Long-term outcomes of the bronchial artery embolization are diagnosis dependent.

BACKGROUND: Bronchial artery embolization (BAE) is an established, safe, and effective procedure for the treatment of hemoptysis but long-term outcomes of the BAE have never been investigated before. OBJECTIVES: To retrospectively analyze long-term outcomes of the BAE. MATERIALS AND METHODS: A retrospective chart analysis was done from the hospital central database for all patients undergoing the BAE over a consecutive 14-year period (January 2000-February 2014). A total of 58 patients were identified from the database. Eight patients were excluded due to the lack of follow-up. Data such as patient demographics, reason for hemoptysis, medical imaging results, bronchoscopy findings, recurrence rates, and morbidity/mortality rates after the BAE were collected. RESULTS: Eighty three embolizations were performed in 50 patients. The median follow-up was of 2.2 years. Cystic fibrosis (CF) bronchiectasis was the most common etiology (21/50), followed by non-CF bronchiectasis (9/50). Cavitary lung disease occurred in 12/50 patients, an additional 4/50 had cancer (primary lung and metastatic), and one patient had antineutrophil cytoplasmic antibody (ANCA) vasculitis. In three patients the etiology was unknown. Postprocedural complications occurred in 5/83 (6%) patients, two patients with two major complications - stroke (one) and paraplegia (one) - and three patients with minor complications - chest pain (two) and bronchial artery dissection (one). A total of 15/50 patients died during the follow-up. Three patients died of hemoptysis, and the remaining deaths were unrelated to the procedure or hemoptysis. Twenty four patients had recurrent hemoptysis. A Kaplan-Meier analysis revealed an excellent long-term survival that was 85% at 10 years. CONCLUSIONS: The BAE is a safe and effective procedure with excellent overall long-term survival.

Pan-Resistant Achromobacter xylosoxidans and Stenotrophomonas maltophilia Infection in Cystic Fibrosis Does Not Reduce Survival After Lung Transplantation.

BACKGROUND: The number of cystic fibrosis (CF) patients undergoing lung transplantation continues to grow, as does the prevalence of multidrug-resistant (MDR) gram-negative rods. However, the posttransplant survival of patients with MDR pathogens, specifically pan-resistant Achromobacter xylosoxidans and Stenotrophomonas maltophilia, is poorly characterized. METHODS: This was a retrospective review of CF patients (n = 186; all age, > 16 years) transplanted at the University of North Carolina from 1990 through 2013. Respiratory cultures before transplantation were reviewed for Achromobacter xylosoxidans and Stenotrophomonas maltophilia and their antibiotic susceptibility patterns. Bacteria were defined as pan-resistant if they were resistant or intermediate to all antibiotics tested; otherwise, organisms were defined as MDR. Patients were divided into 5 groups: pan-resistant Achromobacter xylosoxidans (n = 9), MDR Achromobacter xylosoxidans (n = 15), pan-resistant Stenotrophomonas maltophilia (n = 5), MDR Stenotrophomonas maltophilia (n = 26), and CF patients without Achromobacter xylosoxidans, Stenotrophomonas maltophilia or Bulkholderia cenocepacia (n = 131). Survival was compared, and cause of death was described. RESULTS: The survival was similar between all cohorts (P = 0.29). Recurrence of the primary pathogen was the most common with pan-resistant Achromobacter xylosoxidans (100%) followed by MDR Stenotrophomonas maltophilia (46%), MDR Achromobacter xylosoxidans (33%), and finally, pan-resistant Stenotrophomonas maltophilia (20%). Death attributable to the primary pathogen was uncommon, occurring in 2 patients with MDR Stenotrophomonas maltophilia and 2 patients with MDR Achromobacter xylosoxidans. CONCLUSIONS: The CF patients with Achromobacter xylosoxidans and Stenotrophomonas maltophilia have similar posttransplant survival as compared to other CF patients, irrespective of their antibiotic susceptibility patterns. The presence of these organisms should not preclude lung transplantation.

Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation.

