Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least one F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor.

OBJECTIVE: To describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers. STUDY DESIGN: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. RESULTS: Among 608 patients on ETI, 109 (17.9%) reported at least one AE. The majority (N=85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs. 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA p-value 0·026). CONCLUSIONS: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

Risk of CFTR-related disorders and cystic fibrosis in an Italian cohort of CRMS/CFSPID subjects in preschool and school age.

The identification of cystic fibrosis screening-positive, inconclusive diagnosis (CFSPID) in infants is a controversial outcome of newborn screening for cystic fibrosis (CF). Today, despite improvements in the knowledge of CFSPID and the description of several cohorts, little data are available on cohorts with a follow-up period of more than 6 years. In this study, we report the outcomes of an Italian cohort of CFSPID individuals with CFSPID or formerly CFTR-related disorders (CFTR-RD) (CFSPID > CFTR-RD) or diagnosed with CF (CFSPID > CF). This was an observational and multicentre Italian study collecting clinical data on CFSPID born between the period January 1, 2011, and December 13, 2019. A total of 268 participants were included: 243 with persistent CFSPID, 7 with CFSPID > CFTR-RD, and 18 with CFSPID > CF. The trend of sweat chloride (SC) values, percentage of definitive diagnoses, lung function in school-aged children, and development of CF-related complications were evaluated. At the end of the observation period, almost 80% of the individuals with CFSPID did not have a conclusive diagnosis. A total of 29 children (10.8%) transitioned to a diagnosis of CF for pathological SC values (≥ 60 mmol/L) or multi-organ involvement, and 18 (6.7%) to CFTR-RD. Children who were followed up for > 6 years (median age, 7.5 years; range, 6.04-10.5) had normal lung function and were pancreatic sufficient, and the evolution in CF was only present in two cases. CONCLUSION: Most Italian preschool and school-aged children with CFSPID did not have a conclusive diagnosis, and progression to CF was unlikely in children > 6 years of age. An annual follow-up could be indicated to identify early evolution in clinical features consistent with a CFTR-RD. WHAT IS KNOWN: • Cystic Fibrosis newborn screening identifies also subjects with an inconclusive diagnosis (CFSPID). • Over time a variable percentage of CFSPIDs will be diagnosed as CF. • Little data is available on CFSPIDs with a follow-up period of more than six years. WHAT IS NEW: • 80% of Italian preschool and school-age CFSPIDs not have a conclusive diagnosis. • Italian preschool and school-age CFSPIDs have normal lung function and are pancreatic sufficient. • Annual follow-up after 6 years is recommended in CFSPID with abnormal LCI2.5 or with a CF-causing variant in trans with a VVCC.

Unilateral temporary diaphragmatic paralysis secondary to bronchial artery embolization in a girl with cystic fibrosis and massive hemoptysis: a case report.

BACKGROUND: Massive hemoptysis is a serious complication in Cystic Fibrosis (CF), occurring commonly in older patients. Bronchial artery embolization (BAE) can be performed to stop the bleeding. BAE is generally safe and effective, but can sometimes lead to serious complications. We report the first case of temporary unilateral diaphragmatic paralysis associated to lung consolidation following BAE in a pediatric CF female patient. This complication worsened the lung function of the patient who underwent lung transplantation after 9 months. CASE PRESENTATION: A 14 years old female CF patient followed by the CF center of Florence presented low-grade fever, cough increase and recurrent episodes of major hemorrhages such as to carry out a BAE. Within 24 h the patient started to complain of severe thoracic pain in the right hemithorax, increased dyspnea and fever. A computed tomographic angiography and a dynamic fluoroscopic evaluation revealed the right diaphragmatic paralysis, not present before the procedure. After 4 days the clinical condition and radiological imaging had improved with restored mobility of the right hemidiaphragm. Nine months later, she required mechanical ventilation, and subsequently the initiation of extracorporeal membrane oxygenation (ECMO) for a pulmonary exacerbation with septic shock. Lung transplantation in ECMO was performed with success. CONCLUSION: Clinicians should be aware of the possibility of phrenic nerve injury with BAE in pediatric CF patients.

A critical review of definitions used to describe Pseudomonas aeruginosa microbiological status in patients with cystic fibrosis for application in clinical trials.

