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Am J Respir Crit Care Med

Elemental content of airway surface liquid from infants with cystic fibrosis.

Hull J. Skinner W. Robertson C. Phelan P.
Department of Thoracic Medicine, Royal Children's Hospital, Parkville, Melbourne, Australia.
We tested the hypothesis that airway surface liquid (ASL) electrolyte composition is altered in infants with cystic fibrosis (CF) and that the presence of airway inflammation affects ASL composition. We measured the tracheal ASL sodium and chloride concentration and examined bronchoalveolar lavage (BAL) fluid cytology, interleukin-8 (IL-8) concentrations, and quantitative bacterial culture in 19 infants and young children with CF. Seven infants undergoing bronchoscopy for the evaluation of stridor served as non-CF controls. In addition, we measured nasal ASL sodium and chloride concentrations from 10 young adults with CF and from 10 control subjects. On the basis of the BAL findings, the infants with CF were divided into three groups: one with little evidence of pulmonary inflammation (CF-NI, n = 5); one with obvious pulmonary inflammation (CF-I, n = 7); and an intermediate group (CF-MI, n = 7). We found the ASL sodium was not different among any of the four groups (means mM +/- SE, 85 +/- 10 controls; 78 +/- 16 CF-NI; 83 +/- 9 CF-MI, 84 +/- 9 CF-I). In contrast the ASL chloride was lower in the CF-NI group when compared with control subjects (108 +/- 5 control subjects; 77 +/- 7 CF-NI, p < 0.01). In the CF-I and CF-MI groups, the ASL chloride concentrations were of intermediate values (CF-I 95 +/- 10 mM; CF-MI 96 +/- 9 mM) and not significantly different from controls. Results from the nasal ASL analysis showed no significant differences in sodium and chloride concentrations in the CF group compared with control subjects. These results suggest that the primary abnormality of ASL composition is a reduction in chloride concentration. ASL composition appears to be affected by the presence of airway inflammation.

Small airways function in patients with inflammatory bowel disease.

Tzanakis N. Samiou M. Bouros D. Mouzas J. Kouroumalis E. Siafakas NM.
Department of Thoracic Medicine, Medical School University of Crete, Greece. tzanak@cc.uch.gr
It has been reported that in patients with inflammatory bowel disease (IBD), the airways are involved, and a number of clinical manifestations have been described. The aim of this study was to investigate the function of the small airways in IBD. Thirty patients with IBD (mean age, 47 yr), 12 with Crohn's disease and 18 with ulcerative colitis, were studied and compared with a control group of 16 normal subjects. Maximal expiratory flow-volume curves were performed breathing room air and a mixture of 80% helium, 20% oxygen. The differences of flows at 50% of FVC (delta Vmax50) and the volume of equal flows (Visov) were calculated as indices of small airways function. In addition, spirometry, lung volumes, and diffusing capacity were measured. Visov was statistically significantly greater in patients with either CD or UC than in control subjects (x +/- SD) (24.99 +/- 1.35 and 25.95 +/- 1.5 versus 20.1 +/- 1.39), (p < 0.01 and p < 0.001, respectively). A reduction in TL(CO) was noticed in the active stage of the disease in both groups of patients (p < 0.05). This may indicate that lung parenchyma is also involved in active IBD. Our results suggest that the function of the small airways and diffusion capacity of the lungs are affected in patients with IBD.

DNase I acutely increases cystic fibrosis sputum elastase activity and its potential to induce lung hemorrhage in mice.

Cantin AM.
Unite de Recherche Pulmonaire, Centre Universitaire de Sante de l'Estrie, Fluerimont, Quebec, Canada. a.cantin@courrier.usherb.ca
The potential of DNase I to increase cystic fibrosis sputum elastase activity and lung damage was evaluated. Sputum from CF patients induced little lung hemorrhage when instilled intranasally in C57BL/6 mice. However, sputum treated in vitro by the addition of 1 mg/ml bovine DNase I showed increased neutrophil elastase activity (7.97 +/- 1.56 versus 3.91 +/- 0.62 microM, p < 0.01) and induced marked lung hemorrhage in mice (bronchoalveolar lavage fluid hemoglobin = 192.8 +/- 40.7 versus 44.5 +/- 12.0 microg/ml, p < 0.01). These effects were not observed with DNase I alone in phosphate buffer and were suppressed by the human neutrophil elastase inhibitor methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone (MeOSAAPV-CMK). In vivo administration of 2.5 mg aerosolized recombinant human DNase I to patients with CF resulted in a 2.2-fold increase of sputum elastase activity within 1 h of treatment. Elastase levels returned to pre-rhDNase therapy levels 24 h after aerosol treatment. Sputum collected 1 h after rhDNase on 4 separate days from two of six patients in which elastase levels were highest, induced lung hemorrhage when instilled intranasally in mice. We conclude that DNase I therapy of patients with cystic fibrosis can acutely increase the elastase activity of sputum and also its potential to induce hemorrhage in the murine lung.

