Prevalence, risk factors and outcomes of cardiac disease in cystic fibrosis: a multinational retrospective cohort study.

BACKGROUND: Although people living with cystic fibrosis (PwCF) often have some risk factors for cardiovascular disease, including diabetes and chronic inflammation, little is known about the long-term cardiac risk in this condition. We aimed to determine the characteristics, rates and outcomes for cardiac disease in CF. METHODS: We looked at rates and outcomes for cardiac disease in 5649 adult PwCF in the UK CF Registry and 6265 adult PwCF in TriNetX (a global federated database of electronic healthcare record data). We used propensity matching to compare risk of major adverse cardiac events (MACE) (myocardial infarction, left-sided heart failure and atrial fibrillation) in PwCF against matched non-CF comparators in the general population and other inflammatory diseases. RESULTS: PwCF had a high prevalence of diabetes but low rates of hypertension and obesity. Some cardiac risk factors (age, diabetes and hypertension) were associated with MACE, but relationships between disease-specific risk factors (lung function and intravenous antibiotic days) were also observed. In propensity score-matched analyses, PwCF had higher risk of MACE than matched general population comparators (hazard ratio (HR) 1.65, 95% CI 1.40-1.95; p<0.001) and an equivalent or higher relative risk compared with other inflammatory conditions considered "high risk" for cardiovascular disease, including systemic lupus erythematosus (HR 0.95, 95% CI 0.82-1.09; p=0.44), rheumatoid arthritis (HR 1.21, 95% CI 1.00-1.48; p<0.001) and HIV (HR 0.93, 95% CI 0.82-1.06; p=0.29). CONCLUSIONS: PwCF are at increased risk of adverse cardiac disease events. Future work should focus on defining determinants of cardiovascular risk such that appropriate risk stratification can be employed.

Dynamic chest radiography: a state-of-the-art review.

Dynamic chest radiography (DCR) is a real-time sequential high-resolution digital X-ray imaging system of the thorax in motion over the respiratory cycle, utilising pulsed image exposure and a larger field of view than fluoroscopy coupled with a low radiation dose, where post-acquisition image processing by computer algorithm automatically characterises the motion of thoracic structures. We conducted a systematic review of the literature and found 29 relevant publications describing its use in humans including the assessment of diaphragm and chest wall motion, measurement of pulmonary ventilation and perfusion, and the assessment of airway narrowing. Work is ongoing in several other areas including assessment of diaphragmatic paralysis. We assess the findings, methodology and limitations of DCR, and we discuss the current and future roles of this promising medical imaging technology.Critical relevance statement Dynamic chest radiography provides a wealth of clinical information, but further research is required to identify its clinical niche.

Feasibility of dynamic chest radiography to calculate lung volumes in adult people with cystic fibrosis: a pilot study.

INTRODUCTION: Dynamic chest radiography (DCR) is a novel, low-dose, real-time digital imaging system where software identifies moving thoracic structures and can automatically calculate lung areas. In an observational, prospective, non-controlled, single-centre pilot study, we compared it with whole-body plethysmography (WBP) in the measurement of lung volume subdivisions in people with cystic fibrosis (pwCF). METHODS: Lung volume subdivisions were estimated by DCR using projected lung area (PLA) during deep inspiration, tidal breathing and full expiration, and compared with same-day WBP in 20 adult pwCF attending routine review. Linear regression models to predict lung volumes from PLA were developed. RESULTS: Total lung area (PLA at maximum inspiration) correlated with total lung capacity (TLC) (r=0.78, p<0.001), functional residual lung area with functional residual capacity (FRC) (r=0.91, p<0.001), residual lung area with residual volume (RV) (r=0.82, p=0.001) and inspiratory lung area with inspiratory capacity (r=0.72, p=0.001). Despite the small sample size, accurate models were developed for predicting TLC, RV and FRC. CONCLUSION: DCR is a promising new technology that can be used to estimate lung volume subdivisions. Plausible correlations between plethysmographic lung volumes and DCR lung areas were identified. Further studies are needed to build on this exploratory work in both pwCF and individuals without CF. TRIAL REGISTRATION NUMBER: ISRCTN64994816.

Physical activity assessment and vascular function in adults with cystic fibrosis and their non-CF peers.

