Acute Pulmonary Exacerbations Research Articles

Biomarkers associated with pulmonary exacerbations in a randomized trial of nintedanib for radiation pneumonitis

Background and purposeRadiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP. Materials and methodsWe analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes. ResultsThirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01–1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1–1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89–1, p = 0.036). ConclusionWe identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.

Changes in urinary glutathione sulfonamide (GSA) levels between admission and discharge of patients with cystic fibrosis

There is an urgent need to develop sensitive, non-invasive biomarkers that can track airway inflammatory activity for patients with cystic fibrosis (CF). Urinary glutathione sulfonamide (GSA) levels correlate well with GSA levels in BAL samples and other markers of neutrophilic inflammation, suggesting that this biomarker may be suitable for tracking disease activity in this population. We recruited 102 children (median 11.5 years-old) and 64 adults (median 32.5 years-old) who were admitted to hospital for management of an acute pulmonary exacerbation and/or eradication of infectious agents such as Pseudomonas aeruginosa or Staphylococcus aureus. Our aim was to explore how urinary GSA levels changed across admission timepoints. Urine samples were collected at admission and discharge, and GSA measured by liquid chromatography with mass spectrometry. Paired admission-discharge results were compared using Wilcoxon signed-rank test. Paired admission-discharge samples were available for 53 children and 60 adults. A statistically significant difference was observed between admission-discharge for children and adults. Spearman's correlation analysis identified a correlation between urinary GSA levels and sex and S. aureus infection for children only. Our preliminary findings suggest that urinary GSA is responsive to the resolution of an acute pulmonary exacerbation and therefore warrants further studies in this population.

2226. Trough- Versus AUC-Based Vancomycin Monitoring for Treatment of Acute Pulmonary Exacerbations of Adult Cystic Fibrosis Patients

Abstract Background Therapeutic drug monitoring (TDM) for IV vancomycin (VAN) in adults with cystic fibrosis (CF) historically has utilized trough concentrations. Recent VAN TDM guidelines recommend area under the curve (AUC)-monitoring to reduce the risk of vancomycin-induced kidney injury. However, limited data is available in adult CF patients to support this practice. The aim of the study was to determine the safety and efficacy of VAN AUC-monitoring in adult CF patients. Methods This single-center, retrospective, observational cohort study included adult CF patients admitted from July 1, 2017 to July 1, 2022 with an acute pulmonary exacerbation that received VAN for at least 72 hours with available VAN plasma concentrations for TDM. Eligible patients with multiple hospital admissions during the study period were incorporated as separate encounters. The primary outcome was incidence of acute kidney injury (AKI). A subgroup efficacy analysis was performed in patients with methicillin-resistant S. aureus (MRSA) in the sputum 3 months prior to or 3 weeks after hospitalization. Results One hundred forty-three patients were included in the study [AUC cohort (n=39) and trough cohort (n=104)]. Concurrent nephrotoxins was more common in the AUC cohort than in the trough cohort (97% vs 81%; p = 0.01), but rate of AKI was similar (7.7% vs 10.6%, respectively; p = 0.76). No significant differences were seen in achievement of TDM goal, incidence of supratherapeutic exposure or vancomycin accumulation, duration of vancomycin, length of stay, or number of vancomycin concentrations. AUC monitoring was associated with earlier achievement of TDM goal [median 0 days (0-2) vs 2 days (0-4); p < 0.01], lower total daily doses to achieve TDM goal [38.6 ±13 mg/kg/day vs 58.4 ±18.7mg/kg/day; p < 0.01], and fewer regimen changes [median 1 change (0-2) vs 2 changes (1-3); p < 0.01] compared to trough monitoring. In patients with MRSA, pulmonary function recovery, readmission, and mortality was similar. Conclusion In adult CF patients, the rates of AKI were similar between VAN TDM methods, but VAN AUC monitoring resulted in a therapeutic regimen sooner at lower total daily VAN doses and fewer number of regimen changes without significantly increasing the number of concentrations compared to trough monitoring. Disclosures James Sanders, PhD, PharmD, Merck & Co., Inc.: Grant/Research Support|Shionogi Inc.: Grant/Research Support

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis.

