IgG subclass antibody responses to alginate from Pseudomonas aeruginosa in patients with cystic fibrosis and chronic P. aeruginosa infection.

Chronic bronchopulmonary infection with alginate-producing, mucoid Pseudomonas aeruginosa is characteristically associated with cystic fibrosis (CF). A significant correlation between the antibody response to alginate and poor lung function has been reported. Enzyme-linked immunosorbent assays were developed for the quantitation of human IgG1, IgG2, IgG3, and IgG4 antibodies to P. aeruginosa alginate. We investigated the pattern of IgG subclass antibodies against P. aeruginosa alginate in serum of patients with CF, others with chronic P. aeruginosa infection, and healthy controls. Healthy controls and patients with CF, before they acquired P. aeruginosa infection, had no or very low titers of antibodies against P. aeruginosa alginate. The latter with chronic infection had significantly higher antibody levels than all others groups, including patients with chronic P. aeruginosa infection but no CF. CF with chronic P. aeruginosa infection led to an inverse correlation between lung function parameters and levels of IgG3 and IgG4. Fifty-seven patients with CF have been followed for an average of 12 years with multiple antibody assays covering the preinfection, early, and late stage of chronic infection. All of them developed IgG1 and IgG3 antibodies to alginate at the start of infection. IgG2 antibodies developed later and showed only a slow increase during the chronic infection. Patients who died had significantly higher IgG2 anti-alginate antibody levels than other investigated groups. Elevated levels of IgG2 and IgG3 antibodies to P. aeruginosa alginate are a sign of poor prognosis in CF.     

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.     

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.     

Human IgG antibodies to Pseudomonas aeruginosa core lipopolysaccharide determinants are detected in chronic but not acute pseudomonas infection

Human IgG response to Pseudomonas aeruginosa core lipopolysaccharide determinants was measured after both acute and chronic pseudomonas infection by using lipopolysaccharide purified from PAC605 cells (the most lipopolysaccharide-defective or "roughest" mutant of P. aeruginosa yet described) as a solid phase antigen in ELISA and Western blot immunoassay. The geometric mean IgG anti-PAC605 lipopolysaccharide titer of sera from 18 cystic fibrosis (CF) patients with chronic pseudomonas pulmonary infection was 1808, compared to 171 for convalescent sera of 10 patients with acute pseudomonas bacteremia (p less than 0.001) and 211 for 5 normal human volunteers (p less than 0.001). Western blot immunoassay demonstrated specific IgG anti-core antibodies in 11/18 sera from CF patients but not in the sera of the convalescent bacteremic patients or normal volunteers. IgG anti-Pseudomonas core lipopolysaccharide antibodies appear to be a marker of chronic infection; the possible protective role of these antibodies remains to be established.     

Allotypes of α1-antitrypsin in patients with cystic fibrosis,homozygous and heterozygous for deltaF508

In cystic fibrosis (CF) neutrophil released serine proteinase activity may facilitate Pseudomonas aeruginosa lung colonization, leading to chronic infection. Since such activity is mostly controlled by α₁-antitrypsin (α₁-AT), we postulated that patients with CF carrying deficient α₁-AT variants might be at higher risk for P. aeruginosa acquisition and might reveal other phenomena, specific for serine proteinase activity. In 215 Danish patients with CF, homozygous (80%) or heterozygous (20%) for the major CF mutation deltaF508, α₁-AT variants were determined. Carriage of deficient α-AT variants was correlated to an earlier onset of P. aeruginosa lung infection (P < 0.001), higher total IgG (P < 0.001), and P. aeruginosa-specific serum antibodies (P < 0.0001). The two groups did not differ in lung function, probably due to intensive antimicrobial treatment. Pediatr Pulmonol. 1994; 18:3–7. © 1994 Wiley-Liss. Inc.     

