Biomedical subjects
R B Moss
Publications and source records attributed to R B Moss.
Immunoglobulin G subclasses.
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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.
Sinus disease in patients with severe cystic fibrosis: relation to pulmonary exacerbation.
Four adult cystic fibrosis patients were selected for aggressive surgical management of sinus disease on the basis of severe pulmonary involvement, high frequency of hospital admission, chronic headache, and wheezing unresponsive to conventional treatment. They underwent bilateral Caldwell-Luc procedure with perioperative anti-Pseudomonas antimicrobials. There were substantial improvements in headache and respiratory symptoms and a significant reduction in the frequency of hospital admission after the operation. These findings suggest that sinus disease is associated with pulmonary exacerbation in patients with cystic fibrosis, and strengthens a similar observation in patients with asthma.
Pseudomonas hyperimmune globulin passive immunotherapy for pulmonary exacerbations in cystic fibrosis.
We studied the effect of an intravenously administered gamma globulin [Ps-ivIG] enriched fivefold over conventional ivIG for Pseudomonas aeruginosa lipopolysaccharide [PA LPS] antibodies on ten patients with cystic fibrosis [CF] aged 19-32 years during hospitalization for pulmonary deterioration. All were colonized with greater than or equal to 1 PA phenotype resistant to all antibiotics at the time of admission and they received 500 mg/kg Ps-ivIG intravenously as a single dose in addition to conventional treatment, including antibiotics and chest physiotherapy. No adverse effects occurred. Circulating immune complexes and complement levels remained unchanged from baseline. Serum levels of anti-PA LPS IgG, as measured by ELISA for eight PA LPS immunotypes, increased to 244 +/- 65% (mean +/- SE) of baseline levels 1 hour post-infusion (P less than 0.01), remained significantly elevated during a mean hospital stay of 17 days, and returned to near baseline by follow-up 4 weeks after hospital discharge. Plasma half-life and clearance values were similar to those of other subjects receiving conventional ivIG. Sputum PA density declined from 3.0 to 1.2 x 10(8) cfu/mL 1 week post-infusion (P approximately equal to 0.05), and returned to baseline at follow-up. Serum anti-PA opsonic activity increased after infusion (P less than 0.01), but returned to baseline by 72 hours. Clinical scores improved from admission to discharge (P less than 0.005) without decline at follow-up. Forced vital capacity [FVC] and forced expiratory volume in one second [FEV1] increased from admission to discharge (P less than 0.01 and P less than 0.05, respectively) without decline at follow-up. Using autologous historical control data, standard hospital therapy without Ps-ivIG resulted in no improvement in FVC or FEV1, and a subsequent decline in these parameters (P less than 0.05 for each) during a similar follow-up period. This occurred despite the fact that half the patients did not have antibiotic-resistant PA on the control admission. We conclude that Ps-ivIG is a safe adjunctive therapy for pulmonary exacerbations in moderately ill cystic fibrosis patients colonized with resistant PA, and may be associated with both greater and more prolonged improvement in pulmonary function than standard therapy alone.
Orthodontic management of ankylosed teeth.
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Regarding article by Earl and Sullivan.
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Suppression of the late cutaneous response by immunotherapy.
In a prospective, double-blind, placebo-controlled study, we examined the effect of mountain cedar (MC) immunotherapy on the MC-induced late cutaneous response (LCR). Fourteen MC-sensitive patients were intradermally skin tested before and after immunotherapy with MC extract. We measured the size of the wheal at 15 minutes and the area of tissue swelling at 6 hours. Patients were matched by the size of the LCR and started receiving either MC immunotherapy or placebo immunotherapy. MC-specific immunoglobulins (MC sIgG, MC sIgG1, MC sIgG4, and MC sIgE) were measured by ELISA. Symptom-medication scores (SMSs) were recorded on a daily basis during the MC season and tabulated at the end of the study. Comparison of the 14 paired patients revealed no significant differences between MC-treated and placebo-treated groups in preimmunotherapy MC sIgG1 and SIgG4. However, when MC immunotherapy was compared to placebo immunotherapy, patients receiving MC immunotherapy developed significantly higher MC sIgG1 (p less than 0.04) and MC sIgG4 (p less than 0.01) after immunotherapy. Patients receiving MC immunotherapy also demonstrated significantly greater suppression of the LCR after immunotherapy (p less than 0.005) with the postimmunotherapy LCR correlating significantly with both MC sIgG4 (rs = 0.715; p = 0.008) and cumulative dose of MC received (rs = 0.808; p = 0.004). MC sIgE was similar in both groups after immunotherapy. The reduction in SMSs in the MC-treated group did not reach significance, nor was there a correlation of SMSs with MC sIgE, sIgG, sIgG1, or sIgG4.(ABSTRACT TRUNCATED AT 250 WORDS)
Microstress, mood, and natural killer-cell activity.
