Gregory Tino

Prevalence and Economic Burden of Bronchiectasis

We employed a retrospective cohort design to estimate the prevalence and economic burden of bronchiectasis. Data were obtained from the health-care claims processing systems of more than 30 US health plans (with a combined total of 5.6 million covered lives) and spanned the period January 1, 1999, to December 31, 2001. Study subjects consisted of all persons who were aged ≥18 years in 2001 and had diagnoses of bronchiectasis between 1999 and 2001; those with diagnoses of cystic fibrosis were excluded. For purposes of comparison, a cohort of persons without diagnoses of bronchiectasis was randomly selected and matched on age, sex, geographic region, and comorbid conditions. Prevalence of bronchiectasis ranged from 4.2 per 100,000 persons aged 18–34 years to 271.8 per 100,000 among those aged ≥75 years. Prevalence was higher among women than men at all ages. Persons with bronchiectasis averaged 2.0 (95% confidence interval 1.7–2.3) additional days in hospital, 6.1 (6.0–6.1) additional outpatient encounters, and 27.2 (25.0–29.1) more days of antibiotic therapy than those without the disorder in 2001; average total medical-care expenditures were

Non–Cystic Fibrosis Bronchiectasis

5681 (

Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial

4862–

Adult Patients With Bronchiectasis: A First Look at the US Bronchiectasis Research Registry

6593) higher for bronchiectasis patients. Our findings suggest that over 110,000 persons in the United States may be receiving treatment for bronchiectasis, resulting in additional medical-care expenditures of

Fatal Hyperammonemia after Orthotopic Lung Transplantation

630 million annually.

Adult Bronchiectasis Patients: A First Look at the United States Bronchiectasis Research Registry.

There is renewed interest in non-cystic fibrosis bronchiectasis, which is a cause of significant morbidity in adults and can be diagnosed by high-resolution chest computed tomography scan. No longer mainly a complication after pulmonary infection with Mycobacterium tuberculosis, diverse disease processes and mechanisms have been demonstrated to result in the chronic cough, purulent sputum production, and airway dilation that characterize this disease. Improved understanding of the role of mucus stasis in causing bacterial colonization has led to increased emphasis on the use of therapies that enhance airway clearance. Inhalational antibiotics reduce the bacterial burden associated with a worse outcome. Low-dose, chronic macrolide therapy has been shown to decrease exacerbation frequency and airway inflammation. For the first time, a number of therapies for non-cystic fibrosis bronchiectasis are undergoing testing in clinical research trials designed specifically for this population. This concise clinical review focuses on the major etiologies, diagnostic testing, microbiology, and management of patients with adult non-cystic fibrosis bronchiectasis. Systematic evaluation identifies a specific cause in the majority of patients and may affect subsequent treatment. We outline current therapies and review the data that support their use.

Pulmonary exacerbation in adults with bronchiectasis : a consensus definition for clinical research

Rationale Bronchiectasis is characterised by excessive production of mucus and pulmonary exacerbations. Inhaled osmotic agents may enhance mucociliary clearance, but few long-term clinical trials have been conducted. Objectives To determine the impact of inhaled mannitol on exacerbation rates in patients with non-cystic fibrosis (CF) bronchiectasis. Secondary endpoints included time to first exacerbation, duration of exacerbations, antibiotic use for exacerbations and quality of life (QOL) (St Georges Respiratory Questionnaire, SGRQ). Methods Patients with non-CF bronchiectasis and a history of chronic excess production of sputum and ≥2 pulmonary exacerbations in the previous 12 months were randomised (1:1) to 52 weeks treatment with inhaled mannitol 400 mg or low-dose mannitol control twice a day. Patients were 18–85 years of age, baseline FEV1 ≥40% and ≤85% predicted and a baseline SGRQ score ≥30. Main results 461 patients (233 in the mannitol and 228 in the control arm) were treated. Baseline demographics were similar in the two arms. The exacerbation rate was not significantly reduced on mannitol (rate ratio 0.92, p=0.31). However, time to first exacerbation was increased on mannitol (HR 0.78, p=0.022). SGRQ score was improved on mannitol compared with low-dose mannitol control (−2.4 units, p=0.046). Adverse events were similar between groups. Conclusions Mannitol 400 mg inhaled twice daily for 12 months in patients with clinically significant bronchiectasis did not significantly reduce exacerbation rates. There were statistically significant improvements in time to first exacerbation and QOL. Mannitol therapy was safe and well tolerated. Trial registration number NCT00669331.

Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis

Objectives We sought to describe the characteristics of adult patients with bronchiectasis enrolled in the US Bronchiectasis Research Registry (BRR). Methods The BRR is a database of patients with non‐cystic‐fibrosis bronchiectasis (NCFB) enrolled at 13 sites in the United States. Baseline demographic, spirometric, imaging, microbiological, and therapeutic data were entered into a central Internet‐based database. Patients were subsequently analyzed by the presence of NTM. Results We enrolled 1,826 patients between 2008 and 2014. Patients were predominantly women (79%), white (89%), and never smokers (60%), with a mean age of 64 ± 14 years. Sixty‐three percent of the patients had a history of NTM disease or NTM isolated at baseline evaluation for entry into the BRR. Patients with NTM were older, predominantly women, and had bronchiectasis diagnosed at a later age than those without NTM. Gastroesophageal reflux disease (GERD) was more common in those with NTM, whereas asthma, primary immunodeficiency, and primary ciliary dyskinesia were more common in those without NTM. Fifty‐one percent of patients had spirometric evidence of airflow obstruction. Patients with NTM were more likely to have diffusely dilated airways and tree‐in‐bud abnormalities. Pseudomonas and Staphylococcus aureus isolates were cultured less commonly in patients with NTM. Bronchial hygiene measures were used more often in those with NTM, whereas antibiotics used for exacerbations, rotating oral antibiotics, steroid use, and inhaled bronchodilators were more commonly used in those without NTM. Conclusions Adult patients with bronchiectasis enrolled in the US BRR are described, with differences noted in demographic, radiographic, microbiological, and treatment variables based on stratification of the presence of NTM.

Giant Gastric Ulcers and Risk Factors for Gastroduodenal Mucosal Disease in Orthotopic Lung Transplant Patients