BACKGROUND: Lung transplantation is limited by chronic lung allograft dysfunction. Acute cellular rejection (ACR) is a risk factor for allograft dysfunction; however, the role of antibody-mediated rejection (AMR) is not well characterized. METHODS: This was a retrospective review from 2007 to 2011 of lung transplant recipients with human leukocyte antigen (HLA) antibody testing using Luminex (Luminex Corp, Austin, TX) single-antigen beads. Statistics included Fisher's exact test for significance. RESULTS: Donor-specific antibodies (DSA) developed in 13 of 44 patients. Of the 13 with DSA, 12 had cystic fibrosis compared with 18 of 31 in the non-DSA group (p = 0.035). Of those with DSAs, 23.1% occurred within the first year, and 69.2% occurred between 1 and 3 years. Twelve of 13 DSA patients had anti-HLA DQ specificity compared with 2 of 31 non-DSA patients (p = 0.0007). AMR developed in 10 of the 13 DSA patients compared with 1 of 31 non-DSA patients (p = 0.0001). The DSA group experienced 2.6 episodes/patient of cellular rejection vs 1.7 episodes/patient in the non-DSA group (p = 0.059). Bronchiolitis obliterans syndrome developed in 11 of 13 in the DSA group vs 10 of 31 in the non-DSA group (p = 0.0024). In the DSA group, 11.5% HLAs matched compared with 20.4% in the non-DSA group (p = 0.093). AMR developed in 11 of 22 patients in the non-DSA HLA group compared with 0 of 22 in the group without non-DSA HLA antibodies (p = 0.002). Survival at 1 and 3 years was 92% and 36% in the DSA group, respectively, and 97% and 65% in the non-DSA group. CONCLUSIONS: DSAs and non-DSAs occur frequently after lung transplantation. DSAs are prevalent in the cystic fibrosis population and are associated with AMR, bronchiolitis obliterans syndrome, and possibly, ACR.

European cystic fibrosis bone mineralisation guidelines.

Patients with cystic fibrosis (CF) are at risk of developing low bone mineral density (BMD) and fragility fractures. This paper presents consensus statements that summarise current knowledge of the epidemiology and pathophysiology of CF-related skeletal deficits and provides guidance on its assessment, prevention and treatment. The statements were validated using a modified Delphi methodology.

Vitamin d deficiency in cystic fibrosis.

Cystic Fibrosis is the most common inherited genetic respiratory disorder in the Western World. Hypovitaminosis D is almost universal in CF patients, likely due to a combination of inadequate absorption, impaired metabolism, and lack of sun exposure. Inadequate levels are associated with the high prevalence of bone disease or osteoporosis in CF patients, which is associated with increased morbidity including fractures, kyphosis, and worsening pulmonary status. Treatment goals include regular monitoring 25 hydroxyvitamin D (25OHD) levels with aggressive treatment for those with levels <75 nmol/L (<30 ng/mL). More research is needed to determine optimal supplementation goals and strategies.

'Old' bones in young bodies: the tale of cystic fibrosis.

PURPOSE OF REVIEW: Cystic fibrosis (CF) is the most common genetic disease within the white population and leads to premature respiratory failure. Approximately, 60 000 individuals are currently living with CF in North America and Europe, almost half of whom are adults. RECENT FINDINGS: Dozens of studies across the globe indicate that CF adults have low bone density and increased rates of fractures. This genesis of the problem appears to be in late childhood to adolescence. SUMMARY: Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased serum levels of proinflammatory, bone-active cytokines, malnutrition and low body weight, physical inactivity and glucocorticoid therapy) for poor bone health. This review will address the pathogenesis, diagnosis and treatment of bone disease in CF. It will also discuss best practice guidelines for optimizing bone health in patients with CF.

Update on cystic fibrosis-related bone disease: a special focus on children.