A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function.

Rubenstein RC. Zeitlin PL.
Eudowood Division of Pediatric Respiratory Sciences, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. rrubenst@welchlink.welch.jhu.edu
Sodium 4-phenylbutyrate (Buphenyl, 4PBA) is a new FDA approved drug for management of urea cycle disorders. We have previously presented data suggesting that 4PBA, at clinically achievable concentrations, induces CFTR channel function on the plasma membrane of deltaF508-expressing cystic fibrosis (CF) airway epithelial cells in vitro (Rubenstein, R. C., and P. L. Zeitlin, 1997. J. Clin. Invest. 100:2457-2463). We hypothesized that 4PBA would induce epithelial CFTR function in vivo in individuals homozygous for deltaF508-CFTR. A randomized, double-blind, placebo-controlled trial in 18 deltaF508-homozygous patients with CF was performed with the maximum approved adult dose of 4PBA, 19 grams p.o. divided t.i.d., given for 1 wk. Nasal potential difference (NPD) response patterns and sweat chloride concentrations were determined before and after study drug treatment, and 4PBA and metabolites were assayed in plasma and urine at the end of study drug treatment. Subjects in the 4PBA group demonstrated small, but statistically significant improvements of the NPD response to perfusion of an isoproterenol/amiloride/chloride-free solution; this measure reflects epithelial CFTR function and is highly discriminatory between patients with and without CF. Subjects who had received 4PBA did not demonstrate significantly reduced sweat chloride concentrations or alterations in the amiloride-sensitive NPD. Side effects due to drug therapy were minimal and comparable in the two groups. These data are consistent with 4PBA therapy inducing CFTR function in the nasal epithelia of deltaF508-homozygous CF patients.

Improved clearability of cystic fibrosis sputum with dextran treatment in vitro.

Year 1998
Feng W. Garrett H. Speert DP. King M.
Pulmonary Research Group, University of Alberta, Edmonton, Canada.
Most patients with cystic fibrosis (CF) are infected by Pseudomonas aeruginosa. Dextran exhibits anti-adhesive effects in preventing attachment of P. aeruginosa to epithelial cells (1). The initial purpose of this study was to evaluate the potential of dextran to alter the rheology and ciliary transportability of CF sputum prior to initiation of a clinical trial in patients with CF. Sputum samples were collected from 25 patients with CF not receiving rhDNase therapy for use in in vitro testing. Aliquots of CF sputum were treated with 10% vol. Ringer's or the same volume of Dextran 4000 to give a final concentration of 0.4% (4 mg/ml) or 4% (40 mg/ml) dextran in the sputum. Dog mucus samples were collected from seven healthy, anesthetized dogs from the endotracheal tube cuff. Aliquots of dog mucus were subjected to the same concentrations of dextran as the CF sputum. All treated samples were incubated for 30 min at 37 degrees C, and their rheologic properties (viscoelasticity) were evaluated by magnetic microrheometry. For 17 of the sputum samples, frog palate mucociliary transportability was determined from sputum movement on the ciliated, mucus-depleted frog palate, relative to native frog mucus control. Spinnability (cohesiveness) was evaluated by the filancemeter technique for eight sputum samples. Overall, whether for CF sputum or healthy dog mucus, Dextran 4000 treatment significantly reduced viscoelasticity and increased predicted mucociliary and cough clearability. Direct measurements of sputum mucociliary clearability on frog palate increased significantly with 0.4% dextran and 4% dextran compared with saline control. Sputum spinnability (cohesiveness) decreased significantly with both dextran concentrations, too. The effects on viscoelasticity and spinnability were greater at 4% than at 0.4%. There was a significant positive correlation between spinnability and viscoelasticity, and negative relationships between spinnability and both forms of clearability as predicted from viscoelastic measurements. This study suggests that treatment with Dextran 4000 can reduce the crosslink density and cohesiveness of CF and improve mucociliary and cough clearability. Dextran 4000 is an inexpensive and nontoxic agent that may be of benefit in patients with CF lung disease and perhaps in other respiratory disease where mucus retention is an important feature.