To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis. This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, -0.16; 95% CI, -0.28 to -0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, -0.03; 95% CI, -0.08 to 0.01), and none of the studies reported deaths. Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

Laparoscopic Abdominal Surgery Under Thoracic Epidural Anesthesia in Patients with Interstitial Lung Disease: Retrospective Observational Cohort Study.

Patients with interstitial lung disease who present with abdominal disease carry a perioperative risk of morbidity and mortality, including the risks of general anesthesia and postoperative pulmonary complications. We investigated the efficacy of laparoscopic surgery in such patients under epidural anesthesia. All patients with interstitial lung disease who underwent laparoscopic abdominal surgery were retrospectively studied. At 30 days, our primary end point was acute exacerbation of pulmonary complications. The second end point was nonpulmonary complications and 30-day hospital mortality. Eighteen patients were enrolled in this study after reviewing their medical and surgical records. Our study revealed that none of the patients suffered from acute pulmonary exacerbations, and only 1 patient experienced a nonpulmonary event. There was no reported mortality. The conversion rate was low, with 1 patient necessitating conversion from laparoscopic to open surgery, which was conducted under epidural anesthesia. No conversions from epidural to general anesthesia were performed. Epidural anesthesia is safe in a patient with interstitial lung disease, and laparoscopic surgery can be completed with low rate of conversion and, with minor complications.

Electronic home monitoring of children with cystic fibrosis to detect and treat acute pulmonary exacerbations and its effect on 1-year FEV1

BackgroundWe aimed to investigate the effect of the use of electronic home spirometry in children with cystic fibrosis (CF) on 1-year FEV1 (% predicted, pp) change. MethodsThis is a randomised, one-year prospective study including children with CF between 6 and 18 years of age. Subjects were randomised into home spirometry group (HSG) and usual care group (UCG). Children in HSG performed two pulmonary function tests (PFT) per week. Data regarding acute pulmonary exacerbations (PEx) was obtained from patients’ records. At baseline and 12th month, health related quality of life questionnaire for CF patients (CFQ-R) and lung clearance index (LCI) were performed. ResultsSixty children were recruited with a median (IQR) age of 13.3 (11.4–15.4) years. Absolute change in FEV1pp from baseline to 12th month as median (IQR) was +1% (-6.75–9.75) in HSG and -2.50% (-7.50–3.25) in UCG (p = 0.10). Sensitivity analysis including only adherent children in HSG (n = 22), yielded an increase of 5% (-3.50–12) in HSG and a decrease of 2.50% (-7.50–3.25) in UCG (p = 0.009). A total of 29 (96.7%) subjects in HSG and 23 (76.7%) in UCG had PEx (p = 0.05). Absolute change in median (IQR) LCI2.5 from baseline to the 12th month was -1.6 [-2.9–0] (p<0.001) in HSG and -1.5 [-2.8-(-0.6)] (p<0.001) in UCG (p = 0.94). There was a significant increase in the social domain of the CFQ-R in HSG (from 59.1 to 76.2, p = 0.01). ConclusionsElectronic home monitoring of children with CF by spirometry may result in improvement in lung function.

Impact of model-informed precision dosing on achievement of vancomycin exposure targets in pediatric patients with cystic fibrosis.

Vancomycin is commonly used to treat acute pulmonary exacerbations in pediatric patients with cystic fibrosis (CF) and a history of methicillin-resistant Staphylococcus aureus. Optimizing vancomycin exposure during therapy is essential and area under-the-curve (AUC)-guided dosing is now recommended. Model-informed precision dosing (MIPD) utilizing Bayesian forecasting is a powerful approach that can support AUC-guided dose individualization. The objective of the current study was to examine the impact of implementing an AUC-guided dose individualization approach supported via a MIPD clinical decision support (CDS) tool on vancomycin exposure, target attainment rate, and safety in pediatric patients with CF treated with vancomycin during clinical care. A retrospective chart review was performed in patients with CF at a single children's hospital comparing pre- and post-implementation of a MIPD approach for vancomycin supported by a cloud-based, CDS tool integrated into the electronic health record (EHR). In the pre-MIPD period, vancomycin starting doses of 60 mg/kg/day (<13 years) or 45 mg/kg/day (≥13 years) were used. Dose adjustment was guided by therapeutic drug monitoring (TDM) with a target trough 10-20 mg/L. In the post-MIPD period, starting dose and dose adjustment were based on the MIPD CDS tool predictions with a target 24 h AUC (AUC24 ) 400-600 mg*h/L. Exposure and target achievement rates were retrospectively calculated and compared. Rates of acute kidney injury (AKI) were also compared. Overall, 23 patient courses were included in the pre-MIPD period and 21 patient courses in the post-MIPD period. In the post-MIPD period, an individualized MIPD starting dose resulted in 71% of patients achieving target AUC24 compared to 39% in the pre-MIPD period (p < 0.05). After the first TDM and dose adjustment, target AUC24 achievement was also higher post-MIPD versus pre-MIPD (86% vs. 57%; p < 0.05). AKI rates were low and similar between periods (pre-MIPD 8.7% vs. post-MIPD 9.5%; p = 0.9). An MIPD approach implemented within a cloud-based, EHR-integrated CDS tool safely supported vancomycin AUC-guided dosing and resulted in high rates of target achievement.

