Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis.

BACKGROUND: Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. OBJECTIVE: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. METHODS: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. RESULTS: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ-induced gene expression, but we found impaired responses to IFN-γ restimulation. CONCLUSION: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ-mediated inflammation.

Vaccine-acquired rotavirus in infants with severe combined immunodeficiency.

Live pentavalent human-bovine reassortant rotavirus vaccine is recommended in the United States for routine immunization of infants. We describe three infants, two with failure to thrive, who had dehydration and diarrhea within 1 month after their first or second rotavirus immunization and subsequently received a diagnosis of severe combined immunodeficiency. Rotavirus was detected, by means of reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, in stool specimens obtained from all three infants, and gene-sequence analysis revealed the presence of vaccine rotavirus. These infections raise concerns regarding the safety of rotavirus vaccine in severely immunocompromised patients.

Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology.

A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.

Corrigendum: Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

[This corrects the article on p. 798 in vol. 8, PMID: 28769923.].

Standardization and performance evaluation of mononuclear cell cytokine secretion assays in a multicenter study.

BACKGROUND: Cryopreservation of peripheral blood mononuclear cells has been used to preserve and standardize immunologic measurements for multicenter studies, however, effects of cryopreservation on cytokine responses are incompletely understood. In designing immunologic studies for a new multicenter birth cohort study of childhood asthma, we performed a series of experiments to determine the effects of two different methods of cryopreservation on the cytokine responses of cord and peripheral blood mononuclear cells. RESULTS: Paired samples of PBMC were processed freshly, or after cryopreservation in a Nalgene container (NC) or a controlled-rate freezer (CRF). Although there were some differences between the methods, cryopreservation inhibited PHA-induced IL-10 secretion and Der f 1-induced IL-2 secretion, and augmented PHA-induced IL-2 secretion and spontaneous secretion of TNF-alpha. In separate experiments, NC cryopreservation inhibited secretion of several cytokines (IL-13, IL-10, IFN-gamma, TNF-alpha) by PHA-stimulated cord blood mononuclear cells. With the exception of PHA-induced IL-13, results from fresh and cryopreserved cord blood samples were not significantly correlated. Finally, in reproducibility studies involving processing of identical cell samples in up to 4 separate laboratories, variances in cytokine responses of fresh cells stimulated at separate sites did not exceed those in cryopreserved cells stimulated at a central site. CONCLUSION: Collectively, these studies indicate that cryopreservation can affect mononuclear cell cytokine response profiles, and that IL-10 secretion and antigen-induced responses may be especially vulnerable. These studies also demonstrate that mononuclear cell responses can be standardized for performance in a small number of laboratories for multicenter studies, and underscore the importance of measuring reproducibility and of testing whether cryopreservation techniques alter specific immunologic outcomes.

Repair of congenital heart lesions combined with lung transplantation for the treatment of severe pulmonary hypertension: a 13-year experience.

OBJECTIVE: In patients with severe pulmonary hypertension associated with congenital heart disease, we prefer to perform repair of the congenital heart disease and lung transplantation whenever feasible so as to augment the donor pool and avoid the cardiac complications associated with heart transplantation. We report our experience with repair of congenital heart disease and lung transplantation and compare the results with those of patients who underwent heart-lung transplantation during the same period. METHODS: The records of patients who had repair of congenital heart disease and lung transplantation (n = 35) and heart-lung transplantation (n = 16) between 1990 and 2003 were reviewed. RESULTS: The underlying congenital heart disease in the repair of congenital heart disease and lung transplantation group included transposition of great vessels (n = 2), atrioventricular canal defect (n = 2), ventricular septal defect (n = 9), pulmonary venous obstruction (n = 7), scimitar syndrome (n = 2), pulmonary arterial atresia or stenosis (n = 5), and others (n = 8). Thirteen of the patients undergoing repair of congenital heart disease and lung transplantation (37.1%) had the congenital heart disease repaired before lung transplantation; the remaining congenital heart disease repairs were performed concurrently with transplantation. Sixteen patients underwent heart-lung transplantation because of poor left ventricular function or single-ventricle anatomy. Freedoms from bronchiolitis obliterans at 1, 3, and 5 years were 72.9%, 54.7%, and 54.7% for the repair of congenital heart disease and lung transplantation group and 77.8%, 51.9%, and 38.9% for the heart-lung transplantation group, respectively. Survivals at 1, 3, and 5 years were 62.9%, 51.4%, and 51.4% for the repair of congenital heart disease and lung transplantation group and 66.5%, 66.5%, and 60% for the heart-lung transplantation group, respectively. CONCLUSION: Repair of congenital heart disease and lung transplantation is a feasible treatment option. Long-term outcome is determined by associated complications related to lung transplantation. Despite the complexity of combined congenital heart disease repair with lung transplantation and the resulting perioperative morbidity, the patients had similar outcomes to those of patients who underwent heart-lung transplantation.

