Mary Ellen B. Wohl

Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis

BACKGROUND Respiratory disease in patients with cystic fibrosis is characterized by airway obstruction caused by the accumulation of thick, purulent secretions, which results in recurrent, symptomatic exacerbations. The viscoelasticity of the secretions can be reduced in vitro by recombinant human deoxyribonuclease I (rhDNase), a bioengineered copy of the human enzyme. METHODS We performed a randomized, double-blind, placebo-controlled study to determine the effects of once-daily and twice-daily administration of rhDNase on exacerbations of respiratory symptoms requiring parenteral antibiotics and on pulmonary function. A total of 968 adults and children with cystic fibrosis were treated for 24 weeks as outpatients. RESULTS One or more exacerbations occurred in 27 percent of the patients given placebo, 22 percent of those treated with rhDNase once daily, and 19 percent of those treated with rhDNase twice daily. As compared with placebo, the administration of rhDNase once daily and twice daily reduced the age-adjusted risk of respiratory exacerbations by 28 percent (P = 0.04) and 37 percent (P < 0.01), respectively. The administration of rhDNase once daily and twice daily improved forced expiratory volume in one second during the study by a mean (+/- SD) of 5.8 +/- 0.7 and 5.6 +/- 0.7 percent, respectively. None of the patients had anaphylaxis. Voice alteration and laryngitis were more frequent in the rhDNase-treated patients than in those receiving placebo but were rarely severe and resolved within 21 days of onset. CONCLUSIONS In patients with cystic fibrosis, the administration of rhDNase reduced but did not eliminate exacerbations of respiratory symptoms, resulted in slight improvement in pulmonary function, and was well tolerated.

Epidemiologic study of cystic fibrosis: Design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada

Cystic fibrosis (CF) is a complex illness characterized by chronic lung infection leading to deterioration in function and respiratory failure in over 85% of patients. An understanding of the risk factors for that progression and the interaction of these factors with current therapeutic strategies should materially improve the prevention of this progressive lung disease. The Epidemiologic Study of Cystic Fibrosis (ESCF) was therefore designed as a multicenter, longitudinal, observational study to prospectively collect detailed clinical, therapeutic, microbiologic, and lung function data from a large number of CF treatment sites in the U.S. and Canada. The ESCF also serves an important role as a phase‐IV study of dornase alfa. To be eligible for enrollment, subjects must have the diagnosis of CF and receive the majority of their care at an ESCF site.

Lung Growth and Airway Function after Lobectomy in Infancy for Congenital Lobar Emphysema

To characterize the outcome of lobectomy in infancy and the low expiratory flows which persist after lobectomy for congenital lobar emphysema, 15 subjects with this history were studied at age 8-30 yr. Total lung capacity was normal in all, but higher values (P < 0.05) were observed in nine subjects with upper lobectomy than in five subjects with right middle lobectomy. Ratio of residual volume to total lung capacity was correlated (P < 0.05) with the amount of lung missing as estimated from normal relative weights of the respective lobes. Xe(133) radiospirometry in eight subjects showed that the operated and unoperated sides had nearly equal volumes at total lung capacity, but that the operated side was larger than the unoperated side at residual volume. Perfusion was equally distributed between the two sides. Similar findings were detected radiographically in four other subjects. Forced expiratory volume in 1 s and maximal midexpiratory flow rate averaged 72 and 45% of predicted, respectively. Low values of specific airway conductance and normal density dependence of maximal flows in 12 subjects suggested that obstruction was not limited to peripheral airways. Pathologic observations at the time of surgery and morphometry of the resected lobes were not correlated with any test of pulmonary function. These data show that lung volume can be completely recovered after lobectomy for congenital lobar emphysema in infancy. The volume increase occurs on the operated side, and probably represents tissue growth rather than simple distension. The response to resection is influenced by the particular lobe resected and may be associated with decreased lung recoil near residual volume. Low expiratory flows in these subjects could be explained by several mechanisms, among which a disproportion between airway and parenchymal growth in infancy (dysanaptic growth) is most compatible with our data.