Monocytes in cystic fibrosis: responsiveness to microbial stimuli

Peripheral blood monocytes were obtained from 19 patients with cystic fibrosis (CF) and age-matched paired normal individuals. The oxidative metabolic response of these cells was measured by superoxide anion production before and after stimulation with Salmonella typhimurium or Pseudomonas aeruginosa lipopolysaccharide (LPS). CF monocytes showed slightly greater spontaneous superoxide anion production (14.1 +/- 2.1 SEM nanomoles superoxide anion/10(6) monocytes/180 min; n = 12) than normal monocytes (9.5 +/- 1.4; n = 12), P = 0.009. No differences between CF and normals were found in LPS-stimulated superoxide anion production (CF = 33.5 +/- 4.6, n = 13; normal = 33.8 +/- 4.2, n = 13). Furthermore, CF monocytes responded to both P. aeruginosa and S. typhimurium LPS stimulation as well as to recombinant interferon-gamma. Superoxide anion production of CF monocytes was comparable in autologous serum and in normal serum, and responses of patients colonized with P. aeruginosa and P. cepacia did not differ. We conclude that CF monocytes have a slightly increased metabolic level and, despite chronic infection, are capable of a further response to exogenous microbial stimuli.     

Antibody response to Pseudomonas aeruginosa in cystic fibrosis patients: A marker of therapeutic success?—A 30‐year Cohort study of survival in Danish CF patients after onset of chronic P. aeruginosa lung infection

We studied the effects of increasingly intensive treatment regimens on anti-pseudomonal antibody response and survival in five successive cohorts of a total of 157 Danish cystic fibrosis patients after they had acquired chronic P. aeruginosa lung infection. The time periods were 1971-1975 (N = 21), 1976-1980 (N = 64), 1981-1986 (N = 27), 1987-1993 (N = 26), and 1994-2000 (N = 19). During this 30-year period, we introduced elective 2-week courses of chemotherapy every third month in all chronically infected patients, early aggressive treatment with inhalation of colistin and oral ciprofloxacin for 3 months whenever P. aeruginosa was cultured in sputum from noncolonized patients, and inhalation of recombinant human dornase alfa. There was a significant correlation between the calendar year when chronic P. aeruginosa infection was acquired and the subsequent increase in the level of precipitins (P < 0.00001). The median number of precipitins increased by 5 per year in the oldest calendar year cohort, and 1 per year in the youngest. The median age of onset of chronic P. aeruginosa increased from 9.3 years from 1981-1986 to 13.8 years from 1987-2000. Survival after acquisition of chronic P. aeruginosa lung infection improved with time (P = 0.008). Our study shows that CF patients who are treated intensively have lower antibody responses and longer survival after acquisition of chronic P. aeruginosa lung infection.     

Small-colony variants of Pseudomonas aeruginosa in cystic fibrosis.

In the context of chronic lung infection due to Pseudomonas aeruginosa in cystic fibrosis (CF), attention has been focused on the presence of the most common mucoid phenotype. In this study, the presence of small-colony variants (SCVs) of P. aeruginosa in respiratory tract specimens from patients with CF was investigated, and the clinical conditions predisposing to SCVs were analyzed. P. aeruginosa SCVs were isolated from 33 of 86 P. aeruginosa-positive CF patients over a 2-year period. Fast-growing revertants with larger surface colonies could be isolated from SCV populations. Electron microscopy revealed no significant difference in cell size or morphology. MICs of a broad range of antipseudomonas agents for SCVs were two- to eightfold higher than values for revertants. Recovery of SCVs was correlated with parameters revealing poor lung function and was significantly associated with daily inhalation of tobramycin or colistin.     

The effect of alginate on the invasion of cystic fibrosis respiratory epithelial cells by clinical isolates of Pseudomonas aeruginosa