Hyperammonemia has been reported in association with a variety of disorders causing hepatic dysfunction: portosystemic encephalopathy (1), inborn errors of the urea cycle (2), the Reye syndrome (3), transient hyperammonemia of the newborn (4), Jamaican vomiting sickness (5), Udorn encephalopathy (6), valproic acid therapy (7), asparaginase therapy (8), and urinary tract infection from urea-splitting organisms (9). Idiopathic hyperammonemia has also been described in patients after bone marrow transplantation (10) and chemotherapy for leukemia (11). In a previous report, we described a case of fatal hyperammonemia occurring after orthotopic lung transplantation in a patient without evidence of significant biochemical hepatic dysfunction (12). In addition, we reported on hepatic glutamine synthetase enzyme deficiency in the livers of two patients with hyperammonemia after orthotopic lung transplantation (13). In the current study, we measured the incidence of post-orthotopic lung transplantation hyperammonemia; herein, we summarize and analyze its associated clinical features. Methods We collected clinical data from 145 patients who underwent orthotopic lung transplantation at the University of Pennsylvania Medical Center between November 1991 and November 1996. The first patient who had had orthotopic lung transplantation at our center died of hyperammonemia. Subsequently, 142 of 144 patients routinely had plasma ammonium levels measured at the time of transplantation and if their mental status changed. Hyperammonemia was diagnosed if the plasma ammonium level was greater than twice the normal level (9 to 33 mol/L) and had exceeded 200 mol/L on at least one occasiona standard definition in common practice (10). The standard immunosuppressive regimen was intravenous methylprednisolone (a 500-mg to 1000-mg bolus given intraoperatively, followed by 0.5 mg/kg of body weight per day), azathioprine (2 mg/kg per day) and cyclosporine (titrated to therapeutic trough levels between 250 and 350 g/L through high-performance liquid chromatography). Antilymphocyte -globulin was administered (5 to 10 mg/kg per day) for 3 to 7 days. Acute rejection was diagnosed according to standard clinical and histologic criteria (14) and was treated with a 3-day regimen of high-dose intravenous methylprednisolone (15 mg/kg per day). Major gastrointestinal complications were defined as diseases of the gastrointestinal tract requiring surgical intervention or resulting in hemodynamic changes. Total parenteral nutrition was composed of 10% Travesol amino acids (Travesol Laboratories, Inc., Deerfield, Illinois), 10% glucose, and 20% Intralipid (Cutter Laboratories, Inc., Berkeley, California). To treat hyperammonemia, patients received sodium benzoate, sodium phenylacetate, or both, with a loading dose of 250 mg/kg intravenously followed by 250 mg/kg per day intravenously. The dosage of intravenous arginine hydrochloride was 210 mg/kg per day. Comparisons of data between the patients with hyperammonemia and the remaining patients who had had orthotopic lung transplantation were performed by using the Student t-test or Fisher exact test when appropriate (15). The study was approved by the University of Pennsylvanias institutional review board. Results Incidence Hyperammonemia was identified in 6 of the 145 (4.1%) patients who had had orthotopic lung transplantation at the University of Pennsylvania Medical Center between November 1991 and November 1996. The median number of ammonium levels checked in these patients was three. Most patients had multiple measurements. Transplantation Characteristics of Patients with Hyperammonemia None of the 145 patients had significant liver-associated laboratory abnormalities before transplantation (aminotransferase levels<2 times the upper limit of normal) or a history of inborn errors of metabolism. Patient 6 had the Ellis van Creveld syndrome, which is not known to be associated with hyperammonemia. The Table shows the peritransplantation clinical variables of patients with and those without hyperammonemia. Development of major gastrointestinal complications, use of total parenteral nutrition, and lung transplantation for primary pulmonary hypertension were associated with hyperammonemia. Table. Comparison of Peritransplantation Clinical Features of Patients with and Those without Hyperammonemia Presentation Hyperammonemia occurred between postoperative day 5 and day 26 (mean SD, 15.2 8.8 days). All patients with hyperammonemia had symptoms of metabolic encephalopathy, lethargy (n=4), agitation (n=2), seizure (n=3), or tremor (n=1); they eventually became unresponsive and comatose. Evidence of cerebral edema was identified in all patients by intracranial pressure monitoring or computed tomography of the head. Patients 2 and 3 developed peritonitis secondary to colonic perforation 48 and 72 hours before the onset of hyperammonemia, respectively. This complication required emergency laparotomy in both cases. Patient 3 also had a candidal lung abscess in the left lower lobe 5 days before onset of encephalopathy. Patients 1 and 4 developed acute graft rejection and received pulse methylprednisolone 24 to 48 hours before the onset of hyperammonemia. In patient 4, hemodynamically significant upper gastrointestinal bleeding occurred 1 day before a sharp increase in the plasma ammonium level. Primary graft dysfunction preceded the onset of neurologic symptoms in patient 5. Patient 6 developed sepsis 1 day before the diagnosis of hyperammonemia. Laboratory Studies The postoperative daily maximum ammonium levels for all patients with hyperammonemia are shown in the Figure. These patients had only mildly abnormal results on liver-associated laboratory tests, if any, at the onset of hyperammonemia (aminotransferase levels<4 times the upper limit of normal). As described previously, levels of urinary orotic acid and plasma amino acids in patients 1 and 2 showed no abnormalities that would suggest congenital urea-cycle enzyme defects, whereas the hepatic glutamine synthetase levels were deficient (14). Figure. Maximum daily plasma ammonium levels, total parenteral nutrition use, concurrent medical stressors, and plasma ammonium - decreasing therapies in patients with hyperammonemia. Treatment Upon detection of hyperammonemia, total parenteral nutrition was withheld from all patients except patient 3. Patient 5 died within several hours of hyperammonemia detection and therefore received no therapy to reduce the plasma ammonium level; all other patients with hyperammonemia received lactulose, neomycin, or both. The varied use of dialysis and plasma ammonia-trapping in the patients with hyperammonemia is illustrated in the Figure. Outcome The mortality rate among the patients with hyperammonemia was clearly higher than that among patients without hyperammonemia (Table). Four of the six patients with hyperammonemia died during the initial episode of hyperammonemia, 0 to 7 days after diagnosis (mean, 3.3 2.5 days), on postoperative days 4 through 29 (mean, 17.5 11.3 days). Patient 2 survived the initial episode on postoperative day 9, with normalization of plasma ammonium level and mental status, but died 3 days after the onset of the second episode on postoperative day 34. The plasma ammonium level in patient 6 returned to normal by day 4 of therapy. She regained consciousness by day 10 of therapy and subsequently had near complete recovery of baseline physical and mental function. Autopsy Findings Family consent permitted autopsies on three of the five patients who died of hyperammonemia. Patients 2 and 3 had mild cholestasis, severe microvesicular steatosis, small bowel ischemia, and colonic perforations. Patient 1 had lipofuscin deposits in pericentral hepatocytes. Discussion We describe severe hyperammonemia in a cohort of patients who had undergone orthotopic lung transplantation. The presentation of hyperammonemia in these patients was invariably fulminant, with associated cerebral edema; most patients died. Risk factors for hyperammonemia are unknown; however, the development of hyperammonemia in these patients appears to be multifactorial. All patients with hyperammonemia had received immunosuppressive agents and total parenteral nutrition. In addition, the occurrence of hyperammonemia was uniformly preceded by at least one major medical stressor, especially major gastrointestinal complications. However, under similar conditions, not every patient who had had orthotopic lung transplantation developed hyperammonemia. Therefore, these factors may be necessary but not sufficient for the development of hyperammonemia. Hepatic glutamine synthetase deficiency may play a role in the pathogenesis of hyperammonemia under these conditions, as we have demonstrated in two of the patients. Finally, further studies are necessary to determine the significance of a statistical association between lung transplantation for primary pulmonary hypertension and the occurrence of hyperammonemia. Although the exact relation between these medical stressors and hyperammonemia is not clear, all patients with hyperammonemia developed critically increased intracranial pressure and other severe neurologic symptoms, such as status epilepticus, which are clearly the main cause of the high mortality rate. In our previous report on two patients with hyperammonemia who underwent liver biopsies before their deaths, we demonstrated a significantly reduced hepatic glutamine synthetase activity (13). It is unclear whether this activity is an acquired deficiency or a carrier state with an acquired component. Hepatic glutamine synthetase activity may be the crucial factor in the development of hyperammonemia in patients who have had orthotopic lung transplantation and may account for the variability in the development of hyperammonemia among patients after transplantation under similar stressors. However, measurement of hepatic glutamine synthetase activ

