Birgitte Frederiksen

Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis

Chronic pulmonary infection with Pseudomonas aeruginosa (PA) develops in most patients with cystic fibrosis (CF) and is associated with a poor prognosis. Much effort has been directed toward treating the chronic infection, but it is almost impossible to eradicate it once established; therefore, prevention is preferable. Since 1989 CF patients at the Danish CF Center in Copenhagen have been treated with an intensive three‐step‐protocol consisting of colistin inhalations and oral ciprofloxacin at the time of initial PA colonization. This study compares 48 patients treated according to this intensive protocol with 43 historic controls. The study was carried out over 44 months and included 218 patient‐years. Only 16% of the treated patients developed chronic PA infection after 3 1/2 years compared with 72% of the control patients (Kaplan Meier estimate, P < 0.005, log rank test). This indicates that aggressive treatment prevented or delayed chronic PA infection in 78% of the patients for 3 1/2 years. Furthermore, aggressive treatment maintained or increased pulmonary function (forced vital capacity and forced expiratory volume in 1 second in percent of predicted values) during the year after inclusion compared with the control group, in which pulmonary function declined (P < 0.01, Mann‐Whitney test). Although some of the treated patients eventually developed chronic PA infection, these patients had significantly better pulmonary function at the onset of chronic PA infection compared with control patients (P < 0.001, Mann‐Whitney test). When the different steps in the intensive three‐step‐protocol were analyzed, there was a trend suggesting that 3 months of high‐dose treatment with colistin inhalation and oral ciprofloxacin produced the best results in terms of postponement or prevention of chronic PA infection (P < 0.05). Pediatr. Pulmonol. 1997; 23:330–335.

Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis

Mannose-binding lectin (MBL) is a key factor in innate immunity, and lung infections are the leading cause of morbidity and mortality in cystic fibrosis (CF). Accordingly, we investigated whether MBL variant alleles, which are associated with recurrent infections, might be risk factors for CF patients. In 149 CF patients, different MBL genotypes were compared with respect to lung function, microbiology, and survival to end-stage CF (death or lung transplantation). The lung function was significantly reduced in carriers of MBL variant alleles when compared with normal homozygotes. The negative impact of variant alleles on lung function was especially confined to patients with chronic Pseudomonas aeruginosa infection. Burkholderia cepacia infection was significantly more frequent in carriers of variant alleles than in homozygotes. The risk of end-stage CF among carriers of variant alleles increased 3-fold, and the survival time decreased over a 10-year follow-up period. Moreover, by using a modified life table analysis, we estimated that the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes. Presence of MBL variant alleles is therefore associated with poor prognosis and early death in patients with CF.

Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment.

We report survival data for Danish center‐treated cystic fibrosis (CF) patients, covering the period 1974–1993 and using cross‐sectional cumulative survival probability based on annual age‐specific mortality rates. Analyses by age and by years after diagnosis were made. No significant differences were noted in the survival probability when patients were grouped according to sex or absence/presence of meconium ileus. The annual mortality rate for 1989–1993 was 0–1.2%. Using the age‐specific mortality rate for 1989–1993, we were unable to calculate the median survival probability because the curve did not fall below 50% (age up to 45 years); however, it was possible to show that the survival probability for a newborn CF child to reach his 45th birthday was 80.4% (confidence interval 76.5–84.6%). The median age at diagnosis was 0.63 years with no sex difference. The probability of surviving 40 years after the diagnosis of CF was made was 83.3% (confidence interval 80.1–86.6%). This is considerably higher than any other published survival probability. An early anti‐Pseudomonas aeruginosa treatment regimen seemed important in achieving the observed improved survival. Pediatr Pulmonol. 1996; 21:153–158.

Changing Epidemiology of Pseudomonas aeruginosa Infection in Danish Cystic Fibrosis Patients (1974–1995)

Recurrent and chronic lower airway infection with Pseudomonas aeruginosa (PA) is an important component of cystic fibrosis (CF) pulmonary disease. Different modes of treatment and control of CF patients have been introduced at the Copenhagen CF Centre over the past 20 years and have been associated with improved survival. Treatment consisted of: 1) elective antibiotics for 14 days every 3 months to patients with chronic PA infection (started in 1976), 2) cohort isolation to prevent cross‐infection (patients with PA were separated from patients without PA, starting in 1981); and 3) early intensive treatment with inhaled colistin and oral ciprofloxacin from time of initial PA colonization (started in 1989). The aim of the present study was to evaluate the impact of each of these interventions on the changes in the epidemiology of PA.