A high prevalence of low bone mineralization is documented in adult patients with cystic fibrosis (CF). Osteopenia is present in up to 85% of adult patients and osteoporosis in 10% to 34%. In children, study results are discordant probably because of comparisons to different control populations and corrections for bone size in growing children. Malnutrition, inflammation, vitamin D and vitamin K deficiency, altered sex hormone production, glucocorticoid therapy, and physical inactivity are well known risk factors for poor bone health. Puberty is a critical period for bone mineralization and requires a careful follow-up to achieve optimal bone peak mass. Strategies for optimizing bone health, such as monitoring bone mineral density (BMD) and providing preventive care are necessary from childhood through adolescence to minimize CF-related bone disease in adult CF patients.

Managing complications following lung transplantation.

Lung transplantation has become a proven therapeutic option for patients with end-stage lung disease, extending life and providing improved quality of life to those who otherwise would continue to be breathless and oxygen-dependent. Over the past 20 years, considerable experience has been gained in understanding the multitude of medical and surgical issues that impact upon patient survival. Today, clinicians have an armamentarium of tools to manage diverse problems such as primary graft dysfunction, acute and chronic allograft rejection, airway anastomotic issues, infectious complications, renal dysfunction, diabetes and osteoporosis, hematological and gastrointestinal problems, malignancy, and other unique issues that confront immunosuppressed solid organ transplant recipients.

Post-transplantation lymphoproliferative disease: Epstein-Barr virus DNA levels, HLA-A3, and survival.

RATIONALE: Elevation in Epstein-Barr virus (EBV) circulating DNA has been proposed as a marker for development of post-transplant lymphoproliferative disease (PTLD), but few published data exist in the study of lung-transplant recipients. OBJECTIVES: To determine if elevated EBV DNA levels, in combination with other risk factors, were predictive of PTLD. METHODS: We conducted a retrospective, single-center study examining all lung transplant recipients (n = 296) and EBV DNA levels (n = 612) using real-time TaqMan polymerase chain reaction. There were 13 cases of PTLD overall, of which 5 occurred in the era of EBV DNA monitoring. MEASUREMENTS AND MAIN RESULTS: EBV DNA levels were distributed differently among seropositive and seronegative patients, with the latter having higher values (P < 0.0001). Among the cohort of pretransplantation seropositive patients, there was one diagnosed with PTLD. The EBV DNA level in this patient was elevated at the time of PTLD diagnosis (sensitivity = 100%, specificity = 100% for PTLD). Among the cohort of pretransplantation seronegative patients, there were four with a diagnosis of PTLD. In all four patients, the EBV DNA level was detectable (sensitivity = 100%, specificity = 24%), but in only two was it elevated (sensitivity = 50%, specificity = 22%). HLA-A3 expression in the recipient and/or donor conferred additional risk for PTLD among the seronegative patients (P = 0.026 to 0.003). No other PTLD risk factor was found. CONCLUSIONS: EBV DNA levels are a useful but imperfect predictor of PTLD in patients with lung transplants. Pretransplant EBV status affected the results of the assay and should be considered when interpreting test results. HLA-A3 was strongly linked to PTLD and may be a novel marker of PTLD risk.

Burkholderia gladioli: five year experience in a cystic fibrosis and lung transplantation center.

BACKGROUND: The impact of infection with Burkholderia gladioli in cystic fibrosis, other chronic airway diseases and immunosuppressed patients is unknown. METHODS: A six-year retrospective review of all patients with B. gladioli infection was performed in a tertiary referral center with cystic fibrosis and lung transplantation programs. In addition, a targeted survey of all 251 lung transplant recipients was performed. Available B. gladioli isolates were analyzed via pulsed field gel electrophoresis. RESULTS: Thirty-five patients were culture positive for B. gladioli, including 33 CF patients. No bacteremia was identified. Isolates were available in 18 patients and all were genetically distinct. Two-thirds of these isolates were susceptible to usual anti-pseudomonal antibiotics. After acquisition, only 40% of CF patients were chronically infected (> or =2 positive cultures separated by at least 6 months). Chronic infection was associated with resistance to > or =2 antibiotic groups on initial culture and failure of eradication after antibiotic therapy. The impact of acquisition of B. gladioli infection in chronic infection was variable. Three CF patients with chronic infection underwent lung transplantation. One post-transplant patient developed a B. gladioli mediastinal abscess, which was treated successfully. CONCLUSIONS: The majority of patients' culture positive for B. gladioli at our center have CF. B. gladioli infection is often transient and is compatible with satisfactory post-lung transplantation outcomes.