Chronic infection in the cystic fibrosis (CF) lung is characterized by Pseudomonas aeruginosa strains that overproduce the mucoid exopolysaccharide, alginate. Previous experiments have shown that long-term survival of P. aeruginosa in the CF lung may be facilitated by increased adherence and decreased invasion of respiratory epithelial cells. Therefore, mucoid and nonmucoid clinical isolates of P. aeruginosa were assayed for their ability to associate with and invade the CF respiratory epithelial cell line, CF/T43. Association assays and gentamicin exclusion assays demonstrated that mucoid P. aeruginosa associates with and invades CF/T43 cell monolayers significantly less than nonmucoid P. aeruginosa strains (P = .004, .02). Fluorescence microscopy invasion assays confirmed these results. The differences in association and invasion by the P. aeruginosa strains were not due to differences in lipopolysaccharide phenotype or cytotoxicity for CF/T43 respiratory epithelial cells. Exogenous bacterial alginate had no effect on the invasion of CF respiratory epithelia by a nonmucoid strain. Invasion assays with the wild-type P. aeruginosa strain PAO1 and isogenic algU and mucA mutant strains failed to show differences in invasion (P = .25). We conclude that (i) mucoid P. aeruginosa isolates associate with and invade CF/T43 respiratory epithelial cells with less efficiency than nonmucoid P. aeruginosa, (ii) these differences are not due to variations in lipopolysaccharide phenotype between strains, (iii) neither exogenous nor endogenous alginate affects the ability of P. aeruginosa to invade CF/T43 respiratory epithelial cells, and (iv) invasion of CF/T43 respiratory epithelial cells by a laboratory reference strain of P. aeruginosa does not appear to be regulated by AlgU.     

Mouse models of chronic lung infection with Pseudomonas aeruginosa: models for the study of cystic fibrosis

The discovery of the CFTR gene in 1989 has lead to rapid progress in understanding the molecular basis of cystic fibrosis (CF) and the biological properties of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. However, more than 10 years later, recurrent lung infections with Pseudomonas aeruginosa, which lead to chronic lung disease and eventual respiratory failure, remain the major cause of morbidity and mortality among CF patients. A distinguishing feature of lung disease in CF is an exaggerated and persistent inflammatory response, characterized by the accumulation of excessive numbers of neutrophils and dysregulated cytokine production. The events leading to the establishment of lung infection with P. aeruginosa, especially the inflammatory and immunological events, and the relation between the CF defect and infection, remain largely undefined. Progress in this area has been hampered by the lack of a suitable animal model. An exciting achievement in the past few years has been the development of a number of variants of CFTR-deficient mice which exhibit defective cAMP-mediated Cl(-) conductance and have a range of clinical phenotypes from mild to severe. In parallel, a model of chronic P. aeruginosa lung infection has been established in genetically and immunologically well-defined inbred mouse strains which differ in susceptibility to this infection in the lung. BALB/c mice are resistant, while DBA/2 mice are extremely susceptible, with high mortality within 3 days of infection. C57BL/6 and A/J mice are relatively susceptible and experience low mortality. Furthermore, the bacterial load correlates with the magnitude and quality of the inflammatory response in the infected lungs of BALB/c and C57BL/6 mice. Although results of infection studies in CFTR-deficient mice have been variable, C57BL/6-Cftr(m1UNC)/Cftr(m1UNC) knockout mice compared to littermate control mice are highly susceptible to chronic P. aeruginosa infection in the lung. The availability of CFTR knockout mice and non-CF inbred mice differing in susceptibility to chronic P. aeruginosa infection offers useful tools for progress in understanding the genesis of chronic P. aeruginosa infection and the ensuing inflammation in the CF lung, as well as the relation between the CF defect and infection. Information generated from these studies will provide the rationale for the development of novel immunomodulatory measures capable of ameliorating or modulating the chronic inflammation associated with CF lung disease.     

Assessment of humoral immune response in patients with chronic hepatitis C virus infection