Neutrophil adhesion molecule surface expression and responsiveness in cystic fibrosis.

Year 1998
Russell KJ. McRedmond J. Mukherji N. Costello C. Keatings V. Linnane S. Henry M. Fitzgerald MX. O'Connor CM.
Department of Medicine and Therapeutics, University College Dublin, Belfield, Ireland.
The neutrophil-dominated inflammation of the lung in cystic fibrosis (CF) has traditionally been seen as a physiological response to continuous opportunistic infection. Recent studies suggest, however, that regulation of the inflammatory response itself may be altered in CF. Neutrophil migration from the bloodstream involves alterations in surface expression of the adhesion molecules L-selectin and Mac-1 (CD11b/CD18). The aim of this study was to assess neutrophil adhesion molecule expression and responsiveness in CF. Neutrophils from chronic (n = 16) and acutely infected (n = 13) CF patients and 15 normal control subjects were directly assessed by Fluorescence-activated cell sorter (FACS) analysis for surface expression of L-selectin and CD11b before and after stimulation with interleukin 8 (IL-8) or f-Met-Leu-Phe (fMLP). Neutrophils from stable (n = 5) and acutely infected (n = 5) non-CF bronchiectasis patients were also assessed. Surface upregulation of CD11b was similar in all groups. Basal levels of L-selectin were also comparable among all groups, however, when stimulated, neutrophils from both stable and acutely infected CF patients shed significantly less L-selectin than those from control subjects (p < 0.05 and p < 0.01, respectively). This decreased responsiveness was not observed in either stable or acutely infected non-CF bronchiectasis patients. These results add to the accumulating evidence suggestive of a defective inflammatory response in CF.

Lung growth and maturation after tracheal occlusion in diaphragmatic hernia.

Year 1998
Benachi A. Chailley-Heu B. Delezoide AL. Dommergues M. Brunelle F. Dumez Y. Bourbon JR.
Unite de Medecine Foetale, Hopital Port-Royal-Baudelocque, Paris, France.
Tracheal occlusion (TO) was performed at 120 d of gestation by noninvasive endoscopic technique using a releasable latex balloon, in fetal lambs with diaphragmatic hernia (DH) established at 85 d. The lungs were studied at 139 d in five fetuses with DH + TO, five fetuses with DH only, and six control fetuses. Fluid retention consecutive to TO allowed fetal lungs to grow. Histological pulmonary structure was more mature in DH + TO than in DH alone. The growth-inducing effect of TO was however incomplete, with an increased protein/DNA ratio. Tissue phospholipids were increased, but this was not reflected in the surfactant compartment. The major surfactant component, disaturated phosphatidylcholine, was reduced to 58% of its control value in DH, and further reduced to 17.5% of its control value in DH + TO. The proportion of surfactant protein B immunoreactive cells, assumed to represent the proportion of type II cells, was increased in DH (27% of all parenchymal cells), and reduced in DH + TO (7.8%) as compared with control fetuses (15%). In conclusion, although noninvasive tracheal occlusion in utero is feasible and may partly compensate the adverse effects of DH on lung organogenesis, it reduces the number of type II cells and induces a dramatic surfactant deficit. Using this technique in human fetuses requires careful consideration until further evaluation of lung functional characteristics has been achieved in this experimental model.

Haemophilus influenzae in lung explants of patients with end-stage pulmonary disease.