Changes in bone turnover after high-dose vitamin D supplementation during acute pulmonary exacerbation in cystic fibrosis

In people with cystic fibrosis (CF), chronic inflammation and infection increase the risk for low bone mineral density and CF-related bone disease. During acute pulmonary exacerbations (APE), people with CF have increases in markers of bone resorption. Vitamin D has been proposed as a potential nutrient to lower inflammation. In this ancillary analysis of the Vitamin D for the Immune System in CF study, we hypothesized that vitamin D administered at the time of APE would have favorable changes on bone turnover markers compared to placebo. Participants with CF were randomized to receive a single dose of 250,000 IU of vitamin D or placebo during an APE and followed for 1 year for the primary outcome of APE or death after randomization. Bone turnover markers: C-terminal telopeptide (CTX-1) and procollagen type 1 intact N-terminal propetide (P1NP) were assessed at randomization (during APE) and after recovery from the APE in 45 participants. Participants randomized to vitamin D had significant decreases in markers of bone turnover; participants who received placebo had non-significant increases in markers of bone turnover. Vitamin D supplementation during an APE may help reduce the risk for CF-related bone disease.

WS07.01 Inter-species interactions alter antimicrobial susceptibility in polymicrobial cultures

People with cystic fibrosis (p/wCF) often develop chronic lung infections punctuated by periods of acute pulmonary exacerbation. One of the pathogens present in many p/wCF is Pseudomonas aeruginosa (PA). In many infection scenarios, PA shares the airway environment with a veritable “zoo” of other microbes, including Gram-negative, Gram-positive and fungal species – yet these are rarely taken into account when testing new anti-pseudomonal agents. The aim of this project is to examine how the presence of other co-habiting species affects the biology of PA during antibiotic challenge.

Palliation of Dyspnea with Mouthpiece Ventilation in Patients with Chronic Obstructive Pulmonary Disease: A Pilot Feasibility Study.

Background: Mouthpiece ventilation (MPV) reduces hypoventilation, but its efficacy in relieving dyspnea in patients with acute chronic obstructive pulmonary disease exacerbation (AECOPD) is unclear. Objective: To assess the feasibility of MPV in relieving dyspnea among patients with AECOPD. Methods: In this prospective single-arm pilot study, the change in dyspnea on numeric rating scale (NRS) after using MPV and side effects of the treatment were studied in 18 patients with AECOPD. Results: The median decrease in dyspnea was 1.5 (95% confidence interval = 0.0-2.5, p = 0.006) on NRS after the intervention lasting a median of 16.9 minutes. Of the patients, 61% found MPV beneficial. The use of MPV did not increase the sense of anxiety or pain. Conclusions: MPV is feasible and may relieve dyspnea in patients with AECOPD, but the intervention needs further evaluation. clinicaltrials.gov study number: NCT03025425.

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

New Recommendations of a Height-Based Dosing Regimen of Tobramycin for Cystic Fibrosis in Adults: A Population Pharmacokinetic Analysis.