High incidence of gastric bezoars in cystic fibrosis patients after lung transplantation.

BACKGROUND: Bezoars are concretions of ingested matter which accumulate in the gastrointestinal tract and manifest as symptomatic foreign bodies. The aim of this study is to evaluate the incidence of gastric bezoars after lung transplantation and identify associated risk factors. METHODS: We performed a retrospective analysis of patients who underwent lung transplantation from December, 1992 through July, 2005 at our tertiary care medical center. Patients who had endoscopically confirmed gastrointestinal bezoars in the posttransplant setting were identified and compared with patients without bezoars. RESULTS: Of the 215 patients who received lung transplantation, 17 (7.9%) developed gastric bezoars confirmed by upper endoscopy. Cystic fibrosis was the leading indication for lung transplantation (n=145), and 11% of cystic fibrosis patients (16 of 145) formed gastric bezoars after transplant. Additionally, 94% of patients with bezoars (16 of 17) had cystic fibrosis (P=0.02), with the exception being a subject with primary ciliary dyskinesia. No patient who underwent lung transplant for another indication was found to have a bezoar. The mean time to diagnosis was 34 days, with two-thirds of bezoars diagnosed within one month after transplant. The annual incidence was unchanged during the study period. CONCLUSIONS: Gastric bezoars are common in cystic fibrosis patients after lung transplantation. The etiology is likely multifactorial, related to gastric motility, respiratory secretions, and medications. Further investigation is needed to understand the pathogenesis of bezoar formation in this selected population, and strategies for primary prevention may be beneficial.

C-C chemokine receptor 5 on stromal cells promotes pulmonary metastasis.

We have shown that mice that express the C-C chemokine receptor 5 (CCR5) have enhanced local tumor growth and an impaired response to vaccine therapy compared with CCR5 knockout (CCR5(-/-)) mice. Here, we extend these observations to evaluate the function of CCR5 in pulmonary metastasis and the mechanism underlying the diminished tumor growth in CCR5(-/-) mice. Lung metastases were counted in wild-type (WT) and CCR5(-/-) mice following the injection of 1 x 10(6) B16-F10 melanoma cells. These results were compared with those from syngeneic bone marrow chimeric mice formed by the transfer of WT bone marrow into irradiated CCR5(-/-) and CCR5(-/-) marrow into irradiated WT mice. Intact CCR5(-/-) mice developed fewer metastases than WT mice (40.2 versus 70.6; P < 0.05). Bone marrow chimeras formed by the transfer of WT bone marrow into CCR5(-/-) hosts had fewer metastases than WT hosts injected with knockout marrow (46.6 versus 98.6; P < 0.01). Adoptive transfer of CCR5-expressing leukocytes also failed to promote metastasis in CCR5(-/-) mice. However, the i.v. transfer of WT pulmonary stromal cells into CCR5(-/-) mice increased the number of metastases compared with transfer of CCR5(-/-) stromal cells (102.8 versus 26.0; P < 0.05). These results show for the first time that CCR5 expression on stromal and not hematopoietic cells contributes to tumor metastasis. Therefore, recently developed CCR5 inhibitors may have a novel benefit in cancer therapy.

Guide to bone health and disease in cystic fibrosis.

