A retrospective analysis of the safety and efficacy of apixaban use after lung transplant.

Direct acting oral anticoagulants (DOACs) have become the mainstay of treatment for patients requiring anticoagulation for atrial arrhythmias and venous thromboembolism (VTE) but safety and efficacy has not been established in lung transplantation. This is a retrospective review of 28 adult lung transplant patients who were prescribed apixaban for stroke prevention in atrial arrhythmias or treatment of VTE between October 15, 2015 and December 31, 2018. The primary outcome was a composite of efficacy and safety measured by recurrence or breakthrough of stroke or thromboembolism and bleeding events. Seven patients were treated for atrial arrhythmias and 21 treated for VTE. Fifteen patients received CYP3A4 or P-gp inhibitors at initiation of anticoagulation, and 4 of these patients received strong CYP3A4 inhibitors. During the follow-up period, one breakthrough DVT and one clinically relevant non-major bleed were observed. These data suggest that apixaban may be safe to use for lung transplant patients, and larger studies are warranted to assess long-term outcomes as well as safety and efficacy of alternative DOACs.

Microsporidiosis acquired through solid organ transplantation: a public health investigation.

BACKGROUND: Encephalitozoon cuniculi, a microsporidial species most commonly recognized as a cause of renal, respiratory, and central nervous system infections in immunosuppressed patients, was identified as the cause of a temporally associated cluster of febrile illness among 3 solid organ transplant recipients from a common donor. OBJECTIVE: To confirm the source of the illness, assess donor and recipient risk factors, and provide therapy recommendations for ill recipients. DESIGN: Public health investigation. SETTING: Two transplant hospitals and community interview with the deceased donor's family. PATIENTS: Three transplant recipients and the organ donor. MEASUREMENTS: Specimens were tested for microsporidia by using culture, immunofluorescent antibody, polymerase chain reaction,immunohistochemistry, and electron microscopy. Donor medical records were reviewed and a questionnaire was developed to assess for microsporidial infection. RESULTS: Kidneys and lungs were procured from the deceased donor and transplanted to 3 recipients who became ill with fever 7 to 10 weeks after the transplant. Results of urine culture, serologic,and polymerase chain reaction testing were positive for E. cuniculi of genotype III in each recipient; the organism was also identified in biopsy or autopsy specimens in all recipients. The donor had positive serologic test results for E. cuniculi. Surviving recipients received albendazole. Donor assessment did not identify factors for suspected E. cuniculi infection. LIMITATION: Inability to detect organism by culture or polymerase chain reaction in donor due to lack of autopsy specimens. CONCLUSION: Microsporidiosis is now recognized as an emerging transplant-associated disease and should be considered in febrile transplant recipients when tests for routinely encountered agents are unrevealing. Donor-derived disease is critical to assess when multiple recipients from a common donor are ill.

Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer.

Idiopathic pulmonary fibrosis (IPF) is a lethal scarring lung disease that affects older adults. Heterozygous rare mutations in the genes encoding telomerase are found in approximately 15% of familial cases. We have used linkage to map another disease-causing gene in a large family with IPF and adenocarcinoma of the lung to a 15.7 Mb region on chromosome 10. We identified a rare missense mutation in a candidate gene, SFTPA2, within the interval encoding surfactant protein A2 (SP-A2). Another rare mutation in SFTPA2 was identified in another family with IPF and lung cancer. Both mutations involve invariant residues in the highly conserved carbohydrate-recognition domain of the protein and are predicted to disrupt protein structure. Recombinant proteins carrying these mutations are retained in the endoplasmic reticulum and are not secreted. These data are consistent with SFTPA2 germline mutations that interfere with protein trafficking and cause familial IPF and lung cancer.

Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax.

RATIONALE: Cystic fibrosis (CF) is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. There may be intermittent pulmonary exacerbations or acute worsening of infection and obstruction, which require more intensive therapies. Hemoptysis and pneumothorax are complications commonly reported in patients with cystic fibrosis. OBJECTIVES: This document presents the CF Foundation's Pulmonary Therapies Committee recommendations for the treatment of hemoptysis and pneumothorax. METHODS: The committee recognized that insufficient data exist to develop evidence-based recommendations and so used the Delphi technique to formalize an expert panel's consensus process and develop explicit care recommendations. MEASUREMENTS AND MAIN RESULTS: The expert panel completed the survey twice, allowing refinement of recommendations. Numeric responses to the questions were summarized and applied to a priori definitions to determine levels of consensus. Recommendations were then developed to practical treatment questions based upon the median scores and the degree of consensus. CONCLUSIONS: These recommendations for the management of the patient with CF with hemoptysis and pneumothorax are designed for general use in most individuals but should be adapted to meet specific needs as determined by the individuals, their families, and their health care providers. It is hoped that the guidelines provided in this manuscript will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis.