BACKGROUND: Definition of Pseudomonas aeruginosa (Pa) microbiological status is essential for patients' inclusion in clinical trials. The aim of this study was to agree on the definitions of Pa infection status for initial infection, eradication and chronic infection to be used in clinical trials and to propose additional future study areas. METHODS: An exhaustive literature search was performed. The clinimetric properties of different definitions of Pa microbiological status were evaluated. RESULTS: Historical studies have mostly used culture-based definitions, although some have also involved complementary anti-Pa antibodies. Clinimetric analysis showed great variability in the definitions used, leading to differences in reliability, validity, responsiveness to treatment and correlation with outcome measures. Use of serology for initial Pa infection and successful Pa eradication introduced a greater level of complexity as antibody tests are not standardised. Moreover, the chronology of the immune response to Pa antigenic determinants was not completely clear. Chronic Pa infection was characterized by high levels of antibodies and good concordance between culture results and serology. CONCLUSIONS: Microbiological monitoring, regular sampling from the airways and standardization of culture methods remain essential requisites for microbiological definitions. Despite limitations, serology should be incorporated in the definitions of initial infection and eradication used in clinical trials to better classify patients at enrolment, mainly in non-expectorating children. This requires standardization of serological testing.

Relevance of multidrug-resistant Pseudomonas aeruginosa infections in cystic fibrosis.

Multidrug-resistant (MDR) Pseudomonas aeruginosa is an important issue for physicians who take care of patients with cystic fibrosis (CF). Here, we review the latest research on how P. aeruginosa infection causes lung function to decline and how several factors contribute to the emergence of antibiotic resistance in P. aeruginosa strains and influence the course of the infection course. However, many aspects of the practical management of patients with CF infected with MDR P. aeruginosa are still to be established. Less is known about the exact role of susceptibility testing in clinical strategies for dealing with resistant infections, and there is an urgent need to find a tool to assist in choosing the best therapeutic strategy for MDR P. aeruginosa infection. One current perception is that the selection of antibiotic therapy according to antibiogram results is an important component of the decision-making process, but other patient factors, such as previous infection history and antibiotic courses, also need to be evaluated. On the basis of the known issues and the best current data on respiratory infections caused by MDR P. aeruginosa, this review provides practical suggestions to optimize the diagnostic and therapeutic management of patients with CF who are infected with these pathogens.

Evidence of transmission of a Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus clone: a family affair.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) may represent a serious public health problem, owing to the spread of toxin-producing lineages. The presence of genes encoding for Panton-Valentine leukocidin (PVL) is an important virulence marker, as the clinical sequelae of PVL-positive infections are often described as more severe than those of PVL-negative S. aureus infections. To date, the presence of PVL has not appeared to be common in Italy; we describe the intrafamilial transmission of an epidemic PVL-producing CA-MRSA lineage, Southwest Pacific clone (SWP). Our data suggested that the strain circulated from the father, who was recurrently affected by a soft tissue infection, to the mother, who showed nasal colonization, and to their child, who was hospitalized with symptoms of necrotizing pneumonia. In this case, we found that a recurrent skin infection that is not normally taken into account may represent a serious threat if caused by a PVL-producing strain. Our findings may have considerable implications for strategies for infection control and treatment of methicillin-resistant S. aureus infections.

Molecular epidemiology of meticillin-resistant Staphylococcus aureus in Italian cystic fibrosis patients: a national overview.

BACKGROUND: The genetic background, transmissibility and virulence of MRSA have been poorly investigated in the cystic fibrosis (CF) population. The aim of this multicentre study was to analyse MRSA strains isolated from CF patients attending nine Italian CF care centres during a two-year period (2004-2005). All CF patients infected by MRSA were included. METHOD: Antibiotic susceptibility testing, SCCmec typing, Panton-Valentine Leukocidin (PVL) production, and Multi Locus Sequence Typing (MLST) analysis were carried out on collected isolates (one strain per patient). RESULTS: One hundred and seventy-eight strains isolated from 2360 patients attending the participating centres were analysed. We detected 56 (31.4%) SCCmec IV PVL-negative strains, with a resistance rate of 80.3% to clindamycin and of 14.5% to trimethoprim/sulphamethoxazole. MLST analysis showed that many isolates belonged to known epidemic lineages. The largest clone grouping of 29 isolates from 6 centres had the genetic background (ST8-MRSA-IV) of the American lineages USA300 and USA500, thus demonstrating the diffusion of these strains in a population considered at risk for hospital associated infections. CONCLUSIONS: Known MRSA epidemic clones such as USA600, USA800, USA1100, and UK EMRSA-3 were described for the first time in Italy. The diffusion of MRSA strains with high pathogenic potential in the CF population suggests that analysis of the MRSA strains involved in pulmonary infections of these patients is needed.

Early Pseudomonas aeruginosa infection in individuals with cystic fibrosis: is susceptibility testing justified?