Immunodeficiency Associated with Loss of T4+ Inducer T-Cell Function

We investigated the immune function of a patient with anergy and acquired hypogammaglobulinemia. Despite normal numbers of B cells and T4+ inducer and T5+ suppressor T cells, this patients lymphocytes did not produce immunoglobulin, proliferate in response to soluble antigens, or generate helper factors in vitro. In addition, her T4+ T cells did not express la molecules after stimulation by soluble antigen. In mixing experiments, her T cells did not induce immunoglobulin secretion by B cells from a normal, HLA-D-identical sibling; this failure was not due to excessive suppression, since the patients T cells did not abrogate immunoglobulin production by the normal siblings T and B cells. Moreover, the patients B cells secreted immunoglobulin in the presence of the siblings T4+ cells. In contrast to the deficient inducer cells, the patients T5+ T cells were capable of expressing suppressor-cell functions. These results indicate that immunodeficiency may occur because of a selective loss of T4+ inducer function.

The lung following repair of congenital diaphragmatic hernia

To determine the effects of the pulmonary hypoplasia present at birth in infants with congenital diaphragmatic hernia upon subsequent development of the lung, 19 patients who had undergone surgical repair before the age of one year were studied at ages 6 to 18 years. Total lung capacity and vital capacity averaged 99% of predicted value. Diffusing capacity for carbon monoxide was normal. Forced expiratory volume in one second averaged 89% of predicted value and 80% of vital capacity. Total respiratory system conductance and maximum expiratory flow volume curves obtained during air and helium-oxygen breathing were normal. Xenon 133 radiospirometry performed in nine patients revealed equal distribution of lung volumes on the two sides. Ventilation to the hernia side was reduced in only two patients. Blood flow to the hernia side was reduced in all nine patients. Chest radiographs supported the physiologic observations. These findings are consistent with the persistence of a reduction in the number of branches or generations of pulmonary arteries and bronchi on the side of the hernia. Since a substantial part of the vascular resistance resides in peripheral vessels, this developmental abnormality influences the distribution of pulmonary blood flow, although it has little effect on tests reflecting airway resistance or the distribution of ventilation.

Prospective evaluation by computed tomography and pulmonary function tests of children with mediastinal masses

BACKGROUND Our ability to predict respiratory compromise during general anesthesia in a child with an anterior mediastinal mass is limited. Two prior reports have found a correlation between adequacy of ventilation during general anesthesia and the tracheal cross-sectional area obtained from computed tomograms (computed tomography [CT] scans). These and other reports have suggested that pulmonary function tests may provide additional information regarding anesthetic risks, but no studies have evaluated the extent of respiratory compromise in children with an anterior mediastinal mass. METHODS We prospectively evaluated 31 children with mediastinal masses before 34 surgical procedures. At each evaluation the tracheal area (as a percent of the predicted area on the basis of age and gender) was determined by CT. Pulmonary function tests were performed in the sitting and supine positions. The eleven children with either a tracheal area or peak expiratory flow rate (PEFR) of less than 50% of predicted received only a local anesthetic; the majority of children above these levels (17 of 22) received a general anesthetic. RESULTS Eleven of 31 patients had significant pulmonary restriction as defined by total lung capacity of less than 75% of predicted. Eight patients had a PEFR in the supine position of less than 50% of predicted. PEFR was lower in the supine than the upright position in all patients (median value of decrease, 12%). In 28 of 34 evaluations the child had a tracheal area greater than 50% of predicted, a criterion proposed for safe utilization of general anesthesia. This latter guideline, however, did not identify all patients with significant impairment of pulmonary function; five patients had a PEFR of less than 50% of predicted but tracheal areas of greater than 50% of predicted. All children were administered anesthetics uneventfully with these guidelines. CONCLUSIONS Although the tracheal area can be accurately measured with the CT scan, this does not identify all children with mediastinal masses and abnormal pulmonary function. A large mass may produce significant restrictive impairment and hence reduction in PEFR by the intrathoracic volume it occupies and yet not cause tracheal compression. It may also reduce the PEFR by narrowing the bronchi distal to the carina. Currently no CT standards exist for measuring bronchial areas in children. Our study did not evaluate whether impaired pulmonary function as measured by PEFR would be predictive of respiratory collapse during general anesthesia because all were excluded and operated on under local anesthesia. General anesthesia was well tolerated in children with tracheal area and PEFR greater than 50% of predicted. Pulmonary function tests in children with anterior mediastinal masses may add valuable information to the anatomic evaluation obtained by CT scan.

