A.S. Neri

An overview of international literature from cystic fibrosis registries: 2. Neonatal screening and nutrition/growth

BACKGROUND This is the second article related to a review of the literature based on data from national cystic fibrosis (CF) registries up to June 2008 and covering a total of 115 studies. It focuses on two topics: neonatal screening (NS) and nutritional status, with particular reference to growth. METHODS Ten papers meeting the inclusion criteria were found on the topic of NS and its impact on the course of the disease, and were analyzed according to a dedicated grid. The issue of nutrition was addressed by 14 studies, analyzed according to similar criteria. RESULTS Most of the studies report benefits of early diagnosis by NS, albeit to variable degrees. The benefits were assessed in terms of better nutritional status and growth, but also in terms of lower overall morbidity rate as compared to subjects diagnosed by symptoms. The main biases of these studies, which partly undermine the validity of their results, are also analyzed. A part of our analysis on nutrition/growth is dedicated to the identification of the most suitable parameters to define malnutrition: in children older than two years the body mass index percentile (BMIp) appears to be the most sensitive and significantly associated with respiratory function. Better nutritional status and satisfactory growth appear to be associated with better lung function and lower risk of death. The relationship between nutritional status and socio-economic status is also of interest. CONCLUSIONS CF registry studies support the outcome of cohort observational studies i.e. that pre-symptomatic early diagnosis is beneficial, especially in terms of nutritional status and growth. Studies on nutrition indicate that good nutritional status is associated with better respiratory function and prognosis. Regarding methods, the need emerged to manage potential biases of this kind of non randomized studies, resorting to suitable statistical techniques, such as matching and stratification and, above all, to multivariate methods able to provide estimates adjusted for the main covariates tested.

An overview of international literature from cystic fibrosis registries: 1. Mortality and survival studies in cystic fibrosis

Patient registries are organized systems of data collection for scientific, clinical or health strategy purposes. Aims of our review were to document scientific literature based on data and information from cystic fibrosis (CF) registries; to understand which clinical problems have been addressed and for which of these the studies concerned have correctly answered the questions raised (i.e. a methodological critique) and to identify clinical issues in need of further investigation. The review included primary studies starting from a formally constituted CF registry of at least national level, using data from the registry to evaluate research hypotheses. This article is an overview of the research undertaken, focusing in detail on the issues of mortality and survival. The studies considered here focused mainly or secondarily on survival in CF, the aim being to ascertain an improving trend, identify any prognostic factors and, in some cases, attempt to provide a predictive model of survival.

An overview of international literature from cystic fibrosis registries. Part 3. Disease incidence, genotype/phenotype correlation, microbiology, pregnancy, clinical complications, lung transplantation, and miscellanea

This is the third article related to a review of the literature based on data from national cystic fibrosis (CF) patient registries up to June 2008 and covering a total of 115 published studies. It focuses on several topics: CF incidence, genotype/phenotype correlation, microbiology, pregnancy/paternity, clinical complications, lung transplantation, and others. Seventy seven papers meeting the inclusion criteria were found to be related to the topics listed above. Another seven studies, already evaluated in previous papers of this series, were recalled for specific topics. Incidence is described by several studies, results being quite different from one country to another and quite inhomogeneous among regions within the same country. Studies on genetics address the genotype/phenotype correlation and look for a predictive value of CFTR mutations in terms of clinical outcome, with controversial results. Papers on microbiology describe the clinical relevance of different pathogens and their role in the progress of CF lung disease. A few articles give information on the features of CF women undergoing a pregnancy and try to identify the ones associated with a better outcome. Studies on clinical complications discuss prevalence and the role of haemoptysis, pneumothorax, CF related diabetes, ABPA and cancer. Papers on lung transplantation focus on models able to improve the selection criteria for transplantation candidates and the factors linked to post transplantation survival. Finally, several studies deal with a number of interesting topics related to CF epidemiology: clinical trial methodology, quality of care comparison among countries and centers, relationship between diagnosis and age/gender, and evaluation of pharmacological therapy. On the whole, CF Registries have already contributed to important advances in the knowledge of the natural history of CF, establishing the foundations for future improvement in CF research and care.