Primary graft dysfunction and other selected complications of lung transplantation: A single-center experience of 983 patients.

OBJECTIVES: We sought to review the incidence and outcome of lung transplantation complications observed over 15 years at a single center. METHODS: We performed a retrospective review from our databases, tracking outcomes after adult and pediatric lung transplantation. The 983 operations between July 1988 and September 2003 included 277 pediatric and 706 adult recipients. Bilateral (74%), unilateral (19%), and living lobar transplants (4%) comprised the bulk of this experience. Retransplantations accounted for 44 (4.5%) of the operations. RESULTS: The groups differed by indication for transplantation. The adults included 57% with emphysema and 17% with cystic fibrosis, and the children included no patients with emphysema and 50% with cystic fibrosis. Hospital mortality was 96 (9.8%) of 983, including 46 (17%) of 277 of the children and 50 (7%) of 706 of the adults. The overall survival curves did not differ between adults and children ( P = .56). Freedom from bronchiolitis obliterans syndrome at 5 and 10 years was 45% and 18% for adults and 48% and 30% for children, respectively ( P = .53). The causes of death for adults included bronchiolitis obliterans syndrome (40%), respiratory failure (17%), and infection (14%), whereas the causes of death in children included bronchiolitis obliterans syndrome (35%), infection (28%), and respiratory failure (21%) ( P < .01). Posttransplantation lymphoproliferative disease occurred in 12% of pediatric recipients and 6% of adults ( P < .01). The frequency of treated airway complications did not differ between adults and children (9% vs 11%, P = .48). The frequency of primary graft dysfunction did not differ between children (22%) and adults (23%), despite disparity in the use of cardiopulmonary bypass. CONCLUSION: These results highlight major complications after lung transplantation. Despite differences in underlying diagnoses and operative techniques, the 2 cohorts of patients experienced remarkably similar outcomes.

Lung transplantation for pulmonary vascular disease.

BACKGROUND: Pulmonary hypertension (PHT) is a lethal condition resulting in markedly diminished life expectancy. Continuous prostaglandin I2 infusion has made an important contribution to symptom management, but it is not a panacea. Lung or heart-lung transplantation remains an important treatment option for end-stage PHT patients unresponsive to prostaglandin I2. This study reviews the outcomes after transplantation for PHT in our program. METHODS: A retrospective chart review was performed for 100 consecutive patients with either primary PHT (48%) or secondary PHT (52%) transplants since 1989. Living recipients were contacted to confirm health and functional status. RESULTS: Fifty-five adult and 45 pediatric patients underwent 51 bilateral lung transplants, 39 single lung transplants, and 10 heart-lung transplants. Mean age was 23.7 years (range, 1.2 months to 54.8 years) and mean pre-transplant New York Heart Association class was 3.2. Pre-transplant hemodynamics revealed a mean right atrial pressure of 9.6+/-5.4 mm Hg and mean pulmonary artery pressure of 64+/-14.4 mm Hg. Hospital mortality was 17% with early death predominantly because of graft failure and infection. With an average follow-up of 5.0 years, 1- and 5-year actuarial survival was 75% and 57%, respectively. Mean pulmonary artery pressure on follow-up catheterization was 22+/-6.0 mm Hg, and mean follow-up New York Heart Association class was 1.3 (p < 0.001 for both compared with pre-transplant). Diagnosis and type of transplant did not confer a significant difference in survival between groups. CONCLUSIONS: Whereas lung or heart-lung transplant for PHT is associated with higher early mortality than other pulmonary disease entities, it provides similar long-term outcomes with dramatic improvement in both quality of life and physiologic aspects.