An understanding of physical activity (PA) and related health benefits remains limited in adults with Cystic Fibrosis (CF). Raw acceleration data metrics may improve the quality of assessment and further this understanding. The study aimed to compare PA between people with CF (pwCF) and non-CF peers and examine associations between PA, vascular function and health outcome measures. PA was assessed in 62 participants (31 pwCF) using ActiGraph accelerometers. Vascular function (a marker of cardiovascular disease risk) was assessed using flow-mediated dilatation (FMD) in sub-groups of pwCF (n = 12) and matched controls. Average Euclidean norm minus one (ENMO) (total PA) was significantly lower (p = 0.005) in pwCF (35.09 ± 10.60 mg), than their non-CF peers (44.62 ± 13.78 mg). PwCF had PA profiles (intensity gradient) indicative of more time in lower intensity activity (-2.62 ± 0.20, -2.37 ± 0.23). Vigorous activity was positively associated with lung function (rs = 0.359) and Quality of Life (r = 0.412). There were no significant differences (p = 0.313) in FMD% between pwCF (5.29 ± 2.76%) and non-CF peers (4.34 ± 1.58%) and no associations with PA. PwCF engaged in less moderate-to-vigorous PA and demonstrated a steeper PA profile than their non-CF peers.

Developing an ecological approach to physical activity promotion in adults with Cystic fibrosis.

BACKGROUND: There are few examples of interventions designed to promote physical activity (PA) in adults with Cystic fibrosis (CF). Increasing levels of habitual PA may be more feasible and result in greater compliance than conventional exercise training inventions which give little or no attention to long-term PA behaviour. Despite this there is limited research exploring perceptions of PA among adults with CF. The study aimed to understand the ecological correlates of PA in adults with CF and to involve individuals with CF, their families (where applicable) and clinicians in a formative process to inform the development of an ecological approach to PA promotion in this population. METHODS: An iterative approach was utilised, whereby findings from earlier phases of the research informed subsequent phases. Semi-structured interviews were conducted to explore patients' perceptions of PA, devised using the PRECEDE component of the PRECEDE-PROCEED model. Followed by, focus groups to discuss the perceived barriers, facilitators and opportunities for PA participation and how this information could inform the development and delivery of a PA intervention. Separate focus groups were conducted with individuals with CF (n = 11) and their families and CF MDT members. Thematic analysis was used to construct themes. RESULTS: Physical and mental wellbeing manifested as both barriers and facilitators of PA. CF is characterised by a progressive decline in physical function, which presents as a number of challenging symptoms and set-backs for an individual with CF. PA represents an opportunity for participants to slow the rate of this decline and manage the symptoms associated with the condition. Enjoyment was an important facilitator of PA. Exercise professionals and family reinforce PA behaviour, particularly during adolescence. CONCLUSIONS: PA promotion should form part of routine CF care with additional exercise professional support during adolescence.

Eruptive melanocytic naevi following initiation of elexacaftor/ivacaftor/tezacaftor for cystic fibrosis.

A 29 year old woman with cystic fibrosis (CF) presented to CF clinic following the sudden development of over 200 pigmented naevi located predominately on the trunk and limbs 3 months after commencing elexacaftor/tezacaftor/ivacaftor, a novel triple-therapy CFTR modulator therapy for CF. Skin biopsy confirmed benign naevi and the clinical presentation was consistent with eruptive melanocytic naevi. Elexacaftor/tezacaftor/ivacaftor received marketing authorisation in August 2020 and this is the first report of associated naevi. The individual described here remains clinically well, and continues on elexacaftor/tezacaftor/ivacaftor with dermatology follow-up.

Cardiac sarcoidosis in an adult person with cystic fibrosis: a case report.

Cardiac sarcoidosis and cystic fibrosis (CF) are both rare conditions and their co-existence has not previously been noted in adults. For the first time we report a case of isolated cardiac sarcoidosis in a woman with CF, and discuss the possible combined aetiological factors. As the life expectancy of people with CF continues to increase, clinicians should be aware of the emergence of concomitant inflammatory conditions typically diagnosed in adulthood, and the diagnostic challenges this may present.

Elexacaftor/Tezacaftor/Ivacaftor as a Bridge to Lung Retransplant in a Recipient With Cystic Fibrosis.

