Robert M. Aris

Increased Rate of Fractures and Severe Kyphosis: Sequelae of Living into Adulthood with Cystic Fibrosis

Cystic fibrosis is the most common fatal autosomal recessive genetic disease in white persons; it affects approximately 30 000 Americans and a similar number of Europeans [1]. Cystic fibrosis mutations occur in approximately 1 of every 2500 live births in the white population and lead to death or lung transplantation in more than 500 persons annually in the United States alone [2]. Although respiratory disease is the greatest cause of illness and death in patients with cystic fibrosis, improved therapy for chronic pulmonary infection has markedly extended life expectancy and has led to the discovery of myriad other problems that afflict these patients [3]. Osteoporosis, in particular, increases pain and debilitation in patients with cystic fibrosis as they live into adulthood. Patients with cystic fibrosis have increased risk for osteoporosis as a result of multiple factors [4]. Poor nutrition, pancreatic insufficiency, reduced absorption of calcium and vitamin D, reduced physical activity, delayed and reduced production of sex steroids, use of corticosteroids, and increased circulating concentrations of osteoclast-activating factors (such as tumor necrosis factor- and interleukin-1) may all cause reduced bone mineral density in patients with cystic fibrosis. Young patients with cystic fibrosis invariably fail to reach peak bone mass [5-10], and this contributes to low bone mineral density in adulthood. Unbalanced bone formation and resorption [11], caused by accelerated bone loss, may lead to further bone demineralization in early adulthood. Both increased bone resorption and decreased bone formation probably play a role in osteoporosis in cystic fibrosis [8, 12, 13]. Osteoporosis in patients with cystic fibrosis is well documented [5-10, 12-16]. Hahn and colleagues [5] were the first to show low bone mineral density (mean reduction, 15%) in the distal radii of these patients. In the past decade, reductions in bone mineral density for the femur (mean decrease, 11.1%), lumbar spine (mean decreases, 12.5% to 35%), and total body (mean decrease, 10%) [6, 12, 14] have been reported in adults with cystic fibrosis. Henderson and Madsen [7] recently found that patients with cystic fibrosis had low bone mineral density in childhood and that it worsened with age. The average z-scores for the lumbar spine were 0.39 for children aged 5 to 8 years, 0.99 for children aged 8 to 12 years, and 1.69 for children aged 12 to 18 years. Taken together, these results show that osteopenia may occur as early as the first decade of life in patients with cystic fibrosis and that bone loss accelerates during adolescence and early adulthood. Although low bone mineral density in cystic fibrosis has attracted considerable attention, data on the complications of osteoporosis, including fractures and kyphosis, are limited. Despite low bone mineral density and anecdotal reports of increased fracture rates [9, 14, 15, 17-20], no reports have documented significant increases in fracture rates in adults with cystic fibrosis. It has been suggested that the decreased activity level that accompanies progressive cystic fibrosis offers a protective influence with respect to the occurrence of fractures. Our main goal was to quantitate the clinical sequelae of osteoporosis, namely, fractures and kyphosis, in a large group of adults with cystic fibrosis to test the hypothesis that fracture rates and kyphosis angles are greater in patients with cystic fibrosis than in the general population. A second goal was to investigate the role of potentially important clinical variables in the pathogenesis of osteoporosis in cystic fibrosis. Methods Patients The study sample consisted of 70 adults (older than 18 years of age) with advanced cystic fibrosis who were referred for lung transplantation at the University of North Carolina between January 1994 and December 1996. The Committee on Human Research (IRB #96-Med-336) approved this retrospective cohort study and required verbal consent from participating patients. Cystic fibrosis was diagnosed by elevated sweat chloride concentrations and an appropriate clinical picture. All patients had end-stage lung disease and an anticipated survival of less than 2 to 3 years [21]. Fracture History The history, date, and mechanism of fracture were determined by personal interviews done using methods similar to those of the National Health Interview Study [22]. Fractures were required to have patient report of radiographic confirmation at the time of the fracture, but we did not review these radiographs. Confirmation of long-bone fractures required patient report of treatment with casting. Fractures occurring between birth and 6 years of age were not assessed because most patients were unable to provide accurate histories for those years. The number of years that each patient was at risk for fracture was summed by age interval to determine the total number of