The interactions between transient minor negative and positive life events ("microstressors"), concurrent mood states, and immunological functioning were assessed by measuring levels of natural killer-cell activity (NKA), stress, and mood weekly for four weeks. No association was found between the frequency of either positive or negative microstressors and NKA, nor between concurrent mood ratings and NKA. Some individuals showed a marked and unexplained variability in NKA on a week-to-week basis. These results do not support the hypothesis that the minor stresses of everyday living affect immune function. The study does suggest that single cross-sectional determinations of NKA may not be suitable for studies of psychosocial factors and NKA.
Allergic etiology and immunology of asthma.
Although asthma is a complex and multifactorial disease, a relationship between atopic allergic sensitization to common aeroallergens and asthma has been recognized for decades. This recognition has not led to a widespread immunologic orientation to asthma diagnosis and treatment. This review summarizes older epidemiologic evidence using historical data and skin tests that associate IgE-mediated events with asthma, and presents more recent studies utilizing in vitro testing to study new subject groups, to demonstrate that in certain situations up to 75% to 100% of the cases of chronic asthma, as well as many acute episodes, have an allergic etiology. Thus the old distinctions between intrinsic and extrinsic asthma should be discarded in favor of an aggressive search for allergic factors in virtually any patient with asthma. A theoretic basis for the allergic etiology of asthma has arisen from recent studies linking (1) IgE antibody production with cytophilic sensitization of mast cells and possibly other proinflammatory cell types bearing IgE receptors; (2) IgE-dependent, allergen-induced immediate bronchial reactions with late-phase reactions; and (3) occurrence of late-phase reactions with persistent local inflammation and increased nonspecific bronchial hyperreactivity. Understanding of the allergic etiology of asthma in turn gives rise to renewed emphasis upon immunomodulatory approaches to treatment. At present these include allergen avoidance measures that reduce natural exposure and conventional high-dose allergen injection immunotherapy, both of which have well-documented efficacy when properly applied. In the future, better understanding of the cellular and molecular basis of asthma, in particular the events of the late-phase reaction, are likely to lead to new approaches to treatment based upon rational modulation of these events, possibly with recombinant cytokine-based therapy or synthetic peptide antagonists of defined mediator molecules.
Isotypic and antigenic restriction of the blocking antibody response to ryegrass pollen: correlation of rye group I antigen-specific IgG1 with clinical response.
To investigate the role of blocking antibodies in allergen immunotherapy (IT), we analyzed IgE, IgG, and IgG subclass 1 to 4 antibody responses to ryegrass group I antigen (RGGI) in a prospective double-blind, heterologous allergen, allergen-controlled trial of grass-pollen IT in 18 adults with seasonal rhinitis and asthma. Serum was assayed preseasonally before starting IT and again in midseason at time of documented highest natural exposure. Antibodies were measured by ELISA, and immunogenic specificities of ryegrass extract were examined by Western immunoblots. Nine subjects receiving grass-pollen IT and nine control subjects had similar clinical and immunologic status before IT. RGGI-specific IgE antibodies (sIgE) did not change from pretreatment levels in actively treated subjects but increased in control subjects (p less than 0.002). RGGI sIgG increased approximately thirteen-fold with active IT versus threefold during natural seasonal exposure (p less than 0.0005). The IgG-blocking response to RGGI was restricted to IgG1 and IgG4. Ten nonatopic subjects had similar RGGI sIgG1 but lower or undetectable sIgE and sIgG4 than the 18 atopic study subjects. Active IT dramatically increased RGGI sIgG4 (p less than 0.001) and to a lesser extent RGGI sIgG1 (p less than 0.01). Immunoblots demonstrated eight IgE-binding ryegrass-polypeptide allergens, with RGGI ubiquitous, and 11 IgG-binding polypeptides, including all eight allergens. A negative correlation between seasonal rhinitis symptom-medication scores and RGGI sIgG1 levels was found (r = -0.62, p less than 0.01), but no other immunologic parameters assayed were related to clinical improvement. Although RGGI sIgG4 predominates in the blocking response and is a useful marker of effective IT, early beneficial biologic effects may involve IgG1 antibodies.
Effect of total lymphoid irradiation on IgE antibody responses in rheumatoid arthritis and systemic lupus erythematosus.
Thirteen patients with rheumatoid arthritis and four patients with systemic lupus erythematosus and nephritis were treated with total lymphoid irradiation because of severe disease refractory to other forms of treatment. Serum samples before and after irradiation were tested for changes in total serum IgE and for changes in specific IgE antibodies to ryegrass pollen, dust mite, cat dander, and Alternaria. There were no statistically significant changes in total or specific IgE from lymphoid irradiation in these patients. The therapy caused a significant decrease in circulating total lymphocyte and Leu-3 (helper/inducer) T-lymphocyte counts. Therefore, reduction in circulating levels of helper/inducer T cells does not appear to influence preexisting levels of IgE antibodies.
