Effect of Elexacaftor/Tezacaftor/Ivacaftor on Pseudomonas aeruginosa Acquisition and Chronic Infection at a Single Pediatric Cystic Fibrosis Care Center.

OBJECTIVES: As cystic fibrosis (CF) lung disease progresses, the airways become infected with opportunistic pathogens, such as Pseudomonas aeruginosa (PA). In October 2019, the US Food and Drug Administration approved elexacaftor/tezacaftor/ivacaftor (ETI), a highly effective modulator therapy (HEMT), for individuals 12 years and older with 1 copy of the F508del cystic fibrosis transmembrane conductance regulator (CFTR) mutation. ETI increases the amount of and function of CFTR in the respiratory epithelium, improving mucociliary clearance and reducing static airway mucus, a major trigger for chronic infection and inflammation. METHODS: A retrospective analysis of inhaled tobramycin (iTOB) prescriptions between January 1, 2016, and December 31, 2021, was performed. This captured data before and after ETI approval at Children's Mercy Kansas City (CMKC). The number of individuals with new PA acquisition and individuals considered -chronically infected was analyzed. RESULTS: The number of eradication prescriptions declined in 2020 and 2021, with 15 (7%) and 12 (5%) -individuals prescribed therapy for those years, respectively. A similar pattern was observed for -prescriptions for chronic infection. A reduction was seen in 2020 and 2021, with 28 (13%) and 20 (9%) individuals -prescribed therapy for the respective years. CONCLUSIONS: The CMKC experienced a decrease in the number of courses of iTOB prescribed during the last 6 years. The reasons for this are likely multifactorial and may include the implementation of standardized PA surveillance and eradication protocols, the effect of HEMT on mucociliary clearance and airway microbiology, and the poorly understood effects of the SARS-CoV-2 pandemic on the epidemiology of respiratory infections.

New Tic Disorder in a Child With Cystic Fibrosis Treated With Elexacaftor/Tezacaftor/Ivacaftor.

The widespread use of highly effective cystic fibrosis transmembrane-conductance regulator -modulator therapy has dramatically altered the lives of individuals with cystic fibrosis. Clinical trials leading to -modulator approval by the US Food and Drug Administration demonstrated improvements in major -outcome measures including pulmonary function, gastrointestinal symptoms, and quality of life. Subsequent clinical experience has confirmed significant improvement across these domains. Adverse effects reported -during clinical trials included headache and dizziness amongst others including upper respiratory infections, abdominal pain, diarrhea, rash, and elevated serum transaminases. Post marketing clinical experience has suggested that there may be additional central nervous system adverse effects resulting from modulator therapy. Reported events after initiation of cystic fibrosis transmembrane-conductance regulator modulator treatment include headaches and increased prevalence of mental health concerns including anxiety and depression. We report a new tic disorder in a 7-year-old girl with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor.

Child Health and the Pediatric Pulmonology Workforce: 2020-2040.

There is concern as to whether the supply of pediatric pulmonology (PULM) subspecialists will be adequate to meet future demand. As part of an American Board of Pediatrics (ABP) Foundation-sponsored supplement investigating the future of the pediatric subspecialty workforce, this article assesses the current PULM clinical workforce and estimates the clinical workforce supply in the United States through 2040. The current workforce was assessed using ABP certification and Maintenance of Certification data, and a workforce supply model evaluating population growth, clinical effort, and geographic trends was developed after incorporating ABP data. Findings demonstrate that the number of pediatric pulmonologists has gradually increased over the past decade, and the ratio of subspecialists to children is likely to increase another 20% to 40% over the next 2 decades, although absolute numbers remain small. Geographic variation in access will persist in some regions. The proportion of women in the discipline has increased, but the proportion of pediatric pulmonologists from underrepresented in medicine backgrounds still lags behind the general population. Based on current trends, the PULM clinical workforce appears equipped to meet both population growth and the modest increase in demand for clinical services speculated to occur because of changes in the subspecialty's clinical portfolio. However, several factors could inhibit growth, and geographic maldistribution may continue to impact care access. Efforts to address variation in access and demographic diversity in the field are warranted. This article concludes by discussing the training, clinical practice, policy, and future workforce research implications of the data presented.

The history of workforce concerns in pediatric pulmonary Medicine.