Year 1998
Moller LV. Timens W. van der Bij W. Kooi K. de Wever B. Dankert J. van Alphen L.
Department of Medical Microbiology, University of Amsterdam, Academic Medical Center, The Netherlands.
In order to determine the presence and distribution of Haemophilus influenzae in lung tissue sections, we obtained lung explants from 49 lung transplant recipients with cystic fibrosis (CF) (n = 16), chronic obstructive pulmonary disease (COPD) including emphysema (n = 16), bronchiectasis (n = 5), pulmonary hypertension (n = 9), Langerhans cell histiocytosis (n = 1), and idiopathic pulmonary fibrosis (n = 2). Analysis was done by selective culturing, immunoperoxidase (IP) staining, and by polymerase chain reaction (PCR). H. influenzae was cultured from specimens of the lung explants from one CF and one COPD patient. IP staining of tissue sections was positive in 24 patients (10 CF patients, eight COPD patients, two bronchiectasis patients, and four patients with noninfectious pulmonary diseases). IP-positive tissue sections were PCR-positive, and IP-negative sections were PCR-negative. H. influenzae was more frequently detected in tissue sections of lung explants from CF and COPD patients than from patients with bronchiectasis or noninfectious pulmonary diseases. H. influenzae was diffusely present in the epithelium, the submucosa of the bronchi, the bronchioles, the interstitium, and the alveolar epithelium. H. influenzae was localized extracellularly alone and in bacterial clusters, and was also associated with macrophages in CF patients. The results of this study demonstrate that H. influenzae is often present in the lungs of patients with end-stage pulmonary disease, especially CF and COPD patients. H. influenzae is diffusely present in the respiratory epithelium and subepithelial layers of the lungs of these patients.

The effects of acid perfusion of the esophagus on ventilation and respiratory sensation.

Year 1998
Field SK. Evans JA. Price LM.
Department of Medicine, Foothills Hospital and University of Calgary, Alberta, Canada.
The relationship between gastroesophageal reflux (GER) and asthma remains controversial. Asthma symptoms worsen with GER, but are not consistently related to changes in lung function. The purpose of this study was to determine whether acid perfusion (AP) of the esophagus alters ventilation and causes respiratory symptoms. Nonasthmatic patients with normal lung function and esophageal disease (16 females and nine males, FEV1 %predicted = 99+/-9.6), underwent a Bernstein test after motility testing. Airflow, rib cage (Vrc), and abdominal (Vab) tidal volumes, esophageal (Pes) and gastric (Pga) pressure, and surface (Es) and esophageal (Edi) diaphragm electromyographic (EMG) signals were measured. Throat, swallowing, chest, and stomach discomfort and respiratory sensation were estimated with the Borg scale. Minute ventilation (VE) increased during AP and declined during recovery with saline perfusion of the esophagus (7.1+/-1.5 to 8.5+/-2.4 to 7.3+/-2.1 L/min; n = 25; p = 0.0002). Respiratory rate (RR) went from 13.6+/-2.6 to 15.8+/-3.4 to 15.3+/-3.1 breaths/min (n = 25; p = 0.0002) during AP. VE was greater in the Bernstein-positive patients during AP. Tidal volume (VT), Vrc, Vab, Pes, Pga, Es, and Edi did not change during AP. Chest discomfort (D) correlated with ventilation (VE = 0.7 + 0.8 D; r = 0.67; p < 0.001) and respiratory effort sensation (B) (B = 0.2 + 0.4 VE; r = 0.70; p < 0.001) during AP. AP did not inhibit diaphragm activity. Increased VE may explain the paradox of GER worsening respiratory symptoms without changing lung function.

Determinants of aerobic and anaerobic exercise performance in cystic fibrosis.

Year 1998
Shah AR. Gozal D. Keens TG.
Division of Pediatric Pulmonology, Childrens Hospital Los Angeles, California 90027, USA.
We examined aerobic and anaerobic exercise performance in 17 subjects with cystic fibrosis (CF) (age 25+/-10 [SD] yr; 47% females; FEV1 62+/-21% pred) and 17 age- and sex-matched control subjects (age 25+/-8 [SD] yr; 41% females; FEV1 112+/-15% pred) in relation to pulmonary function and nutritional status. Aerobic capacity was determined as maximal oxygen consumption (VO2max) (ml/kg/min) and anaerobic threshold (AT; ml VO2/kg/min) from a graded exercise stress test on an electronically braked bicycle ergometer. Anaerobic performance was assessed from the average work of two bouts of pedaling to exhaustion at a load corresponding to 130% Vo2max from graded exercise. Both aerobic and anaerobic performances were decreased in subjects with CF (p < 0.001). The duration of anaerobic exercise in subjects with CF was similar to control subjects. In control subjects, pulmonary function did not correlate to aerobic or anaerobic exercise. In subjects with CF significant relationships between FEV1, vital capacity, and FEF25-75% to AT were found, suggesting the pulmonary limitation to aerobic capacity. In both patients with CF and control subjects, lean body mass and arm muscle area significantly correlated with anaerobic performance but not with VO2max or AT. We conclude that nutritional status, rather than pulmonary function, is the major determinant of anaerobic exercise capacity in CF. The preserved duration of anaerobic exercise at equivalent workloads (corresponding to 130% of VO2max from graded exercise) suggests that readily available energy stores in muscle may be similar in CF and normal individuals.