An overview of international literature from cystic fibrosis registries. Part 4: Update 2011

A total of 53 national cystic fibrosis (CF) patient registry studies published between July 2008 and November 2011 have been reviewed, focusing on the following topics: CF epidemiology, nutrition, microbiology, clinical complications, factors influencing diagnosis and lung disease, effects of socioeconomic status, therapeutic strategy evaluation, clinical trial methodology. The studies describe the clinical characteristics of CF patients, the incidence and prevalence of disease and role of gender gap, as well as the influence of socioeconomic status and environmental factors on clinical outcomes, covering a variety of countries and ethnic groups. Original observations describe patients as they get older, with special reference to the adult presentation of CF and long-term survival. Methodological aspects are discussed, covering the design of clinical trials, survival analysis, auxometry, measures of quality of life, follow up of lung disease, predictability of disease progression and life expectancy. Microbiology studies have investigated the role of selected pathogens, such as Burkholderia species and MRSA. Pulmonary exacerbations are discussed both as a factor influencing morbidity and an endpoint in clinical trials. Finally, some studies give insights on complications, such as CF-related diabetes and hemoptysis, and emerging problems, such as chronic nephropathy.

Antibiotic Therapy against Pseudomonas aeruginosa in Cystic Fibrosis

Abstract Antibiotic strategies against Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients should consider the natural history of the P. aeruginosa infection, ranging from the first isolation of the germ in the airways to isolation at every microbiological culture, and the patients clinical condition. Antibiotic treatment against P. aeruginosa given at the time of first isolation may prevent or delay chronic infection. The period of intermittent colonization can be considered the time before the development of mucoid P. aeruginosa phenotype. The optimal treatment strategy in this stage remains unclear in terms of agents used and duration of treatment. To treat acute exacerbation, the authors suggest using intravenous administration of two different classes of antibiotics. Maintenance antibiotics are administered to slow the decline in pulmonary function for P. aeruginosa chronic infection. The meaning of maintenance therapy has changed over time, beginning from intravenous quarterly anti- Pseudomonas antibiotics, irrespective of symptoms, to other strategies such as oral macrolides, ciprofloxacin or inhaled antibiotics (tobramycin and colistin). Aerosol delivery can provide a high concentration at the desired site with minimal absorption and therefore low risk of toxicity. There is scientific evidence that antibiotics are clinically effective in CF patients. Antibiotic selection should be based on periodic isolation and identification of pathogens and antimicrobial susceptibility.

The Costs of Treatment of Early and Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis Patients

Abstract The aim of cystic fibrosis (CF) care is to improve both the life expectancy and quality of life of patients. However, rising costs and limited resources of health services must be taken into account. There are many different antibiotic strategies for therapy of Pseudomonas aeruginosa infection in CF patients. In this 5-year retrospective study we found that the cost of treatment of initial infection is considerably lower than the cost of treating chronic P. aeruginosa infections. The percentage distribution of costs of antibiotic treatment in relationship to the administration route was considerably different between outpatients and inpatients. We observed an increase in antibiotic costs with the age of the patient and the decrease in FEV1 values. The implementation of early eradication treatment, in addition to decreasing the prevalence of patients chronically infected by P. aeruginosa, might also bring about a notable decrease in costs.

Parenteral Administration of Tobramycin for Pulmonary Exacerbations in Cystic Fibrosis Patients: Toxicity, Serum Levels and Efficacy

Recent progress in therapy has significantly prolonged the mean survival rate of cystic fibrosis (CF) patients to 36 years at this time 1. This prolonged longevity is due to multiple factors and therapeutic strategies, including parenteral antibiotic administration, which can also be associated with undesirable side effects for the patient 1. in an effort to reduce the incidence of side effects due mainly to the use of parenteral administration of tobramycin, international guidelines recommend to carry out audiometry regularly, to monitor tobramycin serum levels and evaluate renal function. At this point only a few studies have compared the efficacy and risk of side effects of parenteral administration of tobramycin in multiple doses versus single dose, recently introduced into clinical practice 2-6. The aims of the present study were:

Chronic infection sustained by a Pseudomonas aeruginosa High-Risk clone producing the VIM-1 metallo-β-lactamase in a cystic fibrosis patient after lung transplantation