Power washing pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis is an uncommon cause of insidious onset shortness of breath and hypoxemia. It is caused by an accumulation of surfactant within the alveoli. Left untreated, it can be fatal. Standard-of-care treatment is whole-lung lavage; however, in severe cases, the associated hypoxemia can be profound and single-lung ventilation would not be tolerated, potentially preventing a lifesaving treatment. Single cases using veno-venous extracorporeal membrane oxygenation to perform whole-lung lavage have been reported. Here we describe three patients with severe pulmonary alveolar proteinosis who were successfully treated with whole-lung lavage using veno-venous extracorporeal membrane oxygenation for oxygenation support.

Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations.

The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis.

Telomere shortening in familial and sporadic pulmonary fibrosis.

RATIONALE: Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres. OBJECTIVES: To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC. METHODS: Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS: All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 x 10(-8)). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 x 10(-11)). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile. CONCLUSIONS: A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease.

Lung transplantation in cystic fibrosis.

Lung transplantation has become a viable option for those cystic fibrosis (CF) patients with end-stage lung disease. Despite the challenges that the CF patients present, the survival seen after lung transplantation is more favorable than seen in patients with chronic obstructive pulmonary disease and pulmonary fibrosis. Although the CF patients with severe respiratory disease usually are infected with organisms that display in vitro resistance to the commonly used antibiotics, these patients usually have successful outcomes with transplantation. The other challenges include the presence of nontuberculous mycobacteria, the significant incidence of liver involvement, the development of an ileus or the development of the distal intestinal obstruction syndrome, and the presence of gastroesophageal reflux. Most of the patients have metabolic bone disease, even preoperatively, that warrants treatment, especially with the significant loss of bone density seen in the first year after transplant, thought to be related, in part, to the high dose of corticosteroids. Diabetes mellitus and its consequences are not uncommon. The malabsorption of fat seen in the pancreatic-insufficient patients complicates the absorption kinetics of the anti-rejection drugs. In May 2005 the United Network of Organ Sharing instituted a lung-allocation score to better distribute the donated lungs to those patients who would achieve the most benefit. This score uses several variables to balance the likelihood of the patients living one year with a transplant versus one year without a transplant. With this change in the allocation of organs, the median waiting times have significantly decreased, the mortality on the waiting list has decreased, and the number of CF patients transplanted has not changed. With substantial experience, more programs are now transplanting patients who require constant mechanical ventilation or patients who have undergone previous pleural procedures, especially in the treatment of a pneumothorax. The limiting factor now in lung transplantation is the number of organs available. Efforts to increase the donor pool, such as alveolar recruitment strategies to improve gas exchange, have been effective in allowing more patients to be transplanted. Lung transplantation is now an accepted form of therapy in those patients who are developing progressive respiratory failure.

Management of pulmonary embolism at a large academic hospital.

The initial management of patients presenting with acute pulmonary embolism (PE) is individualized based on hemodynamic status and other prognostic factors. Patients at low risk of adverse outcomes are treated conservatively with anticoagulation, whereas high-risk and selected intermediate-risk patients should be considered for advanced interventions. Seeking to better understand local practice patterns, we retrospectively reviewed 196 cases of acute PE diagnosed in the emergency department of Baylor University Medical Center over a 12-month period. Given the available data, we classified 86 cases as low risk, 101 as intermediate risk, and 9 as high risk for early mortality. Four patients with high-risk PE and 11 patients with intermediate-risk PE were treated with thrombolytic therapy. Central embolus location, right ventricular dilation on computed tomography, and right ventricular strain on electrocardiogram were associated with the use of thrombolytic therapy in the intermediate-risk group. In total, 9 patients died and 11 suffered major bleeding. Patients with acute PE are a remarkably heterogeneous group with wide variations in workup, treatment, and outcomes.

Elevated gluconeogenesis and lack of suppression by insulin contribute to cystic fibrosis-related diabetes.

