Warren E. Regelmann

EFFECT OF EXTRACELLULAR SLIME SUBSTANCE FROM STAPHYLOCOCCUS EPIDERMIDIS ON THE HUMAN CELLULAR IMMUNE RESPONSE

Staphylococcus epidermidis infection of plastic catheters is often associated with heavy deposits of slime. To test whether this slime affects the human cellular immune response, its effect on the lympho-proliferative response of mononuclear cells to polyclonal stimulators was measured. Slime drastically reduces this response. Its inhibitory action was not immediate but took place over a few days and resulted in destruction of affected cells. The effect is dose related. This inhibition of cellular response may contribute to S epidermidis infection of implanted prostheses.

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.

Prognostic implications of initial oropharyngeal bacterial flora in patients with cystic fibrosis diagnosed before the age of two years

To evaluate the significance of early bacteriologic findings in infants and younger children with cystic fibrosis, we divided patients identified at < or = 2 years of age into groups by initial oropharyngeal culture: group NF, normal respiratory flora (n = 17); group SA, Staphylococcus aureus without Pseudomonas aeruginosa (n = 20); group PA, P. aeruginosa without S. aureus (n = 6); group PA/SA, P. aeruginosa and S. aureus (n = 7); and group O, other potentially pathogenic bacteria (n = 31). Follow-up of patients ranged in age from 5.4 to 13 years. At diagnosis, group PA/SA had lower Brasfield scores (p < 0.02) and higher gamma-globulin levels (p < 0.03) than the other groups. Five years after diagnosis, Brasfield scores were significantly lower in groups PA and PA/SA compared with the other groups; mean gamma-globulin levels did not differ significantly among the groups. Groups PA and PA/SA also had evidence of significantly greater obstructive pulmonary disease by spirometry than groups NF and O. Group PA/SA had a 10-year survival estimate of 57%, significantly lower than the 92% to 100% estimates of the other four groups (p < 0.0001). Thus P. aeruginosa in initial oropharyngeal cultures from patients < or = 2 years of age with cystic fibrosis was associated with significantly increased morbidity, and the finding of P. aeruginosa and S. aureus together in initial oropharyngeal cultures with a significantly increased mortality rate during the first 10 years after diagnosis.

Immunogenicity of a new purified fusion protein vaccine to respiratory syncytial virus: A multi-center trial in children with cystic fibrosis

A third generation, purified fusion protein (PFP-3) vaccine was developed to prevent severe respiratory syncytial virus (RSV) disease in high-risk groups. A phase II, multi-center, adjuvant-controlled trial was performed in RSV seropositive children with cystic fibrosis (CF); 151 received the adjuvant-control and 143 received the vaccine. Details of the vaccine-induced immune response are presented. At enrollment, RSV-specific, serum antibodies were comparable between both groups. A highly sensitive and specific serum antibody vaccine profile was established for the PFP-3 vaccine. At post-vaccination and end-of-study, RSV-specific, neutralizing antibody (Nt Ab) and binding antibody (Bd Ab) to the fusion (F) protein were significantly higher in PFP-3 vaccinees. After 28 days post-vaccination, Nt Ab and Bd Ab to F protein titers declined slowly at rates of 0.23 and 0.37 log2 per month, respectively. The PFP-3 vaccine-induced a robust immune response that lasted throughout the RSV season.

Clinical significance of the recovery of Aspergillus species from the respiratory secretions of cystic fibrosis patients

The frequent recovery of Aspergillus species from the respiratory tract secretions of cystic fibrosis (CF) patients is well recognized, and the presence of the fungus in the airways may trigger an inflammatory response that can manifest as the clinical entity known as allergic bronchopulmonary aspergillosis (ABPA). In our CF patient population we studied the clinical characteristics of those who had Aspergillus sp. recovered from their respiratory tract secretions (n = 45) and compared them with the characteristics seen, during the same time period. In those patients who were culture negative for Aspergillus sp. (n = 167). There were no differences in peripheral blood eosinophil count (P = 0.9) or serum immunoglobulin E levels (P = 0.61). By logistic regression analysis there seemed to be an increased risk for more advanced lung disease, both radiographically (defined by a Brasfield chest radiograph score <18) and by lung function parameters in those who were culture positive. However, after appropriate adjustment, almost all the increased risk was associated with age and gender, but not with the presence of Aspergillus sp. in respiratory secretions. Additionally, increasing age was strongly correlated with the risk of Aspergillus sp. being cultured from respiratory secretions (P = 0.0025). The presence of Aspergillus sp. in respiratory secretions was not associated with two indicators of atopy in our CF patient population. We do not have evidence that the culture of Aspergillus sp. from CF respiratory secretions is independently associated with an increased risk for more advanced lung disease. Pediatr Pulmonol. 1996; 21:6–10.

Insulin Secretion Improves in Cystic Fibrosis Following Ivacaftor Correction of CFTR: A Small Pilot Study

To determine whether the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector—ivacaftor.

Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study

BACKGROUND Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years. METHODS In the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight <14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145. FINDINGS Between Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of -46·9 mmol/L (SD 26·2, p<0·0001), weight Z score by 0·2 (0·3; p<0·0001), BMI Z score by 0·4 (0·4, p<0·0001), and height Z score by -0·01 (0·3; p=0·84). INTERPRETATION Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted. FUNDING Vertex Pharmaceuticals Incorporated.

The impact of incident methicillin resistant Staphylococcus aureus detection on pulmonary function in cystic fibrosis

The incidence of methicillin resistant Staphylococcus aureus (MRSA) infection is increasing in cystic fibrosis (CF), but the impact of MRSA detection on clinical outcomes is unclear. Our objective was to determine whether incident detection of MRSA is associated with a change in pulmonary function over time in CF patients. We analyzed data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a prospective observational study of CF patients in North America. Multivariable piecewise linear regression was used to model the impact of incident detection of MRSA on pulmonary function over time, measured by percent predicted forced expiratory volume in one second (FEV1% predicted), adjusting for potential confounders. There were 5,090 patients ≥6 years old who were MRSA negative for at least 2 calendar years. Five hundred ninety‐three (12%) of these patients acquired MRSA during the years 2001–2003, with detection rates of MRSA during those years rising from 4.4% to 6.9%. MRSA positive patients had a lower FEV1% predicted and received more antibiotic and other therapies than patients who remained MRSA negative. After adjusting for antibiotic therapy and other potential confounders, MRSA positive patients also had a higher rate of decline in FEV1% predicted both before and after the incident culture, although the rate of FEV1% predicted decline did not change significantly after MRSA detection. In conclusion, although MRSA in CF was a marker for more aggressive therapy and may reflect increased disease severity, incident MRSA detection was not associated with a changing rate of FEV1% predicted decline. Pediatr. Pulmonol. 2008; 43:1117–1123.

Oral glucose tolerance testing in children with cystic fibrosis

Ode KL, Frohnert B, Laguna T, Phillips J, Holme B, Regelmann W, Thomas W, Moran A. Oral glucose tolerance testing in children with cystic fibrosis.

Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR

To determine whether the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector—ivacaftor.