The triple-combination cystic fibrosis transmembrane conductance regulator modulator elexacaftor/- tezacaftor/ivacaftor is known to improve lung function and have extrapulmonary benefits in people with cystic fibrosis. However, there is limited evidence for its use in patients with cystic fibrosis after lung transplant, where the donor lung expresses normal levels of the cystic fibrosis transmembrane conductance regulator. We describe the use of elexacaftor/tezacaftor/ivacaftor as a bridge to potential lung retransplant in a 37-year-old man with cystic fibrosis and chronic lung allograft dysfunction. Although forced expiratory volume in 1 second did not improve, the patient had decreased sputum volume, no pulmonary exacerbations of cystic fibrosis, and no longer required continuous antibiotic therapy. Pancreatic function, revised Cystic Fibrosis Questionnaire scores, sinus symptoms, weight, and corticosteroid dependence significantly improved. There were no reported side effects attributable to elexacaftor/tezacaftor/ivacaftor. However, the patient exhibited declined renal function, which had been initially attributed to lability in cyclosporin levels but which were corrected after lithotripsy for renal calculi. Triple-combination modulators of the cystic fibrosis transmembrane conductance regulator may offer benefits to carefully selected individuals awaiting retransplant, balanced against the risk of worsened immunosuppressant level control.

Use of Dynamic Chest Radiography to Assess Treatment of Pulmonary Exacerbations in Cystic Fibrosis.

Background Although spirometry is an important marker in the management of pulmonary exacerbations in cystic fibrosis (CF), it is a forced maneuver and can generate aerosol. Therefore, it may be difficult to perform in some individuals. Dynamic chest radiography (DCR) provides real-time information regarding pulmonary dynamics alongside fluoroscopic-style thoracic imaging. Purpose To assess the effect of pulmonary exacerbation treatment by using both spirometry and DCR and assess the clinical utility of DCR in participants with CF experiencing pulmonary exacerbations. Materials and Methods In this prospective, observational, single-center pilot study, spirometry and DCR were performed before and after treatment of pulmonary exacerbations in participants with CF between December 2019 and August 2020. Spirometry measured forced expiratory volume in 1 second (FEV1) and forced vital capacity. DCR helped to measure projected lung area (PLA), hemidiaphragm midpoint position, and speed during tidal and deep breathing. Data were analyzed by using the paired t test or Wilcoxon signed-rank test. Correlation was assessed by using the Spearman rank correlation coefficient. Results Twenty participants with CF (mean age, 25 years ± 7 [standard deviation]; 14 women) were evaluated. Spirometry showed that percentage predicted FEV1 improved from a median of 44% (interquartile range [IQR], 17%) before treatment to 55% (IQR, 16%) after treatment (P = .004). DCR showed improvement in median deep breathing excursion for left and right hemidiaphragms (from 18 [IQR, 11] to 25 [IQR, 16] mm [P = .03] and from 13 [IQR, 6] to 19 [IQR, 14] mm [P = .03], respectively) and in median expiratory speed following deep breathing for left and right hemidiaphragms (from 7 [IQR, 2] to 11 [IQR, 5] mm/sec [P = .004] and 6 [IQR, 3] to 9 [IQR, 6] mm/sec [P = .004], respectively). PLA rate of change during full expiration and change in PLA during tidal breathing improved (from a mean of 42 cm2/sec ± 16 to 56 cm2/sec ± 24 [P = .03] and from a mean of 29 cm2 ± 14 to 35 cm2 ± 10 [P = .03], respectively). Conclusion Dynamic chest radiography demonstrated improvement in diaphragm speed and range of chest wall movement during respiration aftere treatment for pulmonary exacerbations in cystic fibrosis and showed potential as a tool to investigate the effect of pulmonary exacerbations on lung mechanics. Clinical trials registration no. NCT01234567 Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Characterisation of hemidiaphragm dysfunction using dynamic chest radiography: a pilot study.