Cystic fibrosis (CF) is the most common genetic disease within the Caucasian population and leads to premature respiratory failure. Approximately 60,000 individuals are currently living with CF in North America and Europe, 40% of whom are adults. The life span of these patients has increased from approximately 2 to 32 yr of age over the last three decades. Bone disease has emerged as a common complication in long-term survivors of CF. Some studies have observed that 50-75% of adults have low bone density and increased rates of fractures. Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased levels of bone-active cytokines, physical inactivity, and glucocorticoid therapy) for poor bone health. This review is a condensed and updated summary of the Guide to Bone Health and Disease in Cystic Fibrosis: A Consensus Conference, a statement that evolved from a meeting convened by the Cystic Fibrosis Foundation in May 2002 to address the pathogenesis, diagnosis, and treatment of bone disease in CF. The goal of this conference was to develop practice guidelines for optimizing bone health in patients with CF.

Management of osteoporosis in adults with cystic fibrosis.

Cystic fibrosis (CF) is the most common genetic disease that causes respiratory failure within the Caucasian population. The life span of patients with CF has gradually increased from a median of 2 years of age to >30 years. Concurrent with this increased lifespan, a variety of other nutritional, endocrine and bone issues have been recognised. Decreased absorption of fat-soluble vitamins (D and K in particular) because of pancreatic insufficiency, altered sex hormone production, chronic inflammation, a lack of physical activity, glucocorticoid treatment and an intrinsic hyper-resorptive bone physiology are some of the factors that contribute to the prominence of bone disease within the CF population. In some series, three-quarters of adult patients with CF have osteopenia or osteoporosis. Lung transplantation is one viable treatment for patients with end-stage CF, which requires a lifetime of antirejection medication. Immunosuppressant therapies have a detrimental effect on bone mineral density (BMD). To combat the multifactorial nature of CF-related bone disease, advances in nutritional and vitamin supplementation, and anti-resorptive and anabolic therapies have evolved. Chronic vitamin D depletion contributes to bone disease in the CF population. The isoform of vitamin D that is the best and safest supplement, with the lowest cost, has yet to be identified. However, it is clear that many patients with CF who receive the standard of care (i.e. two daily combination vitamin A, D, E and K tablets [ADEKs]) may still be vitamin D-deficient. More aggressive supplementation needs to be individualised, with close monitoring of serum 25-hydroxyvitamin D levels. Similarly, routine calcium supplementation may be important, and evidence is accumulating that vitamin K also plays an important role in maximising and maintaining BMD. Early recognition and treatment of delayed puberty in adolescents and hypogonadism in adults with hormone replacement therapy is recommended to maintain BMD in patients with CF. Bisphosphonates, including pamidronic acid, etidronic acid and alendronic acid, reduce bone resorption by inhibiting the recruitment and function of osteoclasts. Pamidronic acid is beneficial in improving BMD in CF patients before and after transplantation. Bisphosphonate therapy and minimisation of glucocorticoid dosage have been shown to be efficacious in glucocorticoid-induced osteoporosis. Teriparatide is the first US FDA-approved anabolic growth agent for bone, and has been shown to increase BMD and decrease fracture incidence in postmenopausal women. Teriparatide may offer a new avenue for treating bone disease in CF since many patients may have poor bone formation as well as accelerated bone breakdown. Numerous clinical trials are underway to optimise treatment of CF osteoporosis.

Efficacy of alendronate in adults with cystic fibrosis with low bone density.

As adults with cystic fibrosis (CF) have enjoyed incremental increases in longevity over the last few decades, they have also been suffering from low bone density and its clinical manifestations, fractures and kyphosis. We conducted a placebo-controlled, randomized, double-blinded trial of alendronate (10 mg/day orally) (n = 24) compared with placebo (n = 24) for 1 year in 48 patients to improve bone mineral density at the spine as the primary endpoint. All patients received 800 IU of cholecalciferol and 1,000 mg of calcium carbonate. Both groups were similar in age, sex, CF mutations, bone density T scores, renal function, and body mass index at study onset. The alendronate-treated patients gained (mean +/- SD) 4.9 +/- 3.0% and 2.8 +/- 3.2% bone density after 1 year versus placebo, which lost (mean +/- SD) 1.8 +/- 4.0% and 0.7 +/- 4.7%, in spine and femur bone density, respectively (p < or = 0.001 for the spine; p = 0.003 for the femur). Urine N-telopeptide, a bone resorption marker, levels declined in the treatment group more than in the control group (p = 0.002), consistent with the known antiresorptive effects of bisphosphonates. Alendronate was more effective than placebo in improving spine and femur bone mineral density and is a promising agent for the long-term prevention and management of bone disease in patients with CF.

