Byron W. Brown

Late Pulmonary Sequelae of Bronchopulmonary Dysplasia

BACKGROUND Bronchopulmonary dysplasia is a chronic lung disease that often develops after mechanical ventilation in prematurely born infants with respiratory failure. It has become the most common form of chronic lung disease in infants in the United States. The long-term outcome for infants with bronchopulmonary dysplasia has not been determined. METHODS We studied the pulmonary function of 26 adolescents and young adults, born between 1964 and 1973, who had bronchopulmonary dysplasia in infancy. We compared the results with those in two control groups: 26 age-matched adolescents and young adults of similar birth weight and gestational age who had not undergone mechanical ventilation, and 53 age-matched normal subjects. RESULTS Sixty-eight percent of the subjects with bronchopulmonary dysplasia in infancy (17 of the 25 tested) had airway obstruction, including decreases in forced expiratory volume in one second, forced expiratory flow between 25 and 75 percent of vital capacity, and maximal expiratory flow velocity at 50 percent of vital capacity, as compared with both control groups (P less than 0.0001 for all comparisons). Twenty-four percent of the subjects with bronchopulmonary dysplasia in infancy had fixed airway obstruction, and 52 percent had reactive airway disease, as indicated by their responses to the administration of methacholine or a bronchodilator. Hyperinflation (an increased ratio of residual volume to total lung capacity) was more frequent in the subjects with a history of bronchopulmonary dysplasia than in either the matched cohort (P less than 0.0006) or the normal controls (P less than 0.0004). Six of the subjects who had bronchopulmonary dysplasia in infancy had severe pulmonary dysfunction or current symptoms of respiratory difficulty. CONCLUSIONS Most adolescents and young adults who had bronchopulmonary dysplasia in infancy have some degree of pulmonary dysfunction, consisting of airway obstruction, airway hyperreactivity, and hyperinflation. The clinical consequences of this dysfunction are not known.

Impact of Prophylactic Immediate Posttransplant Ganciclovir on Development of Transplant Atherosclerosis A Post Hoc Analysis of a Randomized, Placebo-Controlled Study

BACKGROUND Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD. METHODS AND RESULTS One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS). CONCLUSIONS TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

Surgery during pregnancy and fetal outcome

As many as 2% of all pregnant women undergo surgery during gestation, but there are few reports of the effects of anesthesia and surgery on fetal outcome. The present paper presents information on 287 women who had surgery during pregnancy. Surgery during early pregnancy was associated with a significant increase in the rate of spontaneous abortion compared to the rate in a control group that did not have surgery. There were no differences in the incidence of congenital abnormalities in this offspring of women who had surgery during early pregnancy. The data suggest that elective surgery be deferred during early pregnancy to minimize potential fetal loss.

A Phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies

tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was administered to 23 patients in a Phase II, double-blind, randomized, placebo-controlled clinical trial. For each patient, a dose of 100,000 replication units of tgAAVCF was administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment, thereby establishing an inpatient control. Neither the primary efficacy endpoint, defined as the rate of relapse of clinically defined, endoscopically diagnosed recurrent sinusitis, nor several secondary endpoints (sinus transepithelial potential difference [TEPD], histopathology, sinus fluid interleukin [IL]-8 measurements) achieved statistical significance when comparing treated to control sinuses within patients. One secondary endpoint, measurements of the anti-inflammatory cytokine IL-10 in sinus fluid, was significantly (p < 0.03) increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. The tgAAVCF administration was well tolerated, without adverse respiratory events, and there was no evidence of enhanced inflammation in sinus histopathology or alterations in serum-neutralizing antibody titer to adeno-associated virus (AAV) capsid protein after vector administration. In summary, this Phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study. Various potentially confounding factors are discussed.

