung transplant at St. Louis Childrens Hospital between 1990 and 2004 were compared to older children. Patients with cystic fibrosis (exclusively older children) and those who underwent heart–lung, liver–lung, single lung or a second transplantation were excluded from comparisons. One hundred nine lung transplants were compared. Thirty‐six were in infants <1 year old, 26 in toddlers 1–3 years old and 47 in children >3 years old. Graft survival was similar for infants and toddlers (p = 0.35 and p = 0.3, respectively) compared to children over 3 years old at 1 and 3 years after transplant. Significantly more infants (p < 0.0001 and p = 0.003) and toddlers (p = 0.002 and p = 0.03) were free from acute rejection and bronchiolitis obliterans compared to older patients. While most infants and toddlers had only minimal lung function impairment, and achieved normal to mildly delayed developmental scores, somatic growth remained depressed 5 years after transplant. Lung transplantation in infants and young children carries similar survival rates to older children and adults. Further insights into the unique immunologic aspects of this group of patients may elucidate strategies to prevent acute and chronic rejection in all age groups.

Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review

BackgroundDyskeratosis congenita (DC) is a progressive, multi-system, inherited disorder of telomere biology with high risks of morbidity and mortality from bone marrow failure, hematologic malignancy, solid tumors and pulmonary fibrosis. Hematopoietic stem cell transplantation (HSCT) can cure the bone marrow failure, but it does not eliminate the risks of other complications, for which life-long surveillance is required. Pulmonary fibrosis is a progressive and lethal complication of DC.Case presentationIn this report, we describe a patient with DC who developed pulmonary fibrosis seven years after HSCT for severe aplastic anemia, and was successfully treated with bilateral lung transplantation. We also performed a systematic literature review to understand the burden of pulmonary disease in patients with DC who did or did not receive an HSCT. Including our patient, we identified 49 DC patients with pulmonary disease (12 after HSCT and 37 without HSCT), and 509 with no reported pulmonary complications.ConclusionOur current case and literature review indicate that pulmonary morbidity is one of the major contributors to poor quality of life and reduced long-term survival in DC. We suggest that lung transplantation be considered for patients with DC who develop pulmonary fibrosis with no concurrent evidence of multi-organ failure.

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.

The use of multiple transbronchial biopsies as the standard approach to evaluate lung allograft rejection

Abstract:  Flexible bronchoscopy with transbronchial biopsy (TBB) is routinely performed in adult and pediatric lung transplant recipients. The clinical signs and symptoms of acute cellular rejection (ACR) are often identical to those of infection. TBB is a fairly sensitive and specific tool in which to diagnose ACR and can be performed safely in children of all ages. The utility of TBB is unquestioned during periods of worsening clinical symptoms. The utility of TBB for routine surveillance of the allograft remains unproven. The data suggests that during the first 4–6 months post‐transplant there is a high incidence of clinically silent ACR. The significance of subclinical rejection in lung transplantation is unknown. Randomized, controlled trials are required to determine if multiple surveillance TBB, can impact the incidence of obliterative bronchiolitis.