Bronchial airway anastomotic complications after pediatric lung transplantation: incidence, cause, management, and outcome.

OBJECTIVE: Airway complications are a recognized surgical complication and an important source of morbidity after adult lung transplantation. Little is known about these complications after pediatric lung transplantation. METHODS: Data of pediatric lung transplants performed between January 1990 and December 2002 in a single pediatric institution were reviewed retrospectively. RESULTS: A total of 214 patients, with a mean age of 9.8 +/- 6.1 years (range 0.01-19.7 years), underwent 239 lung transplants: 231 bilateral and 8 single. Mean follow-up was 3.4 years. Forty-two airway complications requiring interventions (stenosis = 36; dehiscence = 4; malacia = 2) developed in 30 recipients (complication rate: 9% of 470 bronchial anastomoses at risk). There were airway complications in 29 bilateral lung transplants (13%) and 1 single lung transplant (13%). Mean time to diagnosis was 51 +/- 27 days (median: 53, range 1-96 days), and diagnoses were made in 90% of patients within the first 3 months after transplantation. Preoperative Pseudomonas cepacia, postoperative fungal lung infection, and days on mechanical ventilator were found to be significant risk factors on multivariate analysis (P = .002, P = .013 and P = .003, respectively). Treatment included rigid bronchoscopic dilatation in 17 patients, balloon dilatation in 13 patients, and stent placement in 12 patients. Other treatments consisted of debridement, fibrin glue application, chest tube placement, and pneumonectomy followed by retransplantation. No patients died as a direct result of airway complications. There was no significant difference in the incidence of bronchiolitis obliterans or overall survival in comparison with patients who did not have airway complications. CONCLUSIONS: Airway complications are a significant cause of morbidity after pediatric lung transplantation. The majority are successfully treated, and patient outcomes are not adversely affected.

Role of open lung biopsy in lung transplant recipients in a single children's hospital: a 13-year experience.

BACKGROUND: There are few data in the literature regarding the utility of open lung biopsy for the assessment of graft dysfunction after pediatric lung transplantation. The aim of this study is to review our experience with diagnostic open lung biopsy in lung transplant recipients in a children's hospital. METHODS: Records of lung transplant recipients from January 1990 through December 2002 were reviewed to identify the indications, outcomes, and complications of open lung biopsy. RESULTS: Two hundred twenty-four patients (mean age, 9.9 +/- 6.2 years; median age, 11 years; age range, 0.01-19.6 years) underwent 249 lung transplantations: 231 bilateral, 8 single, and 10 heart-lung transplantations. Mean follow-up was 3.4 years. One hundred three open lung biopsies were performed in 89 (40% of all recipients) patients. Thirteen recipients underwent open lung biopsy twice, and 1 recipient had 3 open lung biopsies. The indications for open lung biopsy were suspicion of bronchiolitis obliterans (n = 70), posttransplantation lymphoproliferative disorder (n = 15), infection (n = 8), and unexplained respiratory failure (n = 10). A new diagnosis was made in 49 biopsies (48%), 50 biopsies (49%) confirmed the preoperative clinical diagnosis, and 4 biopsies (3%) were nondiagnostic. Bronchiolitis obliterans was confirmed in 40 (57%) of 70 open lung biopsies, posttransplantation lymphoproliferative disorder was confirmed in 4 (27%) of 15 open lung biopsies, and infection was confirmed in 6 (75%) of 8 open lung biopsies. A change in therapy occurred in 69% of the cases as a result of the diagnosis made from open lung biopsy. There was no mortality as a direct result of open lung biopsy. Eleven major complications and 22 minor complications occurred in 103 procedures. CONCLUSION: Open lung biopsy can be performed safely, and established or confirmed a diagnosis in 97% of the cases. A change in therapy occurred in 69% of the cases as a result of the diagnosis made from open lung biopsy. In our experience open lung biopsy appears to be a useful tool.