Children are affected by a broad spectrum of acute and chronic respiratory disorders. The number of children with respiratory disease is increasing, as are the complexity of disease pathophysiology and the management demands on pediatric pulmonologists. Despite slowly increasing numbers of board-certified pediatric pulmonologists, large areas of the country are underserved and there is a perception of an impending workforce crisis. There are multiple reasons for these concerns. A joint effort between the Pediatric Pulmonology Division Directors Association and Pediatric Pulmonary Training Directors Association was undertaken to address these issues.

A statement on the current status and future needs of the pediatric pulmonology workforce: Pipeline Workgroup.

There is growing concern that current trends in pediatric pulmonology will lead to a workforce shortage resulting in patients having difficulty accessing subspecialty care. As part of the Pediatric Pulmonology Division Directors Association and Pediatric Pulmonary Training Directors Association Workforce Summit, we examined factors affecting the recruitment of learners into pediatric pulmonary fellowship training (PPFT) programs. The goal of our workgroup was to describe these issues and develop a plan to increase the pipeline of learners who ultimately pursue PPFT. Specifically, we summarize factors that impact decisions to undertake PPFT, describe existing initiatives to enhance recruitment, and propose future strategies to increase early career learner interest.

Changes in fecal elastase-1 following initiation of CFTR modulator therapy in pediatric patients with cystic fibrosis.

BACKGROUND: Improvement in exocrine pancreatic function in persons with CF (pwCF) on cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been documented in clinical trials using fecal pancreatic elastase-1 (FE-1). Our group endeavored to evaluate real-world data on FE-1 in children on CFTR modulator therapy at three pediatric cystic fibrosis (CF) centers. METHODS: Pediatric pwCF were offered FE-1 testing if they were on pancreatic enzyme replacement therapy (PERT) and on CFTR modulator therapy according to their center's guideline. FE-1 data were collected retrospectively. The primary outcome was absolute change in FE-1. RESULTS: 70 pwCF were included for analysis. 53 had baseline and post-modulator FE-1 values. There was a significant increase in FE-1 from median 25 mcg/g (IQR 25-60) at baseline to 57 mcg/g (IQR 20-228) post-modulator (p<0.001 by Wilcoxon matched pairs), with an absolute change in FE-1 of median 28 mcg/g (IQR -5-161) and mean 93.5 ± 146.8 mcg/g. Age was negatively correlated with change in FE-1 (Spearman r=-0.48, p<0.001). 15 pwCF (21%) had post-modulator FE-1 values ≥200 mcg/g, consistent with pancreatic sufficiency (PS). The PS group was significant for younger age at initiation of first CFTR modulator and a higher baseline FE-1. CONCLUSIONS: Most pwCF experienced an increase in FE-1 while receiving CFTR modulator treatment and a small percentage demonstrated values reflective of PS. These data suggest that PS may be attained in those that initiated modulator therapy at a younger age or had a higher baseline FE-1. FE-1 testing is suggested for children on any CFTR modulator therapy.

Pseudomonas aeruginosa antibiotic susceptibility during long-term use of aztreonam for inhalation solution (AZLI).

OBJECTIVES: Aztreonam for inhalation solution (AZLI) is an inhaled antibiotic for patients with cystic fibrosis (CF) and Pseudomonas aeruginosa airway infection. The risk of selecting for P. aeruginosa isolates with reduced susceptibility to antibiotics is inherent to their use, but is of particular concern following repeated exposure and when complete eradication of lung pathogens is difficult to obtain. We investigated whether repeated treatment courses of AZLI led to decreases in P. aeruginosa susceptibility to aztreonam or other antibiotics. METHODS: Serial sputum specimens were collected and processed for isolation and quantification of all P. aeruginosa isolates in a Phase 3 open-label, 18 month study (NCT00128492) including 274 CF patients receiving up to nine courses of AZLI twice daily (AZLI2) or thrice daily (AZLI3) (28 days on/28 days off). P. aeruginosa antibiotic susceptibility testing was conducted. RESULTS: No changes were observed in the aztreonam MIC(50) for all P. aeruginosa isolates collected from AZLI3 patients, while intermittent increases were observed in the aztreonam MIC(90). Approximately 70% of the P. aeruginosa isolates with the highest aztreonam MIC from each patient receiving AZLI3 remained unchanged or decreased relative to that patient's equivalent isolate at baseline; 30% experienced an increase in MIC. Few decreases in P. aeruginosa susceptibility to other antibiotics were observed in AZLI3 patients, while increases in P. aeruginosa susceptibility to tobramycin were observed. CONCLUSIONS: Few decreases in aztreonam susceptibility were reported in patients receiving AZLI3. Increases in tobramycin susceptibility were observed, suggesting that novel treatment paradigms may be able to prolong antibiotic susceptibility in CF patients.