Disordered eating, menstrual irregularity, and Bone minéral Density in Female runners

PURPOSE To examine the relationships between disordered eating, menstrual irregularity, and low bone mineral density (BMD) in young female runners. METHODS Subjects were 91 competitive female distance runners aged 18-26 yr. Disordered eating was measured by the Eating Disorder Inventory (EDI). Menstrual irregularity was defined as oligo/amenorrhea (0-9 menses per year). BMD was measured by dual x-ray absorptiometry. RESULTS An elevated score on the EDI (highest quartile) was associated with oligo/amenorrhea, after adjusting for percent body fat, age, miles run per week, age at menarche, and dietary fat, (OR [95% CI]: 4.6 [1.1-18.6]). Oligo/amenorrheic runners had lower BMD than eumenorrheic runners at the spine (-5%), hip (-6%), and whole body (-3%), even after accounting for weight, percent body fat, EDI score, and age at menarche. Eumenorrheic runners with elevated EDI scores had lower BMD than eumenorrheic runners with normal EDI scores at the spine (-11%), with trends at the hip (-5%), and whole body (-5%), after adjusting for differences in weight and percent body fat. Runners with both an elevated EDI score and oligo/amenorrhea had no further reduction in BMD than runners with only one of these risk factors. CONCLUSION In young competitive female distance runners, (i) disordered eating is strongly related to menstrual irregularity, (ii) menstrual irregularity is associated with low BMD, and (iii) disordered eating is associated with low BMD in the absence of menstrual irregularity.

Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule. Assessment by endomyocardial biopsy.

Endomyocardial biopsy was done 119 times in 98 patients receiving doxorubicin therapy once every 3 weeks and 41 times in 27 patients receiving doxorubicin therapy weekly. Factors contributing to the degree of anthracycline-induced endomyocardial injury were evaluated. Neither age, sex, type of malignancy, concomitant use of other chemotherapeutic agents including cyclophosphamide, nor history of cardiac disease or hypertension influenced the extent of the endomyocardial injury. The dose of doxorubicin (p = 0.0001) and the schedule (weekly versus 3 weekly) (p = 0.0020) independently predicted the degree of endomyocardial damage in multivariate analyses. Previous cardiac irradiation had borderline significance (p = 0.074) in predicting endomyocardial damage in this analysis. Doxorubicin therapy administered on a weekly schedule is associated with less anthracycline-induced cardiac damage than is doxorubicin therapy delivered in the conventional, 3-weekly schedule.

Prognostic Importance of Intimal Thickness as Measured by Intracoronary Ultrasound After Cardiac Transplantation

BACKGROUND Although intracoronary ultrasound (ICUS) has been validated for the early detection of transplant coronary artery disease (TxCAD), the prognostic importance of findings detected by this new imaging technique is unknown. METHODS AND RESULTS This study examined the relation of clinical outcome in 145 heart transplant recipients (mean age, 45.1 +/- 11.1 years) with the amount of intimal thickness measured by ICUS during routine annual coronary angiography 1 to 10 years (mean, 3.1 +/- 2.2 years) after transplantation. From published autopsy data, a mean intimal thickness of > 0.3 mm was considered significant. During a mean follow-up time of 48.2 +/- 10.2 months, 23 deaths (12 cardiac) occurred, and 6 patients required retransplantation. Angiographic TxCAD developed in 22 of 125 patients (17.6%) in the subgroup with normal angiograms at the time of ICUS and a follow-up annual angiographic study. In the total population and the subgroup, mean intimal thicknesses of > 0.3 and < or = 0.3 mm, respectively, were associated with significantly inferior 4-year actuarial overall survival (73% versus 96%, P = .005; 72% versus 92%, P = .05), cardiac survival (79% versus 96%, P = .005; 80% versus 98%, P = .04), and freedom from cardiac death and retransplantation (74% versus 98%, P < .0001; 70% versus 96%, P = .001). In addition, ICUS predicted freedom from development of subsequent angiographic TxCAD in the subgroup that was initially normal (26% versus 72%, P = .02). A mean intimal thickness by ICUS of > 0.3 mm was associated with inferior clinical outcome regardless of the presence of angiographic TxCAD and predicted the development of subsequent angiographic TxCAD. Despite significantly longer duration after transplantation, higher rejection incidence, and lower average daily cyclosporine dose, none of these covariates were independent risk factors for outcome. CONCLUSIONS These findings confirm the prognostic importance of mean intimal thickening of > 0.3 mm in heart transplant recipients and suggest that these patients should be candidates for early interventional strategies.