Pseudomonas aeruginosa cross-infection among patients with cystic Fibrosis during a winter camp

Twenty‐seven patients with cystic fibrosis from our Danish Cystic Fibrosis Center went to a winter camp for 1 week in November of 1990. This study is based on 22 of these patients. Prior to attending camp, 17 out of 22 patients harbored Pseudomonas aeruginosa in their sputum, but 5 patients did not. After returning from camp, all 22 patients harbored P. aeruginosa in the sputum, including the 5 patients whose sputum was free of P. aeruginosa before they went. Epidemiological typing used pulsed‐field gel electrophoresis of the P. aeruginosa isolates was performed.

Socioeconomic position and participation in colorectal cancer screening.

Background:Colorectal cancer (CRC) screening with faecal occult blood test (FOBT) has the potential to reduce the incidence and mortality of CRC. Screening uptake is known to be inferior in people with low socioeconomic position (SEP) when compared with those with high position; however, the results of most previous studies have limited value because they are based on recall or area-based measures of socioeconomic position, and might thus be subject to selective participation and misclassification. In this study we investigated differences in CRC screening participation using register-based individual information on education, employment, and income to encompass different but related aspects of socioeconomic stratification. Also, the impact of ethnicity and cohabiting status was analysed.Methods:A feasibility study on CRC screening was conducted in two Danish counties in 2005 and 2006. Screening consisted of a self-administered FOBT kit mailed to 177u2009114 inhabitants aged 50–74 years. Information on individual socioeconomic status was obtained from Statistics Denmark.Results:A total of 85u2009374 (48%) of the invited returned the FOBT kits. Participation was significantly higher in women than in men (OR=1.58 (1.55–1.61)), when all socioeconomic and demographic variables were included in the statistical model. Participation also increased with increasing level of education, with OR=1.38 (1.33–1.43) in those with a higher education compared with short education. Also, participation increased with increasing income levels, with OR=1.94 (1.87–2.01) in the highest vs lowest quintile. Individuals with a disability pension, the unemployed and self-employed people were significantly less likely to participate (OR=0.77 (0.74–0.80), OR=0.83 (0.80–0.87), and OR=0.85 (0.81–0.89), respectively). Non-western immigrants were less likely to participate (OR=0.62 (0.59–0.66)) in a model controlling for age, sex, and county; however, this difference might be attributed to low SEP in these ethnic groups ((OR=0.93 (0.87–0.99), when adjusting for SEP indicators).Conclusion:This study based on individual information on several socioeconomic dimensions in a large, unselected population allowed for identification of several specific subgroups within the population with low CRC screening participation. Improved understanding is needed on the effect of targeted information and other strategies in order to reduce socioeconomic inequalities in screening.

Effect of aerosolized rhDNase (Pulmozyme®) on pulmonary colonization in patients with cystic fibrosis

Background: Aerosolized recombinant human deoxyribonuclease (rhDNase I (Pulmozyme®)) has previously been shown to increase pulmonary function and reduce exacerbations of respiratory symptoms in cystic fibrosis (CF) patients with moderate to severe reduction in pulmonary function. Aim: To analyse whether aerosolized Pulmozyme® could reduce the number of bacterial infections in the lower respiratory airways of CF patients without chronic pulmonary infection. Methods: Patients were randomized either to aerosolized Pulmozyme® 2½u2003mg once daily or to no rhDNase treatment. The study period was 1u2003y, and the study was blinded for the Department of Clinical Microbiology. Results: Overall, the number of positive cultures was significantly higher in the untreated group (82%) compared with the treated group (72%) (p<0.05). The most striking difference was found for Staphylococcus aureus, with a prevalence of 30% in the untreated group compared with 16% in the treated group (χ2 test, p<0.0001). Pulmonary function (FEV1) in the treated group showed a significant increase of 7.3% compared to 0.9% in the untreated group (p<0.05).