Altered antibody isotype in cystic fibrosis: impaired natural antibody response to polysaccharide antigens.
Patients with cystic fibrosis (CF) have impaired natural (preinfection) IgG2 antibody responses to Pseudomonas aeruginosa lipopolysaccharide. To investigate the basis for this defect, we measured natural IgG and IgG1-4 antibody levels to Haemophilus influenzae type b polyribophosphate (PRP) and tetanus toxoid by enzyme-linked immunosorbent assay in 24 adult CF patients and 20 normal controls. Immunoglobulin heavy- and light-chain allotypes were determined on 146 Caucasian CF patients and 96 controls. The tetanus toxoid-specific IgG response was predominantly IgG1. CF and control subjects had similar IgG and IgG1 antibody levels. The PRP-specific IgG response was predominantly IgG2. In contrast to tetanus toxoid results, CF patients had lower geometric mean level of PRP-specific IgG compared to normal controls (p = 0.0036). ELISA results were confirmed by liquid-phase 3H-PRP-binding assay: CF patients had a geometric mean serum antibody level of 395 versus 922 ng/ml in controls (p = 0.0044). PRP-specific IgG2 levels were also depressed in CF patients (p = 0.03). CF patients had a lower prevalence of the A2m(2) allotype than the local racially matched control sample (p less than 0.025). Other allotype prevalences including G2m(n) and Km(1) were similar. Impaired IgG2 antibody responses to microbial polysaccharide surface antigens in CF patients might predispose them to persistent endobronchial infection and lead to production of nonopsonizing isotype responses. The potential role of A2m(2), coded for in the H chain locus on chromosome 14, is unknown, but could be related to mucosal IgA2 antibody responses.
Hypergammaglobulinemia in cystic fibrosis. Role of Pseudomonas endobronchial infection.
Hypergammaglobulinemia, chronic endobronchial infection with Pseudomonas aeruginosa (PA), and the resulting systemic humoral immune response to PA are each associated with worsened clinical status and prognosis in patients with cystic fibrosis (CF). Major serum immunoglobulin isotype levels (IgG, IgA, IgM, and IgG1-4 subclasses) were measured in 31 CF patients and ten control subjects. Immunoglobulin levels were related to airway infection with PA and the resulting IgG antibody response against PA lipopolysaccharide (LPS). Hyperimmunoglobulinemia G was present with elevated IgG1 and IgG2 in 48 percent, IgG3 in 52 percent, and IgG4 in 42 percent of CF patients. The PA infection was associated with striking increases in IgG2. IgG2 levels correlated well with IgG2 antibodies to PA LPS (r = +0.70, p less than 0.001). However, even CF patients who were not infected with PA had an increased prevalence of high IgG3 (p less than 0.05) and IgG4 (p less than 0.01). The PA infection thus appears to be a major, but not the only factor causing hypergammaglobulinemia in CF.
Seasonal asthma in northern California: allergic causes and efficacy of immunotherapy.
Inland areas of northern California have an intense grass pollination in the spring of each year. This is accompanied by a stirking rise in the incidence of asthma. We documented this relationship and designed a trial to test the efficacy of immunotherapy for grass-pollen asthma. Aeroallergen counts were performed on the roof of the allergy clinic of David Grant Medical Center from January 1981 to December 1984 by a gravity collector. These counts were compared to counts done on a Rotorod at a nearby hospital from July 1982 to September 1984. Climatologic factors were also tabulated. Visits for asthma and rhinitis to our emergency room and asthma admissions to our hospital were counted for the 4-year period. A randomized, double-blinded, placebo-controlled trial of immunotherapy with grass-pollen extract was performed from November 1984 to June 1985. Two groups of clinically and immunologically well-matched subjects were started on an accelerated preseasonal trial of immunotherapy. One group received a standardized grass extract, and the other group did not. Both groups received other extracts of aeroallergens to which they were skin test positive that occur locally in the spring and summer. This was done because of our dissatisfaction with a histamine placebo used in a previous pilot study. Symptom medication scores (SMS) and immunologic parameters were followed. For the 4-year period, grass-pollen count (GPC) correlated strongly with asthma emergency room visits (r = 0.90; p less than 0.001) and for rhinitis (r = 0.92; p less than 0.001). Asthma admissions also correlated strongly with GPC (r = 0.72; p less than 0.001). Other aeroallergens either did not correlate significantly or occurred in such small numbers that they could not be seriously considered. Rotorod counts supported these conclusions with the exceptions of some Basidiomycetes. Climatologic factors demonstrated no relationship to the incidence of asthma. Asthma SMS were lower in the grass-treated group, p less than 0.05. Rhinitis SMS were also lower but did not reach significance, p = 0.11. RGGI sIgE did not rise significantly in the grass-treated group but did in the placebo-treated group. RGGI sIgE rose in both groups, although to significantly higher levels in the grass-treated group, p less than 0.001. The asthma SMS were inversely related to increasing RGGI cumulative dose, p less than 0.10. Linear regression analysis of the dose-response scattergram suggests that a cumulative dose of approximately 90 micrograms of RGGI may be desirable.(ABSTRACT TRUNCATED AT 400 WORDS)
Association of systemic immune complexes, complement activation, and antibodies to Pseudomonas aeruginosa lipopolysaccharide and exotoxin A with mortality in cystic fibrosis.