patient-years for this cohort. All patients were asked to give their date of puberty; to give a detailed history of corticosteroid use (expressed as cumulative dose of prednisone in grams); to state whether they had received therapy for osteoporosis; and, if they were female, to state whether and when they had had oligomenorrhea. Bone Densitometry Bone mineral density was measured in all patients by a single, registered radiologic technologist using dual-energy x-ray absorptiometry (Hologic QDR 1000/W, Waltham, Massachusetts) [23]. Lumbar spine (L1-L4), nondominant femoral neck, and total-body bone mineral densities were measured; measurements were expressed in grams of bone mineral per cm2 of bone. Quality control was maintained by daily scanning of an anthropomorphic spine phantom. The coefficient of variation for our Hologic QDR 1000/W densitometer is 0.3%, and the reference limits for variation are 1.5%. Results were expressed as T-scores, which are the number of SDs that the bone mineral density measurement is above (positive value) or below (negative value) expected peak bone mass. The age at which peak bone mass is achieved differs slightly for each site but is usually between 20 and 30 years. Using World Health Organization guidelines, we defined osteopenia as a T-score greater than 2.5 and 1.0 or less. Osteoporosis was defined as a T-score of 2.5 or less [24]. Normal bone mineral density was defined as a T-score of 0 1. Laboratory Measurements Serum calcium, phosphorus, alkaline phosphatase, and creatinine concentrations were measured with an automatic analyzer (Hitachi 911, Boehringer Mannheim, Indianapolis, Indiana). Vitamin D metabolites were extracted from serum specimens (obtained while patients were fasting) with column chromatography and were measured with radiobinding assays (Nichols Institute, Raleigh, North Carolina). The 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D assays had sensitivities of 5 pg/mL and 5 ng/mL, respectively. Testosterone levels were measured by using a competitive radioimmunoassay (Diagnostics Product Corp., Los Angeles, California). Genotype analysis for the 15 most common CFTR mutations was done by using published methods [25]. Radiographic Analysis Screening of the most recent posteroanterior and lateral chest radiographs for the extent of thoracic kyphosis as well as rib and vertebral body fractures was done by a single musculoskeletal radiologist on 65 patients (5 patients did not undergo radiography at the University of North Carolina). Thoracic kyphosis was measured from the second or third to the twelfth thoracic vertebral body by using a modification of the method of Cobb [26]. The number of vertebral compression fractures was also determined from the lateral radiograph by measuring anterior and posterior vertebral body height and expressing the difference as a percentage [27]. The posteroanterior chest radiograph was examined for the presence of rib fractures. Nonacute fractures appeared as focal deformities in the rib contour with varying degrees of reparative bone formation. Statistical Analysis Analyses were done with SAS software (version 6.12, SAS Institute, Cary, North Carolina) [28], and significance was based on two-tailed tests with a P value less than 0.05. Discrete variables are summarized as percentages, and continuous variables are summarized as means SD. Nonparametric methods were used when the distribution of the continuous variable was skewed. Student t-tests were used to compare differences in all clinical and anthropomorphic variables except fracture rates [29]. Relationships between spine and femur T-scores and seven continuous variables-age, age at puberty, cumulative steroid dose, body mass index, FEV1, FVC, and vitamin D levels-were assessed with either the Pearson or Kendall correlation coefficients [30]. Backward stepwise regression analysis was used to determine the multivariate relation between spine and femur T-scores and the aforementioned predictors. Clinical predictors and T-scores were compared, using the Kruskal-Wallis test, by dividing the patients into three groups: those without fractures, those with one fracture, and those with more than one fracture. This was done to determine whether differences existed between groups. Using spine or femur z-scores (the number of SDs that a bone mineral density measurement was above or below that of age- and sex-matched normal controls) rather than T-scores gave similar results (data not shown) because most patients were in the age range at which peak bone mass is expected. For the analysis of fractures and kyphosis angles, patients were grouped by age to conform with published databases (normal databases are based on age) [22, 31]. Two separate fracture rate analyses were done: In one, all fractures were used as the numerator; in the other, all persons with any fracture were used as the numerator. The latter analysis was done to eliminate the possibility that fracture clustering had affected the results. We used person-years as the denominator fo