The incidence of diabetes is high in cystic fibrosis (CF) and is an important cause of morbidity and mortality. Understanding the pathophysiology is imperative. Studies have documented increased endogenous (mostly hepatic) glucose production (HGP) but have not distinguished the relative contribution of gluconeogenesis (GNG). The purpose of this study was to quantitate GNG, to determine its contribution to high HGP, and to measure insulin's suppression of GNG. We recruited 31 adult CF subjects (age, 26.2+/-7.9 years; 12 female subjects) and quantified GNG by measuring the incorporation of H into the second and fifth carbons of glucose. Hepatic glucose production was measured using [6,6-H2]glucose. Protein breakdown was measured using [1-C]leucine. Data were compared with that from 11 healthy volunteers (age, 27.5+/-7.0 years) who underwent both GNG and clamp studies. Thirteen CF subjects and all controls had a hyperinsulinemic euglycemic clamp during measures of GNG. Other measures included glucose tolerance and glucagon and cortisol levels. Rate of GNG was higher in CF subjects than controls and comprised a greater percentage of fasting HGP (GNG as percent of HGP: CF=68%; controls=44%; P=0.034). Suppression of GNG by insulin was significantly lower in CF than in controls and was lower in CF subjects with abnormal glucose tolerance than in those with normal glucose tolerance. Gluconeogenesis correlated with protein breakdown. These studies suggest that high HGP in CF is mostly from elevated rates of GNG and that resistance to insulin's suppression of GNG may contribute to abnormal glucose tolerance in CF.

Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health.

RATIONALE: Cystic fibrosis is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. Death is usually a result of respiratory failure. Newly introduced therapies and aggressive management of the lung disease have resulted in great improvements in length and quality of life, with the result that the median expected survival age has reached 36 years. However, as the number of treatments expands, the medical regimen becomes increasingly burdensome in time, money, and health resources. Hence, it is important that treatments should be recommended on the basis of available evidence of efficacy and safety. OBJECTIVES: The Cystic Fibrosis Foundation therefore established a committee to examine the clinical evidence for each therapy and to provide guidance for the prescription of these therapies. METHODS: The committee members developed and refined a series of questions related to drug therapies used in the maintenance of pulmonary function. We addressed the questions in one of three ways, based on available evidence: (1) commissioned systematic review, (2) modified systematic review, or (3) summary of existing Cochrane reviews. CONCLUSIONS: It is hoped that the guidelines provided in this article will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis.

Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect.

Due to genetic defects in apical membrane chloride channels, the cystic fibrosis (CF) intestine does not secrete chloride normally. Depressed chloride secretion leaves CF intestinal absorptive processes unopposed, which results in net fluid hyperabsorption, dehydration of intestinal contents, and a propensity to inspissated intestinal obstruction. This theory is based primarily on in vitro studies of jejunal mucosa. To determine if CF patients actually hyperabsorb fluid in vivo, we measured electrolyte and water absorption during steady-state perfusion of the jejunum. As expected, chloride secretion was abnormally low in CF, but surprisingly, there was no net hyperabsorption of sodium or water during perfusion of a balanced electrolyte solution. This suggested that fluid absorption processes are reduced in CF jejunum, and further studies revealed that this was due to a marked depression of passive chloride absorption. Although Na+-glucose cotransport was normal in the CF jejunum, absence of passive chloride absorption completely blocked glucose-stimulated net sodium absorption and reduced glucose-stimulated water absorption 66%. This chloride absorptive abnormality acts in physiological opposition to the classic chloride secretory defect in the CF intestine. By increasing the fluidity of intraluminal contents, absence of passive chloride absorption may reduce the incidence and severity of intestinal disease in patients with CF.

Effect of phenytoin on mood and declarative memory during prescription corticosteroid therapy.

BACKGROUND: In humans and animals, corticosteroid excess is associated with impairment in declarative memory and changes in hippocampal structure. In animals, phenytoin pretreatment blocks the effects of stress on memory and hippocampal histology, although no studies have examined the use of phenytoin to prevent corticosteroid-associated memory changes in humans. Mood changes are also common with corticosteroids, but few treatment data are available. This report examines whether phenytoin can prevent mood or declarative memory changes secondary to bursts of prescription corticosteroids. METHODS: Thirty-nine patients with allergies or pulmonary or rheumatologic illnesses and given systemic corticosteroid therapy were randomized to receive either phenytoin (300 mg/day) or placebo concurrently with the corticosteroids. Mood was assessed with the Hamilton Rating Scale for Depression, Young Mania Rating Scale, and Activation (ACT) subscale of the Internal State Scale; declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and after approximately 7 days of corticosteroid plus phenytoin or placebo therapy. RESULTS: The two groups were similar in age, gender, education, and corticosteroid dose. The phenytoin-treated group showed significantly smaller increases on the ACT, a mania self-report scale, than the placebo-treated group. Groups did not differ significantly on RAVLT change scores. CONCLUSIONS: This is the first placebo-controlled study to examine whether a medication can prevent mood and memory changes secondary to corticosteroids. Phenytoin blocked the hypomanic effects of prescription corticosteroids; however, phenytoin did not block the declarative memory effects of corticosteroids.