Lepidic intrapulmonary growth of malignant mesothelioma presenting as recurrent hydropneumothorax

Objectives We sought to describe the characteristics of adult patients with bronchiectasis enrolled in the US Bronchiectasis Research Registry (BRR). Methods The BRR is a database of patients with non‐cystic‐fibrosis bronchiectasis (NCFB) enrolled at 13 sites in the United States. Baseline demographic, spirometric, imaging, microbiological, and therapeutic data were entered into a central Internet‐based database. Patients were subsequently analyzed by the presence of NTM. Results We enrolled 1,826 patients between 2008 and 2014. Patients were predominantly women (79%), white (89%), and never smokers (60%), with a mean age of 64 ± 14 years. Sixty‐three percent of the patients had a history of NTM disease or NTM isolated at baseline evaluation for entry into the BRR. Patients with NTM were older, predominantly women, and had bronchiectasis diagnosed at a later age than those without NTM. Gastroesophageal reflux disease (GERD) was more common in those with NTM, whereas asthma, primary immunodeficiency, and primary ciliary dyskinesia were more common in those without NTM. Fifty‐one percent of patients had spirometric evidence of airflow obstruction. Patients with NTM were more likely to have diffusely dilated airways and tree‐in‐bud abnormalities. Pseudomonas and Staphylococcus aureus isolates were cultured less commonly in patients with NTM. Bronchial hygiene measures were used more often in those with NTM, whereas antibiotics used for exacerbations, rotating oral antibiotics, steroid use, and inhaled bronchodilators were more commonly used in those without NTM. Conclusions Adult patients with bronchiectasis enrolled in the US BRR are described, with differences noted in demographic, radiographic, microbiological, and treatment variables based on stratification of the presence of NTM.