Living donor lobar grafts improve pediatric lung retransplantation survival.

OBJECTIVE: Lung retransplantation is a controversial practice due to increased morbidity and mortality and the scarcity of available donor organs. Living donor lobar lung transplantation increases the number of available donor organs and facilitates a more organized procedure than traditional cadaveric donation for this complex reoperation. The purpose of this study was to evaluate our experience with pediatric lung retransplantation and to compare the outcomes of living donor lobar lung transplantation with cadaveric donation. METHODS: Retrospective review of a prospectively collected database identified 39 children who underwent lung retransplantation from 1991 to 2004. Retransplantation was performed with living donor lobar lung transplantation in 13 patients and cadaveric donation in 26 patients. Short- and long-term outcomes were compared between the 2 groups. RESULTS: Perioperative mortality was 1/13 (7.7%) in the patients who had living donor lobar lung transplantation versus 11/26 (42.3%) in the cadaveric donation group (P = .03). Five-year survival for living donor lobar lung transplantation and cadaveric donation was 40.4% and 29.7%, respectively (P = .27). Both groups had a significant improvement in their forced expiratory volume in 1 second 6 months after retransplantation (P < .001). Multivariate analysis identified the use of cadaveric donation (relative risk = 6.16, P = .001) and early graft dysfunction (relative risk = 6.19, P = .001) as the major independent predictors of decreased survival following retransplantation. CONCLUSIONS: Living donor lobar lung transplantation reduces perioperative mortality and is an independent predictor of improved survival following pediatric lung retransplantation. This strategy offers significant benefit for this high-risk group and preserves the limited supply of donor lungs for other children at risk of dying while waiting for lung transplantation.

Lung transplantation in children.

OBJECTIVE: To report the authors' experience with pediatric lung transplantation (LTX) to provide an overview of patients selected for this procedure and their outcomes. SUMMARY BACKGROUND DATA: Pediatric LTX differs from adults in many ways, including recipient size, indications, posttransplant care, and rehabilitation. METHODS: Two hundred seven isolated lung transplants on 190 children under the age of 18 years were performed from 1990 to the present. This represents the single largest series of lung transplants in children in the world. Thirty-two patients were less than 1 year of age, 22 were 1 to 5 years of age, 32 were 5 to 10 years of age, and 121 were 10 to 18 years old. The groups by major diagnostic category were cystic fibrosis (n = 89), pulmonary vascular disease (n = 44), bronchiolitis obliterans (n = 21), pulmonary alveolar proteinosis (n = 12), pulmonary fibrosis (n = 15), and other (n = 26). The average age at the time of transplant was 9.5 +/- 5.9 years (range 36 days to 18 years). RESULTS: Survival by Kaplan-Meier analysis was 77% at 1 year, 62% at 3 years, and 55% at 5 years. There was no significant difference in survival according to primary diagnosis leading to LTX or age at LTX. There were 25 early (<60 days) and 61 late deaths. The most common cause of early deaths was graft failure (13/25, 52%). The most common causes of late death were bronchiolitis obliterans (35/61, 57%), infection (13/61, 21%), and posttransplant malignancies (11/61, 18%). No patient died of acute rejection. In those surviving greater than 3 months (mean follow-up 3.5 years, range 3 months to 11 years), the overall rate of occurrence of bronchiolitis obliterans was 46% (80/175) and the overall incidence of posttransplant malignancies was 24/175 (14%). Major risk factors for the development of bronchiolitis obliterans were age older than 3 years, more than two episodes of acute rejection, and organ ischemic time longer than 180 minutes. CONCLUSIONS: In children, LTX is a high-risk but viable treatment for end-stage pulmonary parenchymal and vascular disease. The major hurdle to overcome in long-term survival is bronchiolitis obliterans.