Clinical and morphologic features of acute, subacute and chronic cor pulmonale (pulmonary heart disease).

Described are certain clinical and morphologic features of one patient with acute, another with subacute, and one with chronic cor pulmonale. All 3 had evidence of severe pulmonary hypertension. The patient with acute cor pulmonale 4 days after coronary bypass for unstable angina pectoris suddenly developed severe breathlessness with cyanosis and had fatal cardiac arrest and necropsy disclosed massive pulmonary embolism. The patient with subacute cor pulmonale had severe right-sided heart failure for 5 weeks and necropsy disclosed microscopic-sized neoplastic pulmonary emboli from a gastric carcinoma without parenchymal pulmonary metastases. The patient with chronic cor pulmonale had evidence of right-sided heart failure for years, the result of primary or idiopathic pulmonary hypertension almost certainly present from birth because the pattern of elastic fibers in the pulmonary trunk was that seen in newborns where the pressure in the pulmonary trunk and ascending aorta are similar. The patient with chronic cor pulmonale had plexiform pulmonary lesions indicative of irreversible pulmonary hypertension. Neither the acute nor the subacute patient had chronic pulmonary vascular changes. All 3 patients had dilated right ventricular cavities and non-dilated left ventricular cavities and only the patient with chronic cor pulmonale had right ventricular hypertrophy.

Bilateral diaphragmatic paralysis associated with the use of the tumor necrosis factor-alpha inhibitor adalimumab.

A 51-year-old woman was referred for evaluation of progressive dyspnea of 3 months- duration. She had received 3 doses of adalimumab for treatment of rheumatoid arthritis prior to the onset of her dyspnea. Her chest examination revealed absent diaphragmatic movement with inspiration. Spirometry showed a severe restrictive defect. Radiologic studies confirmed the diagnosis of bilateral diaphragmatic paralysis. Laboratory and radiologic workup excluded other possible causes of the diagnosis. Adalimumab was discontinued, and she was treated with bilevel positive airway pressure ventilation and intravenous immunoglobulin. Three months later, the diaphragmatic paralysis persisted. This is the second reported case of bilateral diaphragmatic paralysis occurring in a patient who had received adalimumab. Acute neuropathies are rare side effects of tumor necrosis factor-alpha inhibitors.

Cardiac restriction secondary to massive calcific deposits in the left ventricular cavity.

Described herein are clinical and necropsy findings in a 61-year-old woman with fatal left ventricular diastolic failure secondary to massive calcific deposits primarily within the left ventricular cavity. At age 3, an isthmic aortic coarctation was resected, and at age 44, a stenotic congenitally bicuspid aortic valve was replaced. The cause of the intracavitary calcific deposits remains unclear, but surgical resection of the deposits has been an effective form of therapy.

Chylopericardium following orthotopic lung transplantation.

Chylopericardium is an uncommon condition, reported to occur following routine cardiac surgery, orthotopic heart transplantation, cardiac trauma, intrathoracic tumors, or infection. It has not, to date, been reported following uncomplicated orthotopic lung transplantation. This article describes chylopericardium following bilateral orthotopic lung transplantation.

Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations.

BACKGROUND: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations. METHODS AND FINDINGS: We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively. CONCLUSIONS: A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a "telomeropathy" caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.

Use of the insulin pump in treat cystic fibrosis related diabetes.

OBJECTIVES: This study was conducted to determine efficacy and tolerability of the continued subcutaneous insulin infusion (CSII) via an insulin pump for treatment of Cystic Fibrosis Related Diabetes (CFRD). We also tested the hypothesis that CSII would improve body weight, blood sugar control, lean body mass, whole body protein turnover, hepatic glucose production (HGP). METHODS: We recruited 9 CF patients with established diabetes and placed them on insulin pump therapy for six months. Each subject kept daily blood sugar records before and during pump use. Prior to the pump placement and at the end of six months, each patient underwent the following measurements: 1) whole body protein turnover using the stable isotope [1-(13)C] leucine; 2) DEXA scan for measurement of lean body mass; 3) anthropometric measurements; 4) Hemoglobin A1c. Patient data was compared to baseline data and the mean change from baseline was analyzed. RESULTS: There was significant improvement in both fasting and post-prandial blood glucose levels, body weight, HbA1C, and lean mass. Protein catabolism as measured by leucine rate of appearance was significantly lower, as was hepatic glucose production. No patient developed hypoglycemia during the study. CONCLUSIONS: This study demonstrates that CSII is safe and effective for treatment of CFRD and that metabolic benefits are also present.