OBJECTIVES: To test the presumption that Pseudomonas aeruginosa isolates responsible for initial lung infection in individuals with cystic fibrosis (CF) are invariably susceptible to antipseudomonal agents. METHODS: Antibiotic susceptibility was determined (MIC and Etest) in two populations of P. aeruginosa associated with initial lung infection. Population 1: environmental isolates (n=78). Population 2: clinical isolates responsible for first infection in previously non-infected patients (85 isolates from 85 patients). Susceptibility or resistance was determined using current BSAC guidelines; ninth version (2009). RESULTS: The majority (≥ 90%) of isolates in both bacterial populations were susceptible to the front-line antipseudomonal agents; colistin, ciprofloxacin, tobramycin, ceftazidime, amikacin and meropenem. Up to 10% of isolates were resistant to one or more antibiotics. A single isolate from each population would be defined as resistant to tobramycin based on a breakpoint (>128 mg/L) that has been suggested for use in patients receiving inhaled therapy. CONCLUSIONS: The high prevalence of susceptibility found in P. aeruginosa isolates associated with initial infection contrasts with the high prevalence of resistance found in isolates from chronic CF lung infection. However, susceptibility in early isolates cannot be presumed. Until further data are obtained from clinically based studies, susceptibility tests should continue to be performed to assist the choice of antibiotics for treatment of early infection.

Case report: cystic fibrosis, lung transplantation, and the novel H1N1 flu.

The H1N1 pandemic flu is a significant risk factor for both patients with chronic disease who need organ transplantation and transplant recipients. This population needs special care regarding comorbidities and related complications. MB, a 38-year-old Italian cystic fibrosis male patient with lung and pancreatic involvement, was referred to our division in July 2009 for fever-associated arthromyalgia, headache, and rhinitis. Lung transplantation had been performed in September 2005, and he was subsequently treated with immunosuppressive therapy: tacrolimus, everolimus, and prednisolone. In the past, chronic respiratory colonization with Pseudomonas aeruginosa and intermittent infection with Aspergillus flavus, chronic renal failure, hypertension, and diabetes mellitus complicated his clinical history. He started antiviral treatment with oseltamivir despite no travel history and no respiratory symptoms. H1N1 swab was positive. Three days later, the patient was admitted to the hospital for the persistence of fever and the onset of cough. Chest x-ray showed a left lower pneumonia, which was confirmed by computerized tomography. Broad-spectrum antibiotic therapy led to an improvement of the clinical condition. The patient was discharged 8 days later; a control swab was negative. This case report suggests some general considerations regarding solid organ recipients: 1) Flu-related complications require early treatment (both antiviral and antibiotic); 2) active microbiologic surveillance is important to prevent lethal infections (ie, invasive aspergillosis); 3) evaluation of immunosuppressant blood levels is necessary for drug-drug interactions. Active prevention is the best option for decreasing morbidity and mortality in the transplanted patient.

Application of multiplex single nucleotide primer extension (mSNuPE) to the identification of bacteria: the Burkholderia cepacia complex case.

Burkholderia cepacia complex (BCC) is characterized by a complex taxonomy constituted by seventeen closely related species of both biotechnological and clinical importance. Several molecular methods have been developed to accurately identify BCC species but simpler and effective strategies for BCC classification are still needed. A single nucleotide primer extension (SNuPE) assay using gyrB as a target gene was developed to identify bacteria belonging to the B. cepacia (BCC) complex. This technique allows the successful detection and distinction of single nucleotide polymorphisms (SNPs) and is effectively applied in routine medical diagnosis since it permits to analyze routinely many samples in a few times. Seven SNuPE primers were designed analyzing the conserved regions of the BCC gyrB sequences currently available in databases. The specificity of the assay was evaluated using reference strains of some BCC species. Data obtained enabled to discriminate bacteria belonging to the species B. multivorans, B. cenocepacia (including bacteria belonging to recA lineages III-A, III-C, and III-D), B. vietnamiensis, B. dolosa, B. ambifaria, B. anthina and B. pyrrocinia. Conversely, identification failed for B. cepacia, B. cenocepacia III-B and B. stabilis. This study demonstrates the efficacy of SNuPE technique for the identification of bacteria characterized by a complex taxonomical organization as BCC bacteria.

The costs of treatment of early and chronic Pseudomonas aeruginosa infection in cystic fibrosis patients.

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 FEV(1)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.

Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis.

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 patient's 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.

Bone mineral density in cystic fibrosis patients under the age of 18 years.