Circulating adhesion molecules in cystic fibrosis.

Year 1998
De Rose V. Oliva A. Messore B. Grosso B. Mollar C. Pozzi E.
Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
A marked influx of inflammatory cells occurs into the airways of patients with cystic fibrosis (CF), which may contribute to the development of lung injury. Leukocyte-endothelial adhesion molecules play a crucial role in the recruitment of inflammatory cells, and soluble forms of these molecules have been shown to increase in several inflammatory diseases. By using a capture ELISA, we determined serum levels of soluble ICAM-1 (sICAM-1), E-selectin (sE-selectin), and VCAM-1 (sVCAM-1) in patients with CF, in stable clinical conditions (n = 29, mean age: 25.8+/-1.5 yr), and healthy control subjects (n = 12, mean age: 27.6+/-1.5 yr). Clinical, spirometric, microbiological, and hematological assessments were made in all subjects. sICAM-1 and sE-selectin concentrations, but not sVCAM-1 levels were significantly increased in CF patients as compared with normal subjects (both p < 0.001). sICAM-1 levels were inversely related to FEV1 values (r = -0.519, p = 0.004) and Schwachman score (r = -0.405, p = 0.03) in CF patients. In 7 of 29 CF patients, soluble adhesion molecule levels were determined not only at the time of stable clinical conditions, but also before and after antibiotic treatment for a pulmonary exacerbation. sICAM-1 and sE-selectin levels increased in all patients at the time of the exacerbation, compared with levels at the time of stable conditions (p < 0.02 for both comparisons); antibiotic treatment induced a significant decrease of both circulating adhesion molecules (p < 0.02). The elevated serum levels of sICAM-1 and sE-selectin in CF patients, even when they are clinically stable, may reflect the marked and persistent inflammatory process in the disease.

Circulating immunoreactive interleukin-6 in cystic fibrosis.

Year 1998
Nixon LS. Yung B. Bell SC. Elborn JS. Shale DJ.
Section of Respiratory Medicine, University of Wales College of Medicine, Academic Centre, Llandough Hospital NHS Trust, Penarth, South Glamorgan, United Kingdom.
We measured circulating and sputum-sol concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), neutrophil elastase-alpha1-antiproteinase complex (NEAPC), and C-reactive protein (CRP) in an exacerbation, after antibiotic treatment, and in clinically stable patients with cystic fibrosis and chronic pulmonary infection with Pseudomonas aeruginosa. The aim was to determine the compartmental patterns of a proinflammatory and anti-inflammatory cytokine compared with other markers of inflammatory activity in cystic fibrosis. IL-6, NEAPC, CRP, and absolute neutrophil count were reduced after antibiotic treatment, p < 0.01. IL-6 and CRP concentrations were greater, p = 0.007, and p = 0.01, respectively, in a stable group of patients compared with those at the end of an exacerbation. IL-6 and CRP concentrations were related (r = 0.836, p < 0.0001), and both were greater than in matched control subjects (p < 0.001) at all times studied. Sputum-sol concentrations of IL-6 after treatment were positively related to FEV1 and FVC and inversely related to concentrations of neutrophil elastase. The separation between patients and healthy subjects, and the reduction of IL-6 after antibiotic treatment indicates it could be used as a marker of inflammation, but its relationship to other markers depends on the compartment in which it is measured.

Improvement of cystic fibrosis airway mucus transportability by recombinant human DNase is related to changes in phospholipid profile.