BACKGROUND The significance of chronic lung infection by multidrug-resistant (MDR) pathogens in Cystic Fibrosis (CF) transplanted patients remains controversial, and the available information is overall limited. Here we describe the case of a chronic infection, sustained by a metallo-β-lactamase (MBL)-producing P. aeruginosa strain, in a CF patient following lung transplantation. METHODS Twelve P. aeruginosa isolates collected from a CF patient over a 15-years follow-up period after lung transplantation were analysed for their antibiotic susceptibility profile, MBL production and clonal relatedness. Available clinical and microbiological records were reviewed. RESULTS The transplanted CF patient was chronically infected by an MBL-producing P. aeruginosa strain which harboured a blaVIM-1 determinant inserted into a novel class 1 integron. The strain exhibited an MDR phenotype and belonged to the globally widespread ST235 epidemic clonal lineage, which however is not a typical CF-associated epidemic clone. Despite the chronic infection, the long-term outcome of this patient during the post-transplant period was characterized by the absence of acute exacerbations and by a mostly stable pulmonary function. CONCLUSIONS This report provides one of the few descriptions of MBL-producing P. aeruginosa infections in CF patients, and the first description of such an infection after lung transplantation in these patients. Infection with the MBL-producing strain apparently did not significantly affect the patient pulmonary function.

196 FEV1 decline in cystic fibrosis (CF): much attention should be devoted to children and adolescents

Studies suggest that the decline in pulmonary function begins early in CF infants even in those patients without respiratory symptoms. Objective: to describe pulmonary function in CF children younger than 3 years old and to determine if there is any association between pulmonary function and clinical features. Methods: observational and retrospective, study. We collected data from CF patients who underwent an Infant Pulmonary Function Test (IPFT) before the age of three years. IPFTs were assessed by partial flow/volume curves with the rapid thoracicabdominal compression technique to obtain the maximal flow at the functional residual capacity (V′maxFRC). Clinical issues recorded were: age, gender, genetics, pancreatic sufficiency, nutritional status and microbiological findings. Results: 46 patients (31 males) with a median (interquartile range) age of 8 months (5 to 15) were included. Overall V′maxFRC Z score was −0.8 (−1.4 to 0.3), −0.1 (−1.1 to 0.7) in males and −0.9 (−1.8 to 0.3) in females (p =NS). V′maxFRC Z score was −0.3 (−1.1 to 0.2) in children younger than 6 months and −0.1 (−1.3 to 1) in older ones (p =NS). In patients homozygous p.508del V′maxFRC Z score was −0.5 (−1.2 to 0.8) while in patients with other mutations it was −0.2 (−1.2 to 0.6) (p =NS). There was also no statistical difference in V′maxFRC between well-nourished and bad-nourished patients, and between patients with and without Pseudomonas aeruginosa (PA) in sputum. Conclusion: IPFT assessed by partial flow/volume curves was normal in our CF population less than 3 years old. We have not found any difference in pulmonary function comparing CF children with different clinical features.

392 Brave lung: non invasive ventilation (NIV) and pneumothorax

Hypercapnic respiratory failure and recurrent pneumothorax (pnx) in severe cystic fibrosis (CF) requires ad hoc evaluation and ventilatory management. Pnx is a relative contraindication to NIV so its use is not encouraged if pulmonary bubbles and medical history of past pnx are described. The patient is a 26 yo male with severe lung disease (FEV1 20−30% pred.) in nocturnal oxygen therapy (OT) at NIV start. Clinical history is characterised by malnutrition with PEG for enteral feeding, chronic airway infection by P. aeruginosa and MRSA, sinusopathy and depressive syndrome. In 1999 he had recurrent left pnx treated with pleurodesis and a right one ten yrs after drained and talced. A fall in lung function resulting in symptomatic hypoxaemia-hypercapnia, persistent during exacerbations, followed the last pnx. Though large bubbles all through the superior right lobe on CT Thorax, we gradually initiated him to NIV with nasal mask, IPAP and EPAP 11−4 cmH2O in spontaneous mode. BGA motivated us to go on so we acclimatised him to night NIV with OT 1L/min. NIV was well tolerated with disappearance of morning headache, somnolence and better quality of sleep. After a month, IPAP was set at 15 cmH2O and awakening BGA revealed better PaO2 and stable CO2. After 6 months, BGA improved more: awakening CO2 was yet ~50mmHg and PaO2 was fair; CT follow-up did not change. Adherence showed 100% of use for 4 hrs/day with an average of 9h26min. Proven and potential benefits of NIV in CF are well known. Indications and contraindications have not been yet defined but, in our opinion, NIV can be used in severe lung damage with positive results. Nevertheless a prudent and a lowpressures-approach is mandatory.