Acute pulmonary exacerbations (APEs) in patients with adult cystic fibrosis (CF) are treated with a beta-lactam and an aminoglycoside for activity against Pseudomonas aeruginosa (PA). Emerging drug resistance and changing pharmacokinetic profile in an aging population involve a reevaluation of tobramycin dosing recommendations. The objective of this study was to develop a population pharmacokinetic model and establish optimal dosing recommendations for tobramycin using Monte Carlo simulations. This retrospective clinical study and data collection were performed at the CF center of the McGill University Health Center (MUHC), Canada. Model development and simulations were performed using a nonlinear mixed-effect modeling approach (NONMEM, version 7.4.2). The ratios of maximal concentration (C max ) to the minimal inhibitory concentration (MIC) (C max /MIC ≥8 and ≥10) and area under the curve (AUC) to the MIC (AUC/MIC ≥70 and ≥100) were evaluated. Adult patients with CF (n = 51) treated with tobramycin were included in the study. Plasma concentrations of tobramycin were obtained for 699 samples from the MUHC database. The two-compartmental model best described the pharmacokinetics of tobramycin. The association of patient height with the central volume of distribution significantly improved this model. Height, rather than weight, induced the best reduction in objective function. According to simulations, doses between 3.4 mg/cm and 4.4 mg/cm were necessary to achieve C max /MIC values of ≥8 and ≥10, respectively. However, higher doses were required to achieve the AUC/MIC targets. This study demonstrated that height of the patients seems to be more suitable than their weight for dosing adjustments in adult patients with CF. According to this model, initial doses of tobramycin between 3.4 and 4.4 mg/cm should be recommended for patients with a median height of 164 cm and weight of 55 kg to achieve the target plasma concentrations.

Breathing Control Exercises Delivered in a Group Setting for Patients with Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial

Breathing control exercises are an important component of occupational therapy in patients with chronic obstructive pulmonary disease (COPD). Delivering these exercises in group settings may enhance their benefits. Therefore, this study assessed the effectiveness of breathing control exercises delivered in a group format to patients with severe COPD remitting from an acute pulmonary exacerbation. This randomized controlled trial of 6 weeks' duration compared the addition of breathing exercise sessions delivered in a group setting to a standard exercise inpatient rehabilitation program (usual care) versus usual care alone. The standard exercise program consisted of endurance and strength training and therapeutic patient education. The intervention group received, in addition to usual care, 20 sessions of 30 min duration of breathing control exercises in a group setting. The primary outcome was quality of life (Saint George's Respiratory Questionnaire). Secondary outcomes were the COPD assessment test, modified Borg scale, handgrip strength test, and five-time sit-to-stand test. Thirty-seven patients aged 69 ± 7 years were recruited. After the 6-week period, all outcomes significantly improved and exceeded the minimal clinically important difference in the intervention group only. Between-group changes were significant for each outcome. Conclusions: breathing control exercises in a group setting provide clinically relevant benefits in patients with severe COPD who are remitting from an acute pulmonary exacerbation.

Evaluation of the safety of piperacillin-tazobactam extended infusion in pediatric cystic fibrosis patients.

Patients with cystic fibrosis (CF)may be treated with piperacillin-tazobactam (PZT)for acute pulmonary exacerbations. Extending the infusion of PZT is one strategy to increase efficacy. Direct comparison, with respect to the incidence of acute kidney injury (AKI),between these two strategies has not been evaluated in pediatric patients with CF. The primary objective of this study was to compare the incidence of AKI in pediatric CF patients receiving extended infusion (EI) PZT versus traditional infusion (TI). This IRB-approved, retrospective analysis included patients ages 30 days to 18 years that received PZT for at least 48 h between January 1, 2008, and January 1, 2020. PZT was infused over 30 min(TI group) or 4 h(EI group). Two hundred and four patients were included (TI: 109, EI: 95). Median age was 8 years (4-13) and 7 years (3-12) in the TI and EI groups (p = 0.15). The groups did not differ significantly in their baseline characteristics. There were 12 (11%) AKIs in the TI group and 8 (8.4%) in the EI group (p = 0.53). There was one occurrence of serum sickness in the TI group and none in the EI group. The incidence of thrombocytopenia was similar between the two groups. Median treatment duration was 8 days (5-11) and 9 days (5-13) for the TI and EI groups, respectively (p = 0.24). There was no significant increase in AKI in pediatric patients with CF receiving PZT by EI compared withTI. EI may be utilized to optimize the pharmacokinetics of PZT in pediatric CF patients.