Polymorphism of Adhesion Molecule CD31 and Its Role in Acute Graft-Versus-Host Disease

BACKGROUND Graft-versus-host disease (GVHD) caused by poorly defined minor (i.e., other than HLA) histocompatibility antigens remains a serious problem in recipients of bone marrow transplants. We sought to determine whether the CD31 adhesion molecule is a minor alloantigen. METHODS We directly sequenced samples of complementary DNA (cDNA) encoding CD31 molecules from 21 unrelated normal subjects. Sequence-specific primers were then designed to amplify alleles by the polymerase chain reaction, thereby permitting CD31 typing of genomic DNA from additional normal subjects. To assess the relevance of CD31 matching to bone marrow transplantation, we performed CD31 typing of 46 recipients of bone marrow (32 without GVHD and 14 with severe [grade III or IV] acute GVHD) and their HLA-identical sibling donors. The immunoreactivity of CD31 phenotypes with anti-CD31 monoclonal antibodies was compared by flow cytometry. RESULTS Direct sequencing of cDNA for CD31 from the 21 normal subjects identified a single polymorphism, CTG-->GTG (Leu-->Val), at codon 125; we designated the resulting alleles CD31.L and CD31.V, respectively. The CD31 genotypes of these and 142 other unrelated subjects were of the expected frequencies. Among the transplant recipients, 71 percent of those with acute GVHD had CD31 genotypes that were not identical to the donors genotype, as compared with 22 percent of the recipients without GVHD (P = 0.004). The binding of anti-CD31 monoclonal antibodies as measured by fluorescence-activated cell sorting correlated with the CD31 types of homozygous cell lines. CONCLUSIONS The adhesion molecule CD31 is polymorphic. When donor and recipient genotypes are not identical, the risk of GVHD increases. Prospective CD31 typing may reduce the risk of acute GVHD.

Early Reconstitution of Immunity and Decreased Severity of Herpes Zoster in Bone Marrow Transplant Recipients Immunized with Inactivated Varicella Vaccine

Varicella-zoster virus (VZV) causes herpes zoster after bone marrow transplantation (BMT). The immunogenicity of heat-inactivated varicella vaccine and effects on VZV pathogenesis were evaluated in 75 BMT patients randomized to receive vaccine or no intervention. Among 14 patients given a single dose at 1 month after transplantation, the mean (+/-SE) stimulation index (SI) was 12.20 +/- 3.13 compared with 4.83 +/- 2.74 (P = .036) in 14 unvaccinated patients, but clinical disease was not altered. Among 24 patients vaccinated at 1, 2, and 3 months, mean SI was 8.43 +/- 3.89 versus 2.00 +/- 0.33 (P = .014) in 23 unvaccinated patients at 4 months and 8.56 +/- 2.81 versus 5.30 +/- 2.47 (P = .043) at 5 months. Disease severity associated with VZV reactivation was decreased dramatically in vaccinees given three doses; severity scores were 6.4 +/- 1.0 versus 11.8 +/- 1.1 (P = .007). This experience with varicella vaccine in BMT patients is the first evidence that active immunization can reduce morbidity due to herpesvirus reactivation in high-risk populations.

The Physician-Patient as an Informed Consumer of Surgical Services

Abstract The alleged overuse of surgical services in this country is often attributed to lack of consumer knowledge. Assuming that physicians possess such knowledge, we have examined their utilizat...