Hepatitis C infection is a major public health problem worldwide. Hepatitis C virus (HCV) infection has been identified as a major causative agent of post-transfusion hepatitis. The host immune response to HCV infection is composed of both non- specific immune response, including interferon (IFN) production and natural killer (NK) cell activity and a virus-specific immune response, including humoral and cellular components. Susceptibility to infection has been related to immunological disturbances. Several studies have provided experimental evidence of disorders of both cellular and humoral immunity. Humoral Immunity is dependent mainly on immunoglobulins and little data are available about serum immunoglobulin values in chronic hepatitis C. The present study aimed to evaluate humoral immune response by measuring the concentration of serum immunoglobulin isotypes (IgG, IgM, IgA) and IgG-subclasses level (IgG1-4) in chronic hepatitis C patients and healthy controls. This study included 50 patients with chronic hepatitis C. All of them had positive serum anti-HCV antibodies, positive serum HCV-RNA by PCR, and histologically-proven chronic hepatitis. The results were compared with 25 healthy controls. Total IgG, IgA and IgM were assayed by nephelometry. IgG subclasses were assayed using human IgG subclasses enzyme immunoassay. Serum protein electrophoresis was performed in agarose gel. The results showed that no significant difference in serum immunoglobulin levels were found among patients with chronic hepatitis C of minimal liver damage( Knodell index < or =3) and patients with mild liver disease (Knodell index > 3). A significant increase in total serum IgG, IgG1 and IgG2 levels were found in patients with chronic hepatitis than in healthy controls but no difference was found in IgG3 and IgG4 in both patients and controls. Mean serum IgM was increased in patients with HCV infection compared with healthy controls. No significant difference was found in IgA level in both the patients and healthy controls. Our data revealed an increase of humoral immune response in chronic hepatitis C infection. This is evidenced by an elevation in serum immunoglobulin isotypes; IgG and its subclasses IgG1 and IgG2 and IgM. These findings may provide some new insights into the antibody response to HCV.     

Mannose-binding lectin (MBL) therapy in an MBL-deficient patient with severe cystic fibrosis lung disease

Deficiency of mannose-binding lectin has been shown to be a risk factor for cystic fibrosis (CF) patients. We, therefore, decided to treat a patient with CF, mannose-binding lectin deficiency, severe bronchopulmonary Pseudomonas aeruginosa infection, and rapid deterioration of lung function with purified mannose-binding lectin in an attempt to ameliorate the course of the lung disease. The mannose-binding lectin used originated from pooled human donor plasma and was given as an intravenous infusion twice a week for a period of 3 months. The patients's clinical condition was stabilized during the treatment period, but was not improved. No adverse events were observed. However, the lung function assessed as percent forced expiratory volume in 1 sec (FEV1%) and percent forced vital capacirt (FVC%) correlated significantly with the mannose-binding serum lectin levels (rho=+0.68, P=0.008, and rho=+0.73, P=0.004). Additionally, an inverse correlation with the acute phase-reactant C-reactive protein and the proinflammatory cytokine IL-6 was observed (rho=-0.49, P=0.007 and rho=-0.41, P=0.04, respectively). The results emphasize the importance of mannose-binding lectin as a secondary disease modifier in CF. Moreover, purified mannose-binding lectin can safely be administered to chronically ill patients, and may be a potential treatment in CF and other diseases in which mannose-binding lectin deficiency plays a pathophysiological role.     

Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients.

In cystic fibrosis (CF) patients early antibiotic treatment of lung infection has been shown to lead to Pseudomonas aeruginosa eradication. The present study determined: 1) the time period from eradication to new P. aeruginosa acquisition; 2) P. aeruginosa re-growth and new acquisition; and 3) the impact of eradication therapy on lung function, antimicrobial resistance, emergence of other pathogens and treatment costs. Ciprofloxacin and colistin were used to eradicate P. aeruginosa in 47 CF patients. Bacterial pathogens, lung function decline, P. aeruginosa antimicrobial resistance and anti-pseudomonal serum antibodies were assessed quarterly and compared with an age-matched CF control group. Additionally, costs of antibiotic therapy in both groups were assessed. Early antibiotic therapy leads to a P. aeruginosa free-period of a median (range) of 18 (4-80) months. New acquisition with different P. aeruginosa genotypes occurs in 73% of episodes. It also delays the decline of lung function compared with chronically infected patients, prevents the occurrence of antibiotic resistant P. aeruginosa strains, does not lead to emergence of other pathogens, and significantly reduces treatment costs. The treatment substantially lowers P. aeruginosa prevalence in CF. In conclusion, early antibiotic therapy exerts beneficial effects on the patient's clinical status and is cost-effective compared with conventional antibiotic therapy for chronically infected cystic fibrosis patients.     