The pediatric pulmonary and cardiovascular complications of vertically transmitted human immunodeficiency virus (P2C2 HIV) infection study: Design and methods

The P2C2 HIV Study is a prospective natural history study initiated by the National Heart, Lung, and Blood Institute in order to describe the types and incidence of cardiovascular and pulmonary disorders that occur in children with vertically transmitted HIV infection (i.e., transmitted from mother to child in utero or perinatally). This article describes the study design and methods. Patients were recruited from five clinical centers in the United States. The cohort is composed of 205 infants and children enrolled after 28 days of age (Group I) and 612 fetuses and infants of HIV-infected mothers, enrolled prenatally (73%) or postnatally at age < 28 days (Group II). The maternal-to-infant transmission rate in Group II was 17%. The HIV-negative infants in Group II (Group IIb) serves as a control group for the HIV-infected children (Group IIa). The cohort is followed at specified intervals for clinical examination, cardiac, pulmonary, immunologic, and infectious studies and for intercurrent illnesses. In Group IIa, the cumulative loss-to-follow-up rate at 3 years was 10.5%, and the 3-year cumulative mortality rate was 24.9%. The findings will be relevant to clinical and epidemiologic aspects of HIV infection in children.

Polyalveolar lobe: anatomic and physiologic parameters and their relationship to congenital lobar emphysema.

Polyalveolar lobe is one of the recently described pathological entities that can give rise to congenital lobar emphysema (CLE). In polyalveolar lobe, the total alveolar number as determined by microscopic point-counting of randomly taken lung sections is increased three to fivefold. The airways and arteries are normal for age in number, size and structure. Follow-up over 10-20 yr of patients operated upon for congenital lobar emphysema, including those of polyalveolar lobe etiology shows that these patients do well clinically. All patients have some pulmonary function abnormalities, specifically a decrease in airway conductance, and forced expiratory volume. It is not possible to distinguish patients with polyalveolar lobes from other CLE patients on the basis of pulmonary function data. All patients had normal lung volumes and vital capacities, despite losing 8%-20% of their pulmonary parenchyma. Based on compensatory lung growth, it may be preferable to operate earlier, rather than later in these cases.

Safety of repeated intermittent courses of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis

OBJECTIVES To determine the effect of repeated doses of aerosolized recombinant human deoxyribonuclease (rhDNase) on the development of anti-rhDNase antibodies, acute allergic reactions, and pulmonary function in patients with cystic fibrosis. DESIGN A multicenter, open-label study in which 184 patients received 10 mg aerosolized rhDNase twice a day for 14 days followed by a 14-day washout period for a total of 6 treatment cycles. Serial determinations of anti-rhDNase antibodies and pulmonary functions were performed. RESULTS Detectable anti-rhDNase antibodies developed in 16 (8.7%) patients. These patients had no changes in their symptoms from the time they entered the trial. Antibodies detected were all of the IgG isotype. Increases in both forced expired volume in 1 second and forced vital capacity were noted from the beginning to the end of each cycle of treatment returning to baseline during the off-treatment period of each cycle. Seropositivity to rhDNase was not associated with allergic reactions and had no relationship on improvement in pulmonary function. CONCLUSIONS Development of anti-rhDNase antibodies occurred in a small number of patients and was not associated with side effects. Intermittent administration of rhDNase for 24 weeks to patients with cystic fibrosis was well tolerated and was not associated with anaphylaxis in any patient. Pulmonary function improved significantly during the 14-day cycles while rhDNase was administered and returned to baseline when rhDNase was discontinued.

Pneumatocele Complicating Hyperimmunoglobulin E Syndrome (Job's Syndrome)

The case of a boy with hyperimmunoglobulin E syndrome or Jobs syndrome is presented to demonstrate the occurrence of pneumatoceles in this syndrome as well as their unusual natural history and failure to spontaneously resolve. Surgical resection was required for two complications in this patient, persistent bronchopleural fistula and a pulmonary abscess that destroyed one lung and required pneumonectomy. Pathologic examination of the specimens demonstrated the wall of the cysts consisted of granulation tissue with chronic active inflammation surrounded by infarcted pulmonary parenchyma with coagulative necrosis. The mechanism responsible for increased immunoglobulin E production in this syndrome is unknown, as is the manner in which elevated immunoglobulin E levels impair normal immune function.