The implementation of an aminoglycoside induced ototoxicity algorithm for people with cystic fibrosis.

Aminoglycoside antibiotics treat respiratory infections in cystic fibrosis (CF). An aminoglycoside induced ototoxicity algorithm (AIOA) was implemented to assess ototoxicity among people with CF treated with intravenous and/or inhaled aminoglycosides. Prior to AIOA implementation, 14 of 52 patients (27%) treated with intravenous aminoglycosides had an audiogram. In the 24 months post AIOA implementation, 43 of 44 patients (98%) treated with intravenous aminoglycosides had an audiogram, with 27 (63%) demonstrating abnormalities. Prior to AIOA development, 18 of 70 patients (26%) who received at least two courses of inhaled aminoglycosides had an audiogram. Post AIOA implementation, 33 patients qualified for an audiogram after receiving inhaled aminoglycosides. Of these, 19 (58%) had an audiogram and 10 (53%) had abnormalities. Overall, we identified 46 (61%) people with CF with hearing abnormalities compared to 2.4% in the CF Foundation Patient Registry. This suggests an urgent need for CF programs to implement AIOAs.

Innovating and adapting in pediatric pulmonology and sleep medicine during the COVID-19 pandemic: ATS pediatric assembly web committee consensus statement for initial COVID-19 virtual response.

Coronavirus disease 2019 (COVID-19) has been an unprecedented and continuously evolving healthcare crisis. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spread rapidly and initially little was known about the virus or the clinical course for infected children. In the United States of America, the medical response has been regionalized, based on variation in community transmission of the virus and localized outbreaks. Pediatric pulmonary and sleep divisions evolved in response to administrative and clinical challenges. As the workforce transitioned to working remotely, video conferencing technology and multicenter collaborative efforts were implemented to create clinical protocols. The COVID-19 pandemic challenges the framework of current medical practice but also highlights the dynamic and cooperative nature of pediatric pulmonology and sleep medicine. Our response to this pandemic has laid the groundwork for future challenges.

Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis.

RATIONALE: The effectiveness and safety of aztreonam lysine for inhalation (AZLI) in patients with cystic fibrosis (CF) on maintenance treatment for Pseudomonas aeruginosa (PA) airway infection was evaluated in this randomized, double-blind, placebo-controlled study. OBJECTIVES: To evaluate the safety and efficacy of inhaled aztreonam lysine in controlling PA infection in patients with CF. METHODS: After randomization and a 28-day course of tobramycin inhalation solution (TIS), patients (n = 211; > or =6 yr; > or =3 TIS courses within previous year; FEV(1) > or = 25% and < or =75% predicted values) were treated with 75 mg AZLI or placebo, twice or three times daily for 28 days, then monitored for 56 days. The primary efficacy endpoint was time to need for additional inhaled or intravenous antipseudomonal antibiotics. Secondary endpoints included changes in respiratory symptoms (CF Questionnaire-Revised [CFQ-R] Respiratory Scale), pulmonary function (FEV(1)), and sputum PA density. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored. MEASUREMENTS AND MAIN RESULTS: AZLI treatment increased median time to need for additional antipseudomonal antibiotics for symptoms of pulmonary exacerbation by 21 days, compared with placebo (AZLI, 92 d; placebo, 71 d; P = 0.007). AZLI improved mean CFQ-R respiratory scores (5.01 points, P = 0.02), FEV(1) (6.3%, P = 0.001), and sputum PA density (-0.66 log(10) cfu/g, P = 0.006) compared with placebo; no AZLI dose-response was observed. Adverse events reported for AZLI and placebo were comparable and consistent with CF lung disease. Susceptibility of PA to aztreonam at baseline and end of therapy were similar. CONCLUSIONS: AZLI was effective in patients with CF using frequent TIS therapy. AZLI delayed time to need for inhaled or intravenous antipseudomonal antibiotics, improved respiratory symptoms and pulmonary function, and was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00104520).