OBJECTIVES: Dynamic chest radiography (DCR) is a novel real-time digital fluoroscopic imaging system that produces clear, wide field-of-view diagnostic images of the thorax and diaphragm in motion, alongside novel metrics on moving structures within the thoracic cavity. We describe the use of DCR in the measurement of diaphragm motion in a pilot series of cases of suspected diaphragm dysfunction. METHODS: We studied 21 patients referred for assessment of diaphragm function due to suspicious clinical symptoms or imaging (breathlessness, orthopnoea, reduced exercise tolerance and/or an elevated hemidiaphragm on plain chest radiograph). All underwent DCR with voluntary sniff manoeuvres. RESULTS: Paradoxical motion on sniffing was observed in 14 patients, and confirmed in six who also underwent fluoroscopy or ultrasound. In four patients, DCR showed reduced hemidiaphragm excursion, but no paradoxical motion; in three, normal bilateral diaphragm motion was demonstrated. DCR was quick to perform, and well tolerated in all cases and with no adverse events reported. DCR was achieved in ∼5 min per patient, with images available to view by the clinician immediately within the clinical setting. CONCLUSION: DCR is a rapid, well-tolerated and straightforward chest radiography technique that warrants further investigation in the assessment of diaphragm dysfunction.

Measuring the effect of elexacaftor/tezacaftor/ivacaftor combination therapy on the respiratory pump in people with CF using dynamic chest radiography.

BACKGROUND: The CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) leads to significant improvement in the symptoms and spirometry of people with cystic fibrosis (pwCF), but little evidence exists to understand its effect on respiratory pump function. Dynamic chest radiography (DCR) is a novel cineradiographic tool that identifies and tracks the chest wall and diaphragm throughout the breathing cycle, alongside fluoroscopic images of the chest of diagnostic quality. METHODS: In this observational work, we examined the spirometry and DCR of 24 pwCF before and after starting ELX/TEZ/IVA. DCR automatically tracked the hemidiaphragm midpoints and projected lung area (PLA) during tidal and deep breathing manoeuvres. RESULTS: ppFEV1 (61±18 to 73±22, P<0.001) and ppFVC (77±16 to 88±15, P<0.001) improved significantly. DCR demonstrated a significant increase in hemidiaphragm excursion on both the right (18±11 to 26±9 mm, P<0.001) and left (21±11 to 31±11 mm, P<0.001) sides, as well as maximum hemidiaphragm speed during inspiration (right 22±14 to 31±11 mm/s, P=0.03; left 28±11 to 37±16 mm/s, P=0.02). PLA at end-expiration was significantly reduced (334±71 to 290±72cm2, P<0.001), with a significant increase in ΔPLA (83±40 to 117±36cm2, P<0.001). CONCLUSIONS: DCR demonstrated significant improvements in hemidiaphragm excursion and ΔPLA in pwCF started on ELX/TEZ/IVA. These changes likely reflect a reduction in air trapping and improved elastic recoil of the chest, and are consistent with improvements seen in spirometry. The changes seen with DCR are physiologically plausible and correlate well with spirometry. DCR warrants further investigation as a tool for assessing the impact of CFTR-modulating therapies.

Unilateral diaphragm paralysis with COVID-19 infection.

Neurological complications are well described in SARS-CoV-2, but for the first time we report a case of unilateral diaphragm paralysis occurring early in mechanical ventilation for respiratory failure due to such an infection. The patient subsequently required tracheostomy and ventilator support for 37 days, and had increased breathlessness and an elevated diaphragm at clinic review 9 months later. Dynamic chest radiography demonstrated persistent diaphragm paralysis with an accompanying postural change in lung volumes, and he subsequently underwent surgical plication. This case demonstrates that although persistent dyspnoea is a common feature following SARS-CoV-2 infection and is usually due to deconditioning or persistent parenchymal involvement, it can be due to other causes and needs to be investigated appropriately.

Transmission, adaptation and geographical spread of the Pseudomonas aeruginosa Liverpool epidemic strain.