Extended Valganciclovir Prophylaxis to Prevent Cytomegalovirus After Lung Transplantation: A Randomized, Controlled Trial

BACKGROUND Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients. OBJECTIVE To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious. DESIGN Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370) SETTING Multicenter trial involving 11 U.S. lung transplant centers. PATIENTS 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis. INTERVENTION 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66). MEASUREMENTS The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety. RESULTS CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups. LIMITATION Longer-term effects of extended prophylaxis were not assessed. CONCLUSION In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

Non‐tuberculous mycobacteria in end stage cystic fibrosis: implications for lung transplantation

Background: WC and NS contributed equally. Non-tuberculous mycobacteria (NTM) frequently colonise patients with end stage cystic fibrosis (CF), but its impact on the course of the disease following lung transplantation is unknown. Methods: Lung transplant recipients with CF who underwent lung transplantation at our institution between January 1990 and May 2003 (n = 146) and CF patients awaiting lung transplantation in May 2003 (n = 31) were studied retrospectively. Results: The prevalence rate of NTM isolated from respiratory cultures in patients with end stage CF referred for lung transplantation was 19.7%, compared with a prevalence rate of 13.7% for NTM isolates in CF lung transplant recipients. The overall prevalence of invasive NTM disease after lung transplantation was low (3.4%) and was predicted most strongly by pre-transplant NTM isolation (p = 0.001, Fisher’s exact test, odds ratio (OR) 6.13, 95% CI 3.2 to 11.4). This association was restricted to Mycobacterium abscessus (p = 0.005, Fisher’s exact test, OR 7.45, 95% CI 2.9 to 16.9). While NTM disease caused significant morbidity in a small number of patients after transplantation, it was successfully treated and did not influence the post-transplant course of the disease. Conclusion: The isolation of NTM before transplantation in CF patients should not be an exclusion criterion for lung transplantation, but it may alert the clinician to patients at risk of recurrence following transplantation.

Everolimus versus azathioprine in maintenance lung transplant recipients: An international, randomized, double-blind clinical trial

Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double‐blind clinical trial, 213 BOS‐free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1–3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV1 >15%[ΔFEV1 >15%], graft loss, death or loss to follow‐up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of ΔFEV1 >15%, ΔFEV1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after 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 Fishers 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.

Long term results of lung transplantation for cystic fibrosis.

OBJECTIVES We reviewed our experience with lung transplant for cystic fibrosis (CF) over a 10-year period to identify factors influencing long-term survival. METHODS One hundred and twenty-three patients with CF have undergone 131 lung transplant procedures at our institution; 114 have had bilateral sequential lung transplants (DLTX) and nine have had bilateral lower lobe transplants from living donors. Three patients had retransplant for acute graft failure, and five had late retransplant for bronchiolitis obliterans syndrome (BOS). Kaplan-Meier survival was calculated for the entire cohort and for subsets at higher risk of death to determine factors predicting a better outcome. RESULTS Actuarial survival for the entire group of DLTX CF patients was 81% at 1 year, 59% at 5 years, and 38% at 10 years. Lobar transplant was associated with a poorer survival (37.5% at 1 and 5 years). Among DLTX patients, colonization with Burkholderia cepacia was present in 22 patients and was associated with poorer outcome (1- and 5-year survival 60 and 36% in B. cepacia patients vs. 86 and 64% in non-cepacia patients). DLTX patients younger than age 20 (n=22) had a similar survival to patients age 20 or older (n=90). Being on a ventilator at the time of transplant was not associated with poorer survival (n=8). BOS affects increasing numbers of survivors with time. Five CF patients have been retransplanted due to BOS with one operative death and 1-year survival of 60%. CONCLUSIONS DLTX has acceptable long term survival in CF adults and children with end stage disease. CF patients colonized with B. cepacia have a worse outcome but transplantation is still warranted.

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.

Abnormal bone turnover in cystic fibrosis adults.

Abstract: Cystic fibrosis (CF) patients often have low bone mineral density (BMD) and may suffer from fractures and kyphosis. The pathogenesis of low BMD in CF is multifactorial. To study bone metabolism, we collected fasting serum and urine from 50 clinically stable CF adults (mean age 28 years) and 53 matched controls to measure markers of bone formation and bone resorption. The CF subjects had moderate lung disease (FEV1: 46.1 ± 18.6% predicted) and malnutrition (BMI: 20.0 ± 3.3 kg/m2). Only 3 subjects had normal BMD. CF subjects had higher urinary N-telopeptides of type I collagen (81.0 ± 60.0 vs 49.0 ± 24.2 nm BCE/mmol creatinine, p= 0.0006) and free deoxypyridinoline (7.3 ± 5.0 vs 5.3 ± 1.9 nM/mM, p= 0.004) levels than controls. Serum osteocalcin levels were similar in the two groups, a result confirmed by two immunoassays that recognize different epitopes on osteocalcin. Serum bone-specific alkaline phosphatase levels were elevated in CF patients (32.0 ± 11.3 vs 21.8 ± 7.0 U/l, p<0.0001), but were much more closely associated with serum total alkaline phosphatase levels (r = 0.51, p = 0.001) than with age or gender. Parathyroid hormone levels were elevated (p= 0.007) and 25-hydroxyvitamin D levels were depressed (p= 0.0002) in the CF patients in comparison with controls. These results indicate that adults with CF have increased bone resorption with little change in bone formation. Medications that decrease bone resorption or improve calcium homeostasis may be effective therapies for CF bone disease.