Year 1998
Zahm JM. Galabert C. Chaffin A. Chazalette JP. Grosskopf C. Puchelle E.
INSERM U314, IFR53, Reims; Hopital Renee Sabran, Giens; and Laboratoire Roche, Neuilly, France.
The aim of this study was to test whether changes in mucus surface properties by rhDNase treatment could be related to an increased recovery of phospholipids. Purulent sputa from 18 patients with cystic fibrosis (CF) were incubated with either rhDNase (4 microg/ml) or control excipient. The incubation of mucus samples with rhDNase induced a significant increase (p < 0.002) in the sol phase proportion (33.7 +/- 24.0%) compared with that obtained with excipient (12.6 +/- 12.4%). Phospholipids were recovered in significantly (p < 0.05) greater amounts from both mucus gel and sol phases after incubation with rhDNase. The phosphatidylglycerol content of mucus sol phase was significantly increased by rhDNase (p < 0.03), as well as the mucus gel phase surface properties and transport by ciliary activity and by cough (p < 0.05). The improvement of mucus gel surface properties and transport capacity by ciliary activity were significantly related to the increased recovery of phosphatidylglycerol (r = -0.74, p < 0.03 and r = 0.94, p < 0.05, respectively). These results suggest that rhDNase is able to increase the free water content and alter the phospholipid profile of mucus, with a related improvement in CF mucus transportability.

Effects of topically delivered benzamil and amiloride on nasal potential difference in cystic fibrosis.

Year 1998
Hofmann T. Stutts MJ. Ziersch A. Ruckes C. Weber WM. Knowles MR. Lindemann H. Boucher RC.
Cystic Fibrosis Working Group and Selbst. Funktionsbereich Allergologie und Pneumologie der Justus Liebig Universitats-Kinderklinik, Giessen, Germany.
The raised nasal transepithelial potential difference (PD) in cystic fibrosis (CF) reflects accelerated active transport of Na+, and is inhibited by topical administration of the Na+ channel blocker, amiloride. The aim of this study was to investigate the dose-effect and time course of topically administered Na+ conductance inhibitors to inhibit nasal PD, including benzamil, an analog of amiloride. We measured the magnitude of drug inhibition of Na+ transport [percent inhibition of baseline PD (DeltaPD%)] and duration of inhibition of PD, defined as the time when drug inhibition of PD had recovered by 50% (effective time = ET50). Amiloride [10(-)3 M (n = 16), 3 x 10(-)3 M (n = 9), 6 x 10(-)3 M (n = 7), 10(-)2 M (n = 3)] or benzamil [1.7 x 10(-)3 M (n = 7), and 7 x 10(-)3 M (n = 5)] were administered to the nasal surface via an aerosol generated by a jet nebulizer and a nasal mask. The concentration-dependent magnitude (DeltaPD%) of inhibition was similar for amiloride and benzamil ( approximately 67- 77%), whereas the duration of inhibition (ET50) was about two-and-a-half times longer after benzamil administration as compared with equivalent concentrations of amiloride [1.6 +/- 0. 06 versus 4.5 +/- 0.6 h (ET50 +/- SEM), at 6-7 x 10(-)3 M]. In vitro studies of cultured normal nasal epithelia demonstrated directly that benzamil induced an approximately 2-fold more prolonged inhibition of active Na+ transport than amiloride. These data suggest aerosolized benzamil is a candidate long-duration Na+ channel blocker for CF.

Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus.