The Liverpool epidemic strain (LES) is an important transmissible clonal lineage of Pseudomonas aeruginosa that chronically infects the lungs of people with cystic fibrosis (CF). Previous studies have focused on the genomics of the LES in a limited number of isolates, mostly from one CF centre in the UK, and from studies highlighting identification of the LES in Canada. Here we significantly extend the current LES genome database by genome sequencing 91 isolates from multiple CF centres across the UK, and we describe the comparative genomics of this large collection of LES isolates from the UK and Canada. Phylogenetic analysis revealed that the 145 LES genomes analysed formed a distinct clonal lineage when compared with the wider P. aeruginosa population. Notably, the isolates formed two clades: one associated with isolates from Canada, and the other associated with UK isolates. Further analysis of the UK LES isolates revealed clustering by clinic geography. Where isolates clustered closely together, the association was often supported by clinical data linking isolates or patients. When compared with the earliest known isolate, LESB58 (from 1988), many UK LES isolates shared common loss-of-function mutations, such as in genes gltR and fleR. Other loss-of-function mutations identified in previous studies as common adaptations during CF chronic lung infections were also identified in multiple LES isolates. Analysis of the LES accessory genome (including genomic islands and prophages) revealed variations in the carriage of large genomic regions, with some evidence for shared genomic island/prophage complement according to clinic location. Our study reveals divergence and adaptation during the spread of the LES, within the UK and between continents.

Possible COVID-19 reinfection in a patient with X-linked agammaglobulinaemia.

This report highlights the case of a patient with X-linked agammaglobulinaemia (XLA) and resultant bronchiectasis who was discharged from hospital after recovering from real-time reverse transcriptase-PCR positive COVID-19 infection having had a subsequent negative swab and resolution of symptoms, but was readmitted 3 weeks later with recrudescent symptoms and a further positive swab. Although there are reports of COVID-19 infection in XLA, for the first time we report a case of possible reinfection. Lessons learnt from this case include the potential for reinfection of COVID-19 in a patient with a weakened immune system and the importance of repeating COVID-19 swabs in inpatients. Extra caution needs to be taken when providing care in groups of patients who have a weakened or absent immune system.

The clinical and microbiological utility of inhaled aztreonam lysine for the treatment of acute pulmonary exacerbations of cystic fibrosis: An open-label randomised crossover study (AZTEC-CF).

BACKGROUND: The objective of this study was to explore the clinical and microbiological outcomes associated with substituting inhaled aztreonam lysine for an intravenous antibiotic in the treatment of acute pulmonary exacerbations of CF. METHODS: An open-label randomised crossover pilot trial was conducted at a UK CF centre among 16 adults with CF and P. aeruginosa infection. Median [IQR] age was 29.5 [24.5-32.5], mean ± SD forced expiratory volume in 1 second (FEV1) was 52.4 ± 14.7 % predicted. Over the course of two exacerbations, participants were randomised to sequentially receive 14 days of inhaled aztreonam lysine plus IV colistimethate (AZLI+IV), or dual IV antibiotics (IV+IV). Primary outcome was absolute change in % predicted FEV1. Other outcomes evaluated changes in quality of life, bacterial load and the lung microbiota. RESULTS: The difference between mean change in lung function at day 14 between AZLI+IV and IV+IV was +4.6% (95% CI 2.1-7.2, p=0.002). The minimum clinically important difference of the Cystic Fibrosis Revised Questionnaire (CFQ-R) was achieved more frequently with AZLI+IV (10/12, 83.3%) than IV+IV (7/16, 43.8%), p=0.05. No differences were observed for modulation of serum white cell count, C-reactive protein or sputum bacterial load. Microbiome compositional changes were observed with IV+IV (Bray-Curtis r2=0.14, p=0.02), but not AZLI+IV (r2=0.03, p=0.64). CONCLUSION: In adults with CF and P. aeruginosa infection experiencing an acute pulmonary exacerbation, AZLI+IV improved lung function and quality of life compared to the current standard treatment. These findings support the need for larger definitive trials of inhaled antibiotics in the acute setting. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002832-34 ClinicalTrials.org NCT02894684.

Mycobacterium Simiae Infection in a Person With Cystic Fibrosis.

Although non-tuberculous mycobacteria can be found in the airways of people with cystic fibrosis (pwCF), their role as pathogens may be uncertain, and treatment is problematic. We report the first case of Mycobacterium simiae (M. simiae), often associated with asymptomatic disease or colonisation, which caused pulmonary infection requiring treatment in a pwCF. This report shows that M. simiae, rare in pwCF in the United Kingdom, can cause significant illness and highlights the diagnostic difficulty in individuals with positive smear mycobacteria that can be mistaken initially for pulmonary tuberculosis (TB).

Utility and validity of dynamic chest radiography in cystic fibrosis (dynamic CF): an observational, non-controlled, non-randomised, single-centre, prospective study.