Serum concentrations of GM-CSF and G-CSF correlate with the Th1/Th2 cytokine response in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection†

The inflammation in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa lung infection is dominated by polymorphonuclear neutrophils (PMNs). There seems to be a relationship between the PMN‐dominated inflammation, pronounced antibody production and a Th2‐dominated response. Apart from mobilizing monocytes and PMNs from the bone marrow, GM‐CSF, G‐CSF and IL‐3 select subsets of dendritic cells, which subsequently induce distinct Th responses. Therefore, the present study examines the correlation between the mobilizing cytokines in serum and the Th responses. The IFN‐γ and IL‐4 production by peripheral blood mononuclear cells, and the concentrations of GM‐CSF and G‐CSF in serum as well as lung function, were determined in 37 CF patients with and 6 CF patients without chronic P. aeruginosa lung infection. The GM‐CSF/G‐CSF ratio correlated both with the IFN‐γ production and good lung function. In addition, an inverse correlation between IL‐3 and IFN‐γ was observed. The results indicate involvement of endogenous GM‐CSF, G‐CSF and IL‐3 in the skewed Th response in CF, and change to a Th1‐dominated response might be achieved with GM‐CSF treatment.

The impact of socioeconomic factors on 30-day mortality following elective colorectal cancer surgery: a nationwide study.

We investigated postoperative mortality in relation to socioeconomic status (SES) in electively operated colorectal cancer patients, and evaluated whether social inequalities were explained by factors related to patient, disease or treatment. Data from the nationwide database of Danish Colorectal Cancer Group were linked to individual socioeconomic information in Statistics Denmark. Patients born before 1921 and those having local surgical or palliative procedures were excluded. A total of 7160 patients, operated on in the period 2001-2004, were included, of whom 342 (4.8%) died within 30 days of surgery. Postoperative mortality was significantly lower in patients with high income (odds ratio (OR)=0.82 (0.70-0.95) for each increase in annual income of EUR 13,500), higher education versus short education (OR)=0.60 (0.41-0.87), and owner-occupied versus rental housing (OR)=0.73 (0.58-0.93). Differences in comorbidity and to a lesser extent lifestyle characteristics accounted for the excess risk of postoperative death among low-SES patients.

Outcome of 24 years national surveillance in different hereditary colorectal cancer subgroups leading to more individualised surveillance

Background Individuals with hereditary non-polyposis colorectal cancer (HNPCC) have a high risk of colorectal cancer (CRC). The benefits of colonic surveillance in Lynch syndrome and Amsterdam-positive (familial CRC type X familial colorectal cancer type X (FCCTX)) families are clear; only the interval between colonoscopies is debated. The potential benefits for families not fulfilling the Amsterdam criteria are uncertain. The aim of this study was to compare the outcome of colonic surveillance in different hereditary subgroups and to evaluate the surveillance programmes. Methods A prospective, observational study on the outcome of colonic surveillance in different hereditary subgroups based on 24u2005years of surveillance data from the national Danish HNPCC register. Results We analysed 13u2005444 surveillance sessions, including 8768 incidence sessions and 20 450u2005years of follow-up. CRC was more incident in the Lynch subgroup (2.0%) than in any other subgroup (0.0–0.4%, p<0.0001), but the incidence of advanced adenoma did not differ between the Lynch (3.6%) and non-Lynch (2.3–3.9%, p=0.28) subgroups. Non-Lynch Amsterdam-positive and Amsterdam-negative families were similar in their CRC (0.1–0.4%, p=0.072), advanced adenoma (2.3–3.3%, p=0.32) and simple adenoma (8.4–9.9%, p=0.43) incidence. In moderate-risk families, no CRC and only one advanced adenoma was found. Conclusions The risk of CRC in Lynch families is considerable, despite biannual surveillance. We suggest less frequent and more individualised surveillance in non-Lynch families. Individuals from families with a strong history of CRC could be offered 5-year surveillance colonoscopies (unless findings at the preceding surveillance session indicate shorter interval) and individuals from moderate-risk families could be handled with the population-based screening programme for CRC after an initial surveillance colonoscopy.