Aztreonam Lysine Inhalation Solution in Cystic Fibrosis.

Patients with cystic fibrosis (CF) develop pulmonary disease secondary to airway infection and dysregulated inflammation. Therapeutic innovations such as nebulized antimicrobial therapy targeting specific pathogens have resulted in improvements in quality of life and life expectancy. Aztreonam lysine for inhalation (AZLI) solution was initially approved to improve respiratory symptoms in CF patients with Pseudomonas aeruginosa (PA) in 2010 by the Food and Drug Administration. Since then, research broadening labeling and clinical application has been developed. In this review, we analyze published and ongoing research regarding AZLI therapy in CF. A search of the Cochrane Database of Systematic Reviews and the PubMed and ClinicalTrials.gov databases was conducted to identify publications about AZLI. Three pre-approval studies were identified and assessed. Two are Phase 3, placebo-controlled trials, assessing a variety of safety and efficacy endpoints, leading to FDA approval. The third is an open-label extension of the two previous trials. An additional seven post-approval, completed trials were identified and are included in this review. They represent a variety of study designs including safety and efficacy in patients with mild lung disease and young patients, an active comparator trial vs inhaled tobramycin, an eradication study, a study among patients with Burkholderia cepacia, and a study assessing continuous alternating antibiotic therapy. Finally, five ongoing clinical trials are discussed. Overall, studies demonstrated that inhaled aztreonam is a safe and effective antimicrobial treatment for the eradication of newly acquired P. aeruginosa and long-term suppressive therapy of chronic endobronchial infection among people with cystic fibrosis.

Endobronchial Glomus Tumor in a Child.

Glomus tumors (GTs) are rare, usually benign, mesenchymal neoplasms typically located in the cutaneous tissues of the extremities. Visceral locations have been reported in ∼5% of cases. The average age at diagnosis is 42 years. GTs originating in the respiratory tract of pediatric patients are exceedingly rare. We report a 16-year-old male with a GT of the right lower lobe bronchus.

Human metapneumovirus and respiratory syncytial virus infections in older children with cystic fibrosis.

BACKGROUND: Human metapneumovirus (hMPV) has been isolated from children with acute respiratory infection worldwide. Its epidemiology remains to be defined in children with cystic fibrosis (CF). We describe the epidemiology and clinical impact of hMPV in CF children and compared it to respiratory syncytial virus (RSV). METHODS: CF children ages 7-18 years were studied prospectively during the 1998 -1999 RSV season. Nasopharyngeal specimens were collected during acute respiratory illnesses and tested for respiratory viruses. Blood specimens were drawn early, mid, and end of the RSV season, and tested for serological evidence of hMPV and RSV infections. Rates of lower respiratory tract illnesses (LRTI) and hospitalizations for pulmonary exacerbations were compared during the time intervals they developed serological evidence of infection to their non-infection intervals. RESULTS: Six of 44 CF children had a virus positive respiratory illness in 56 LTRI events and 18 hospitalizations. Serological evidence of hMPV and RSV infections occurred in 16 and 20 CF children, respectively; 8 had infections with both viruses. A greater proportion of CF children had >or=1 LRTI during their infection intervals compared to their non-infection intervals (13/25 vs. 5/25; P=0.03). A trend for higher rates of LRTI was observed in the infection intervals compared to non-infection intervals (9.5 +/- 11.0 vs. 4.2 +/- 9.9 per 1,000 child-days; P=0.06), and it was significantly greater with a more conservative estimate (one event per child per interval; 7.4 +/- 7.7 vs. 2.6 +/- 5.4 per 1,000 child-days; P

Enterovirus d68. A focused review and clinical highlights from the 2014 U.S. Outbreak.