Inflammatory markers of lung disease in adult patients with cystic fibrosis

BACKGROUND: Progressive pulmonary disease associated with chronic bacterial infection and inflammation is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Identifying markers of inflammation that correlate with lung injury may be useful in monitoring disease progression and response to therapy. We hypothesized that levels of serum biomarkers would correlate with clinical course of CF as defined by pulmonary function testing (FEV1). OBJECTIVE: To determine whether biomarkers of systemic inflammation correlate with lung function in adults with CF. METHODS: Retrospective cross-sectional analysis of 63 individuals > or = 30 years of age diagnosed with CF in childhood and followed at Children's Hospital, Boston. We collected data on demographics, CFTR genotype, percent predicted forced expiratory volume in 1 sec (FEV1), C-reactive protein (CRP), serum IgE nd IgG, alpha1-antitrypsin, total white blood cell and neutrophil counts, and percent neutrophils. We used univariate analyses and multivariate linear regression modeling to examine whether markers of systemic inflammation varied with FEV1 (% predicted). RESULTS: In two-covariate models including CRP and one other marker, CRP (P < 0.001) and IgG (P = 0.02) were significantly associated with FEV1 (% predicted). In the CRP and IgG model, percent predicted FEV1 decreased by 4.91% (P < 0.0001) for each twofold increase in CRP and by 1.56% (P = 0.02) for each 100 mg/dl increase in IgG. Results were unchanged by adjustment for number of DF 508 CFTR alleles. There was no association between any other marker and FEV1 (% predicted) after adjusting for CRP. CONCLUSION: Severity of lung disease in long surviving adult CF patients is correlated with CRP and IgG levels. Our findings relating CRP and IgG levels and lung function provide a foundation for subsequent longitudinal studies and consideration of novel disease mechanisms and outcome measurements.     

Hypersusceptibility of cystic fibrosis mice to chronic Pseudomonas aeruginosa oropharyngeal colonization and lung infection

No transgenic cystic fibrosis (CF) mouse model developed to date mimics the major clinical phenotype found in humans with CF, chronic Pseudomonas aeruginosa lung infection. In a transgenic CF transmembrane conductance regulator (cftr) mouse colony, we found WT, heterozygous, and homozygous CF mice housed in the same cage became chronically colonized in the oropharynx with environmental P. aeruginosa when the bacterium was present in drinking water. Elimination of P. aeruginosa from drinking water resulted in clearance in most WT and CF heterozygous, but not homozygous mice. For experimental evaluation, a combination of specific animal husbandry techniques and an oral infection route showed cftr(-/-) mice but not WT mice can be chronically colonized by P. aeruginosa with subsequent lung translocation, yielding a pathologic picture indicative of chronic lung infection. In some instances, mucoid isolates of P. aeruginosa were recovered from lungs, indicating conditions were present for conversion to mucoidy. Overexpression of human CFTR in the lungs of WT mice markedly accelerated the clearance rate of P. aeruginosa, demonstrating that lung levels of CFTR play an important role in defense against infection. P. aeruginosa mutants unable to express the surface polysaccharide alginate or the global regulator GacA were deficient in their ability to colonize the mice. CF mice made potent immune responses to P. aeruginosa outer membrane antigens. Overall, we found that under the proper conditions, transgenic CF mice are hypersusceptible to P. aeruginosa colonization and infection and can be used for evaluations of lung pathophysiology, bacterial virulence, and development of therapies aimed at treating CF lung disease.     

IL-10 attenuates excessive inflammation in chronic Pseudomonas infection in mice

Cystic fibrosis (CF) lung disease is characterized by an excessive inflammatory response associated with chronic Pseudomonas aeruginosa endobronchial infection. Compared with bronchoalveolar lavage fluid from healthy subjects, lavage fluid from patients with CF contains elevated proinflammatory cytokines but negligible amounts of the anti-inflammatory cytokine interleukin-10 (IL-10). We sought to determine whether IL-10 deficiency results in increased local and systemic morbidity in mice with chronic endobronchial infection with P. aeruginosa embedded in agar beads and to determine if exogenous IL-10 might reduce these effects. Infected IL-10 knockout mice had more severe weight loss (p = 0.04) and increased area of lung inflammation (28 +/- 4 versus 10 +/- 2%, p < 0.002) but no alterations in bacterial burden compared with wild-type mice. Infected CD-1 mice treated with IL-10 had improved survival (p = 0. 035), less severe weight loss (p < 0.005), fewer bronchoalveolar lavage neutrophils (3 x 10(5)/ml versus 5 x 10(6)/ml, p < 0.02), and decreased area of lung inflammation (11 +/- 2 versus 35 +/- 7%, p < 0.01) but no alterations in bacterial burden compared with placebo-treated mice. These data suggest that IL-10 is an important regulator of the inflammatory response to P. aeruginosa endobronchial infection and that further investigation into the use of IL-10 in CF is warranted.     