Year 1998
Ungo JR. Jones D. Ashkin D. Hollender ES. Bernstein D. Albanese AP. Pitchenik AE.
The University of Miami School of Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Division of Gastroenterology, Department of Internal Medicine, Miami, FL USA.
Until recently it was thought that age greater than 35 yr was the main risk factor for the development of drug-induced hepatitis (DIH) in patients receiving antituberculosis therapy. We conducted a study to determine whether infection with either the hepatitis C virus or the human immunodeficiency virus (HIV) were significant risk factors for the development of DIH in patients receiving antituberculosis therapy. Our study consisted of two parts. In the first part, 134 consecutive patients admitted for the treatment of tuberculosis (TB) were followed for the development of DIH. All of these patients were also screened for the presence of hepatitis C and HIV. In the second part of the study, those patients who were hepatitis C positive and who developed DIH on repeated reintroduction of the anti-TB drugs were offered a liver biopsy. If active inflammation, which may be suggestive of hepatitis C infection, was present on the biopsy specimen, treatment with alpha-interferon was begun and the anti-TB drugs were subsequently reintroduced. During the 18 mo of the study, 22 patients developed DIH. The relative risk of developing DIH if the patient was hepatitis C or HIV positive was fivefold and fourfold, respectively (p < 0.05). If a patient was coinfected with both hepatitis C and HIV the relative risk of developing DIH was increased 14.4-fold (p < 0.002). In the treatment part, four patients were treated with alpha-interferon, and all were able to undergo the reintroduction of anti-TB therapy without reoccurrence of DIH. Infection with hepatitis C and HIV are independent and additive risk factors for the development of DIH during TB therapy. The treatment of hepatitis C with alpha-interferon may allow the reintroduction of anti-TB agents in those who previously developed DIH when exposed to these drugs.

Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease.

Year 1998
Donovan DS Jr. Papadopoulos A. Staron RB. Addesso V. Schulman L. McGregor C. Cosman F. Lindsay RL. Shane E.
Departments of Medicine and Radiology, College of Physicians and Surgeons, Columbia University, New York, USA.
Osteoporosis and fractures are increasingly recognized in children and adults with cystic fibrosis. To investigate the prevalence and pathogenesis of osteoporosis and low bone mass in adults with advanced pulmonary disease due to cystic fibrosis, we examined the relationships between bone mineral density (BMD), anthropomorphic variables, pulmonary status, glucocorticoid therapy, and vitamin D concentrations. BMD of the lumbar spine, hip, and proximal radius was measured by dual energy X-ray absorptiometry in 30 white adults (16 women), age 30 +/- 2 yr (mean +/- SEM). Compared with a normal control population, the patients had significantly reduced BMD at the lumbar spine (17 +/- 3%), total hip and femoral neck (24 +/- 3% and 20 +/- 4%, respectively). The radius was significantly less demineralized (4 +/- 2%; p -1.0) at the lumbar spine, 23% at the hip sites, and 39% at the radius. Age, weight, and body mass index (BMI) were most strongly correlated with bone mass, whereas glucocorticoid therapy and pulmonary function were not predictive. Despite oral vitamin D (400 to 800 IU daily), the mean serum 25-hydroxyvitamin D (25-OHD) concentration was at the low end of the normal range (16 +/- 2 ng/ml; normal 10 to 52 ng/ml); 8 of 20 patients (40%) had frankly low (

Bronchial artery embolization for the treatment of hemoptysis in patients with cystic fibrosis.

Year 1998
Brinson GM. Noone PG. Mauro MA. Knowles MR. Yankaskas JR. Sandhu JS. Jaques PF.
Division of Pulmonary and Critical Care Medicine and the UNC-CF Center, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Hemoptysis is common in patients with cystic fibrosis (CF). Bleeding may vary in severity, ranging from minor blood-streaking of sputum to expectoration of significant quantities of blood. Major hemoptysis, defined as bleeding greater than 240 ml/24 h, represents a medical emergency. Bronchial artery embolization (BAE) is one of the treatment options for hemoptysis. We reviewed the 10-yr experience at the University of North Carolina Hospitals in the treatment of hemoptysis by BAE. Eighteen patients with CF were hospitalized on 29 occasions and underwent 36 BAE procedures for the control of hemoptysis. Most patients (n = 11) had very severe lung disease (FEV1 < 35%) with a high incidence (n = 9, 50%) of multi-drug-resistant bacteria. Fifteen patients (n = 33 procedures) were followed for a mean of approximately 22 mo after BAE. The overall efficacy of BAE for initial control of hemoptysis was 75% (n = 22) after one session, 89% (n = 26) after two sessions, and 93% (n = 27) after three sessions. The overall recurrence rate per episode was 46% (12/26 presentations in four patients) with a mean time for recurrence of approximately 12 mo. There was a high incidence (75%) of bleeding from nonbronchial systemic collateral vessels among patients (n = 7) who had undergone a previous BAE. There were two deaths associated with massive hemoptysis despite BAE. Three patients had transient neurologic deficits during BAE. We concluded that BAE is a relatively safe and effective means of treating significant hemoptysis in patients with CF.

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