INTRODUCTION: Dynamic chest radiography (DCR) uses novel, low-dose radiographic technology to capture images of the thoracic cavity while in motion. Pulmonary function testing is important in cystic fibrosis (CF). The tolerability, rapid acquisition and lower radiation and cost compared with CT imaging may make DCR a useful adjunct to current standards of care. METHODS AND ANALYSIS: This is an observational, non-controlled, non-randomised, single-centre, prospective study. This study is conducted at the Liverpool Heart and Chest Hospital (LHCH) adult CF unit. Participants are adults with CF. This study reviews DCR taken during routine CF Annual Review (n=150), validates DCR-derived lung volumes against whole body plethysmography (n=20) and examines DCR at the start and end of pulmonary exacerbations of CF (n=20). The primary objectives of this study are to examine if DCR provides lung function information that correlates with PFT, and lung volumes that correlate whole body plethysmography. ETHICS AND DISSEMINATION: This study has received the following approvals: HRA REC (11 December 2019) and LHCH R&I (11 October 2019). Results are made available to people with CF, the funders and other researchers. Processed, anonymised data are available from the research team on request. TRIAL REGISTRATION NUMBER: ISRCTN 64994816.

The renoprotective effect of concomitant fosfomycin in the treatment of pulmonary exacerbations in cystic fibrosis.

BACKGROUND: Fosfomycin, effective in Cystic Fibrosis (CF), competes with aminoglycosides at renal binding sites and may therefore afford a renoprotective effect when used in combination therapy. We explored this by using markers of acute renal tubular damage [N-acetyl-ß-d-glucose-aminidase (NAG), alanine amino-peptidase (AAP) and ß2-microglobulin]. METHODS: Using a prospective randomized crossover trial design, at an acute pulmonary exacerbation, 18 adult CF patients received either 14 days of intravenous (IV) tobramycin or IV tobramycin and IV fosfomycin, both in combination with a second IV antibiotic (colomycin). RESULTS: Urinary NAG (P = 0.003) and AAP (P = 0.03) following treatment with concomitant fosfomycin were lower than those after treatment with tobramycin and colomycin alone. Fosfomycin attenuated the total 24-h urinary protein leak (P = 0.0001). The 14-day improvements in all surrogate markers of exacerbation resolution (FEV1% predicted, FVC, white cell count and C-reactive protein) were similar for both treatment regimens. CONCLUSION: The addition of fosfomycin reduces acute renal injury caused by IV aminoglycoside therapy in CF pulmonary exacerbations.

Ivacaftor Is Associated with Reduced Lung Infection by Key Cystic Fibrosis Pathogens. A Cohort Study Using National Registry Data.

Rationale: Ivacaftor can greatly improve clinical outcomes in people with cystic fibrosis (CF) and has been shown to have in vitro antibacterial properties, yet the long-term microbiological outcomes of treatment are unknown.Objectives: To investigate changes in respiratory microbiology associated with long-term ivacaftor use.Methods: This was a retrospective cohort study using data from the UK CF Registry 2011-2016. Primary outcome was the annual prevalence ratios for key CF pathogens between ivacaftor users and their contemporaneous comparators. Multivariable log-binomial regression models were designed to adjust for confounders. Changes in Pseudomonas aeruginosa status were compared between groups using nonparametric maximum likelihood estimate for the purposes of Kaplan-Meier approximation.Results: Ivacaftor use was associated with early and sustained reduction in P. aeruginosa rates (2016 adjusted prevalence ratio, 0.68; 95% confidence interval, 0.58-0.79; P < 0.001) via a combination of increased clearance in those with infection (ivacaftor: 33/87 [37.9%] vs. nonivacaftor: 432/1,872 [22.8%]; P < 0.001) and reduced acquisition in those without infection (49/134 [36.6%] vs. 1,157/2,382 [48.6%]; P = 0.01). The improved prevalence of P. aeruginosa infection was independent of reduced sampling in the ivacaftor cohort. Ivacaftor was also associated with reduced prevalence of Staphylococcus aureus and Aspergillus spp. but not Burkholderia cepacia complex.Conclusions: In this study, long-term ivacaftor use was associated with reduced infection with important CF pathogens including P. aeruginosa. These findings have implications for antibiotic stewardship and the need for ongoing chronic antimicrobial therapy in this cohort.