AIM: The increase in life expectancy of cystic fibrosis (CF) patients has brought about a rise in new clinical problems in these patients, such as a decrease in bone mineral density (BMD). The cause of diminished BMD in CF is multi-factorial. METHODS: The aim of this cross-sectional study, conducted on 39 CF patients under the age of 18 years, was to evaluate the degree of bone mineralization and the prevalence of low BMD in these patients during a follow-up at the Cystic Fibrosis Regional Center of Tuscany, using a dual energy X-ray absorptiometry (DXA) scan, and to then study the factors correlated with low BMD. RESULTS: Areas BMD values (g/cm2) and Z-score values were determined. Eighteen patients (46%) out of the our sample had decreased BMD, while 21 patients (54%) had normal values. A statistically significant association was found between BMD Z-score values and pancreatic insufficiency, BMI<5th percentile and DeltaF508 homozygosis. Subjects treated with oral steroid therapy had a 3.9 times greater risk of developing osteoporosis compared to non-treated subjects (95% C.I.: 1.07-22.6; R.R. 4.9). An association was found between BMD Z-score values and FEV1 values (r=0.29; P=0.06), physical activity total score values (r=0.22; P=0.19) and the Chrispin-Norman chest radiographic score (r=-0.31; P=0.06). CONCLUSION: Early identification of reduced bone mass values would permit early intervention to prevent the development of osteoporosis. Maintaining pulmonary function, guaranteeing optimal nutritional status, following an adequate program of physical activity and controlling steroid intake could maintain BMD over time.

Isolation measures for prevention of infection with respiratory pathogens in cystic fibrosis: a systematic review.

Respiratory infections are the most important cause of morbidity and mortality in patients with cystic fibrosis (CF). These infections are typically caused by a limited number of respiratory pathogens, particularly Burkholderia cepacia complex (BCC) and Pseudomonas aeruginosa (PA). Since the 1980s, several outbreaks of unique strains of PA and BCC among CF patients attending the same CF care centres have been described, leading to a sharp decline in the patients' health. One of the measures adopted in CF centres to interrupt ongoing outbreaks is the separation of patients with a respiratory tract culture that is positive for PA or BCC from patients who are not infected. This type of measure has been implemented routinely in many CF centres to prevent cross-transmission of PA and BCC. The aim of this review was to determine what evidence is available to support the efficacy of isolation (or segregation) practices in preventing, delaying or reducing the risk for CF patients of acquiring PA and BCC. A systematic review of scientific literature from 1980 to 31 December 2004 was performed. Existing guidelines regarding infection control in CF were also analysed. In total, 398 relevant papers were retrieved. Only 10 well-designed studies were found that evaluated the efficacy of isolation practices in preventing the transmission of respiratory pathogens in CF care centres (one prospective controlled study, one retrospective cohort study, five 'before-after' studies and three cross-sectional studies. No systematic reviews or randomized controlled trials exist on this subject. In the absence of studies with an experimental, controlled design, the efficacy of isolation practices in preventing the transmission of respiratory pathogens in CF remains unproven. However, notwithstanding the considerable limits represented by the study designs, which were mainly retrospective, the observational studies reviewed seem to support the implementation of isolation (or segregation) measures to reduce the risk of transmission of BCC and PA in CF patients.

Transmission of Burkholderia cepacia complex: evidence for new epidemic clones infecting cystic fibrosis patients in Italy.

To analyze national prevalence, genomovar distribution, and epidemiology of the Burkholderia cepacia complex in Italy, 225 putative B. cepacia complex isolates were obtained from 225 cystic fibrosis (CF) patients attending 18 CF centers. The genomovar status of these isolates was determined by a polyphasic approach, which included whole-cell protein electrophoresis and recA restriction fragment length polymorphism (RFLP) analysis. Two approaches were used to genotype B. cepacia complex isolates: BOX-PCR fingerprinting and pulsed-field gel electrophoresis (PFGE) of genomic macrorestriction fragments. A total of 208 (92%) of 225 isolates belonged to the B. cepacia complex, with Burkholderia cenocepacia as the most prevalent species (61.1%). Clones delineated by PFGE were predominantly linked to a single center; in contrast, BOX-PCR clones were composed of isolates collected either from the same center or from different CF centers and comprised multiple PFGE clusters. Three BOX-PCR clones appeared of special interest. One clone was composed of 17 B. cenocepacia isolates belonging to recA RFLP type H. These isolates were collected from six centers and represented three PFGE clusters. The presence of insertion sequence IS 1363 in all isolates and the comparison with PHDC reference isolates identified this clone as PHDC, an epidemic clone prominent in North American CF patients. The second clone included 22 isolates from eight centers and belonged to recA RFLP type AT. The genomovar status of strains with the latter RFLP type is not known. Most of these isolates belonged to four different PFGE clusters. Finally, a third clone comprised nine B. pyrrocinia isolates belonging to recA RFLP type Se 13. They represented three PFGE clusters and were collected in three CF centers.

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.