The relevance of circulating immune complexes, plasma complement activation, and serum antibodies against discrete antigens of Pseudomonas aeruginosa, to the clinical course in patients with cystic fibrosis (CF) is unknown. We related these factors to outcome in 49 patients with CF colonized by P. aeruginosa, comparing 14 who died of lung disease with 35 survivors of similar age and duration of colonization, as well as 9 uncolonized patients with CF, 24 patients with other bronchorrheic lung disease, and 10 healthy control subjects. The patients with CF colonized by P. aeruginosa who died had a higher incidence of immune complexes than did survivors (71 versus 40%, p less than 0.05). Moreover, C4 activation was highly associated with immune complexes and mortality (p less than 0.001 for each). Those who died also had much higher levels of IgG antibodies to P. aeruginosa lipopolysaccharide (LPS) and exotoxin A than did survivors colonized by P. aeruginosa (p less than 0.005 and p = 0.01, respectively), whereas both groups had similar levels of P. aeruginosa sonicate, elastase, alkaline protease, and endotoxin core antibodies. We conclude that increasing levels of serum IgG antibodies to P. aeruginosa LPS and exotoxin A and the presence of systemic immune complexes and complement activation are associated with poor prognosis in CF, and may provide useful noninvasive markers for studying the possible immunopathogenesis of CF lung disease.
Altered antibody isotype in cystic fibrosis: possible role in opsonic deficiency.
Patients with cystic fibrosis (CF) whose respiratory tracts are colonized with Pseudomonas aeruginosa (PA) may develop a specific opsonic deficiency for alveolar macrophage phagocytosis of PA. We examined the possible role of altered antibody (Ab) isotype in this phenomenon by measuring serum levels and distribution of IgG and IgG subclass Ab (IgG1, IgG2, IgG3, and IgG4) to the major opsonic immunodeterminant, serotype-specific lipopolysaccharide (LPS), by means of enzyme-linked immunosorbent assays employing monoclonal secondary antibodies, and comparing these results to the serum opsonic capacity in an in vitro murine alveolar macrophage phagocytic assay. Twenty-one patients with CF who were colonized with PA had approximately a 30-fold elevation of PA LPS IgG Ab levels and higher IgG subclass 1-4 Ab compared to 10 uncolonized patients with CF and 11 healthy controls (p less than 0.05-0.0005 depending on the isotype). Colonized patients with CF had a shift in PA LPS Ab distribution toward IgG3 compared to uncolonized patients with CF (p less than 0.02). A surprising finding was that uncolonized patients with CF had lower levels (p less than 0.05) and proportion (p less than 0.002) of PA LPS IgG2 Ab than controls, with an apparent shift to higher levels and proportion of PA LPS IgG4 (p less than 0.01). Serum from colonized patients with CF showed diminished opsonic capacity for phagocytosis of PA compared to uncolonized patients and controls (p less than 0.005), with 42% showing inhibitory activity. Functional Ab was also found to be inhibitory at high (greater than 500 ng/ml) concentrations. Serum opsonic capacity appeared to include a noncomplement cofactor for optimal activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Supraventricular tachycardia in patients with cystic fibrosis.
Reports on arrhythmias in cystic fibrosis (CF) patients are limited. Four CF patients treated at our center had recurrent supraventricular tachycardia (SVT). Three had cor pulmonale, as evidenced by echocardiogram, and all had baseline tachycardia. Twenty-four hour Holter monitoring in three patients showed ectopic atrial pacing and premature atrial and ventricular contractions in one patient, rare PVCs in another, and SVT in all three. All patients had significant bronchospasm requiring the use of theophylline, prednisone, and frequent daily doses of beta-2 adrenergic agonists; two also used nebulized atropine. Average theophylline level for the group was 13.4 micrograms/ml during SVT. There was no correlation between pulmonary obstruction and the frequency of SVT. Factors such as cor pulmonale, ectopy, hypoxia, infection, intensive combination bronchodilator therapy, and corticosteroids probably interacted to precipitate SVT. Altered autonomic responses and a myocardial infiltrative process noted in some patients with CF may also play a role in causing arrhythmias.