Enterovirus D68 (EV-D68), a member of the Picornaviridae family, was first identified in 1962 and is part of a group of small, nonenveloped RNA viruses. As a family, these viruses are among the most common causes of disease among humans. However, outbreaks of disease attributable to EV-D68 have been rarely reported in the previous 4 decades. Reports from a few localized outbreaks since 2008 describe severe lower respiratory tract infection in children. In the late summer of 2014, EV-D68 caused a geographically widespread outbreak of respiratory disease of unprecedented magnitude in the United States. The Centers for Disease Control and Prevention was first notified of increased respiratory viral activity by Children's Mercy Hospitals (CMH) in Kansas City, Missouri, and EV-D68 was identified in 50% of nasopharyngeal specimens initially tested. Between mid-August and December 18, 2014, confirmed cases of lower respiratory tract infection caused by EV-D68 were reported in 1,152 people in 49 states and the District of Columbia. A focused review of EV-D68 respiratory disease and clinical highlights from the 2014 U.S. outbreak are presented here.

Treatment of cast bronchitis with low-dose oral azithromycin.

Cast or plastic bronchitis is an unusual disorder that is rarely encountered in the pediatric population. It is characterized by the expectoration of large, branching plugs of airway debris. These "casts" conform to the shape of portions of the tracheobronchial tree, and give the disorder its name. Cast bronchitis is typically seen in association with several primary pulmonary disorders and cyanotic congenital heart disease. It can be classified as inflammatory or acellular, based on the histologic characteristics of the casts. The presence of large, obstructive plugs filling the airways of lobes or entire lungs can result in a variety of clinical signs and symptoms, and may ultimately lead to respiratory failure and death. Conventional treatment of cast bronchitis has focused on the clearance of obstructing material from the airways combined with therapy for any underlying cardiopulmonary disease. Unfortunately, this approach has not proven very effective, and patient mortality remains high. We report on a case in which a patient with cast bronchitis was treated with long-term, low-dose oral azithromycin. This therapy resulted in clinical, spirometric, and radiographic improvement of the patient.

Pulmonary lipoblastoma in an 18-month-old child: a unique tumor in children.

Lipoblastoma, a rare benign tumor of adipose tissue, typically occurs in the superficial or deep layers of soft tissue on the trunk or extremities. Other sites of occurrence include the head, neck, and retroperitoneum. Lipoblastoma of the chest wall and parietal pleural have been reported, but occurrence within the lung has not been previously described. We report a case of pulmonary lipoblastoma in a young child presenting with complete opacification of the left hemithorax and mediastinal shift on chest radiograph. A lobectomy was performed, and the diagnosis was made by histological examination.

Invasive mechanical ventilation for acute respiratory failure in children with cystic fibrosis: outcome analysis and case-control study.

The outcome for cystic fibrosis (CF) patients requiring intubation and invasive mechanical ventilation (IMV) due to acute respiratory failure (ARF) has been poor. Mortality rates have been reported as high as 60-90%. However, a review of mortality in children has not been published in 20 years. Our objectives were to study outcomes in CF patients requiring IMV due to ARF between 1988-1998, compare recent outcomes with those previously reported, and identify risk factors associated with poor outcome. We additionally attempted to identify factors suggesting an increased risk of developing ARF requiring IMV. A retrospective cohort study design was used, comparing IMV survivors and nonsurvivors with a nested case-control study to identify risk factors for ARF leading to IMV. All patients cared for at our Center who required IMV for ARF between 1988-1998 were identified. Outcome, age, steroid use, forced vital capacity (FVC), forced expired volume in 1 sec (FEV(1)), microbiology, nutritional status, CF-related diabetes (CFRD), liver dysfunction, and history of major hemoptysis (HEM) or pneumothorax (PTX) were recorded. Cases were matched for gender and age with CF controls identified through a clinical database.Thirty-eight episodes of IMV due to ARF were reported in 33 patients. Three subjects underwent IMV on two or more occasions, but only the first episode was included in analysis. Older age was the only factor that was significantly associated with mortality: 9 subjects were <5 years of age (mortality, 22%), while 24 were 5-34 years old (mortality, 75%) (P = 0.013). There was an increased risk of having an episode of ARF requiring IMV in malnourished subjects (OR = 4.2; 95% CI = 1.66-10.51) and in those with a history of HEM (OR = 6.3; 95% CI = 1.75-22.65). Infants and young children with CF requiring IMV due to ARF have a favorable prognosis, whereas those >or=5 years of age suffer significantly higher mortality. Malnutrition and a history of HEM are important risk factors for having an episode of ARF requiring IMV.