Growth factor upregulation during obliterative bronchiolitis in the mouse model.

Obliterative bronchiolitis (OB), or chronic allograft rejection, is a major cause of morbidity and mortality after lung transplantation. The goal of these experiments was to determine whether several important growth factors were upregulated during OB in the mouse heterotopic trachea model. Isografts (BALB/c into BALB/c) and allografts (BALB/c into C57BL/6) were implanted in three sets of cyclosporine-treated animals and were harvested from 2 to 10 weeks. Ribonucleic acid was isolated using the cesium chloride-guanidine method and was reverse transcribed and semiquantitated with the polymerase chain reaction using specific primers for platelet-derived growth factor (PDGF)-A and PDGF-B chains, fibroblast growth factor (FGF) isoforms 1 and 2, transforming growth factor-beta, tumor necrosis factor-alpha (TNF-alpha), edothelin-1, (prepro) epidermal growth factor, insulin-like growth factor-1, and beta-actin as a control. Transforming growth factor-beta, TNF-alpha, endothelin-1, and insulin-like growth factor-1 expression were increased 1.5-fold to 5.0-fold (p < or = 0.04 for each) in the allografts compared with the isografts at Weeks 2 through 6. Significantly increased expression of FGF-1, FGF-2, and PDGF-B was noted in the allografts at 4 weeks (p < 0.05 for each), which reversed at 6 and 10 weeks. No differences were found with the PDGF-A chain. The isografts expressed more epidermal growth factor than allografts (p < 0.001). Treatment with a TNF-alpha-soluble receptor (human TNFR:Fc) significantly reduced epithelial injury (p = 0.01) and lumenal obstruction (p = 0.037) in this model. We conclude that increased expression of a large number of growth factors occurs during OB in this model. Growth factor blockade (in particular with regard to TNF-alpha) may be useful in ameliorating OB in this model.

Six-year molecular analysis of Burkholderia cepacia complex isolates among cystic fibrosis patients at a referral center for lung transplantation.

Over a 6-year period, Burkholderia cepacia complex species were isolated from cystic fibrosis (CF) patients receiving care at The University of North Carolina Hospitals (clinic CF patients) and from those referred from other treatment centers. Fifty-six isolates collected from 30 referred patients and 26 clinic CF patients were characterized by pulsed-field gel electrophoresis (PFGE) and were assayed by PCR to detect the cable pilin gene, cblA. PFGE results indicated that six separate clusters (clusters A to F) were present among the 56 isolates and that three clusters (clusters A, B, and E) consisted only of isolates from referred patients infected with B. cepacia complex isolates prior to referral. However, one cluster (cluster C) consisted of isolates from four CF patients, and hospital records indicate that this cluster began with an isolate that came from a referred patient and that spread to three clinic CF patients. Cluster D consisted of two isolates from clinic CF patients, and hospitalization records are consistent with nosocomial, patient-to-patient spread. cblA was present in only 4 of the 56 isolates and included isolates in cluster E from the referred patients. Our results indicate a lack of spread of a previously characterized, transmissible clone from referred patients to our clinic CF population. Only two instances of nosocomial, patient-to-patient spread could be documented over the 6-year period. An additional spread of an isolate (cluster F) from a referred patient to a clinic patient could not be documented as nosocomial and may have been the result of spread in a nonhospitalized setting. The majority (36 of 56) of our B. cepacia complex-infected CF patients harbor isolates with unique genotypes, indicating that a diversity of sources account for infection. These data suggest that CF patients infected with B. cepacia complex and referred for lung transplantation evaluation were not a major source of B. cepacia complex strains that infected our resident CF clinic population.