Pulmonary function, serum markers of inflammation, and IgG antibodies to core lipopolysaccharide of Burkholderia cepacia in adults with cystic fibrosis, following colonization with Burkholderia cepacia

Eight patients with cystic fibrosis [CF] colonized with Pseudomonas aeruginosa (P. aeruginosa) had serial lung function, peripheral blood inflammatory markers, and serum IgG antibodies to Burkholderia cepacia (B. cepacia) lipopolysaccharide measured in the months preceding and following colonisation with B. cepacia. One patient experienced a fall in FEV(1) from 33% to 19% of predicted values, coinciding with the first sputum isolation of B. cepacia, and he died 12 weeks later. He had a rise in inflammatory markers preterminally, and this change was refractory to antibiotic therapy. There was no significant fall in FEV(1) % of predicted values in the remaining seven patients, and no significant changes in their serum markers of inflammation following colonization with B. cepacia over a median (range) period of 10.9 (7.3-12.0) months.     

Aerosolized prolastin suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection.

High levels of active neutrophil elastase (HNE) are present in the respiratory secretions of patients with cystic fibrosis (CF). We hypothesized that aerosolized Prolastin (alpha(1)-protease inhibitor or alpha(1)PI, purified from human blood) could suppress airway neutrophil inflammation and accelerate bacterial clearance from the lung in a model of chronic Pseudomonas aeruginosa lung infection. Because human alpha(1)PI effectively inhibits rat as well as human neutrophil elastase (NE) activity in vitro, we choose to test this hypothesis using a rat agar bead model of chronic P. aeruginosa lung infection. In this model, aerosolized Prolastin significantly decreased elastase activity (p < 0.01), lung neutrophil counts (p < 0.01), and bacterial colony counts (p < 0.01). Prolastin had no direct bactericidal effect on P. aeruginosa in vitro. Lung tissue histopathology revealed a marked decrease in lung inflammation in animals treated with Prolastin. These studies indicate that Prolastin can significantly decrease the elastase burden in the chronically infected lung. In addition, not only does Prolastin suppress lung inflammation, but it also markedly decreases P. aeruginosa density in a rat model of chronic P. aeruginosa lung infection. These data suggest that aerosolized alpha(1)PI may represent a useful nonantibiotic adjunct in the treatment and control of infection and inflammation associated with CF lung disease.     

Serum immunoglobulins and immunoglobulin G subclasses in cystic fibrosis related to the clinical state of the patient

Levels of serum immunoglobulins and immunoglobulin G subclasses were measured in 32 cystic fibrosis (CF) patients, 30 asthmatics and 27 controls. When compared with the asthmatic patients and controls, the CF patients had raised levels of all IgG subclasses as well as total IgG, IgM and IgA, but there was not a statistically significant increase in IgE. The levels of immunoglobulins in the CF patients were examined in relation to the clinical features of the disease. Raised levels of IgG4 were related to levels of IgE, but these raised levels of IgG4 appeared to be part of a general increase in total IgG and not an isolated feature. There was a significant correlation between the total IgG level and its subclasses, IgG1, IgG2, IgG3, IgG4 and IgA. IgG1 was significantly correlated with IgG2 and IgG4; IgG2 with IgG4; and IgG4 with IgE. Total IgG was the immunoglobulin most closely correlated with poor lung function. Serum IgA was higher in patients with positive immediate skin prick reactions to pollens (p less than 0.005) and death within two years of the study was related to high levels of total IgG (p less than 0.01), IgG3 (p less than 0.001), IgA (p less than 0.001), and IgE (p less than 0.005).