Microbial Epidemiology of the Cystic Fibrosis Airways: Past, Present, and Future.

Progressive obstructive lung disease secondary to chronic airway infection, coupled with impaired host immunity, is the leading cause of morbidity and mortality in cystic fibrosis (CF). Classical pathogens found in the airways of persons with CF (pwCF) include Pseudomonas aeruginosa, Staphylococcus aureus, the Burkholderia cepacia complex, Achromobacter species, and Haemophilus influenzae. While traditional respiratory-tract surveillance culturing has focused on this limited range of pathogens, the use of both comprehensive culture and culture-independent molecular approaches have demonstrated complex highly personalized microbial communities. Loss of bacterial community diversity and richness, counteracted with relative increases in dominant taxa by traditional CF pathogens such as Burkholderia or Pseudomonas, have long been considered the hallmark of disease progression. Acquisition of these classic pathogens is viewed as a harbinger of advanced disease and postulated to be driven in part by recurrent and frequent antibiotic exposure driven by frequent acute pulmonary exacerbations. Recently, CF transmembrane conductance regulator (CFTR) modulators, small molecules designed to potentiate or restore diminished protein levels/function, have been successfully developed and have profoundly influenced disease course. Despite the multitude of clinical benefits, structural lung damage and consequent chronic airway infection persist in pwCF. In this article, we review the microbial epidemiology of pwCF, focus on our evolving understanding of these infections in the era of modulators, and identify future challenges in infection surveillance and clinical management.

Novel antihyperglycaemic drugs and prevention of chronic obstructive pulmonary disease exacerbations among patients with type 2 diabetes: population based cohort study

ObjectiveTo determine whether the use of glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, separately, is associated with a decreased risk of...

135 Electronic home monitoring of children with cystic fibrosis to detect and treat acute pulmonary exacerbations and its effect on 1-year FEV1 loss

135 Electronic home monitoring of children with cystic fibrosis to detect and treat acute pulmonary exacerbations and its effect on 1-year FEV1 loss

487 Evaluating use of doxycycline versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus–associated acute pulmonary exacerbations in people with cystic fibrosis

487 Evaluating use of doxycycline versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus–associated acute pulmonary exacerbations in people with cystic fibrosis

Pharmacokinetics of intermittent dosed intravenous vancomycin in adult persons with cystic fibrosis.

Antibiotics have altered pharmacokinetics (PK) in persons with cystic fibrosis (PwCF) during treatment for an acute pulmonary exacerbation (APE). The Cystic Fibrosis Foundation Pulmonary Guidelines-Treatment of Pulmonary Exacerbations do not provide specific recommendations for treatment of methicillin-resistant Staphylococcus aureus (MRSA) lung infections. However, the American Thoracic Society Guidelines recommend vancomycin as the first-line therapy. Only one study has previously described a single dose of intravenous (IV) vancomycin PK in adult PwCF. Our study aimed to describe intermittent IV vancomycin PK at steady-state in adult PwCF. Adult PwCF who were admitted to University of Utah Hospital between May 11, 2014 and August 31, 2020, and received intermittent IV vancomycin for the treatment of an APE were included in this study. The primary outcome was to describe the drug volume of distribution (Vd), drug clearance, elimination half-life, and total daily dose of vancomycin. Secondary outcomes were rates of acute kidney injury (AKI), liver injury, and infusion-related reactions. Thirteen patients were included. The mean Vd was 0.54 L/kg on Day 3 and 0.53L/kg on Day 7. CLvanco was 5.11L/h on Day 3 and 4.69 L/h on Day 7. Zero patients experienced an AKI, two patients experienced liver injury, and no patients experienced infusion-related reactions. Our results demonstrate that in PwCF intermittent IV vancomycin steady-state PK are similar to previously reported single-dose IV vancomycin. Additionally, CLvanco minimally changes from Day 3 to Day 7, although this study was not powered to detect a difference.

Acute Pulmonary Exacerbation Phenotypes in Patients with Cystic Fibrosis.

Rationale: The etiology of cystic fibrosis (CF) pulmonary exacerbations (PEx) is likely multifactorial with viral, bacterial, and non-infectious pathways contributing. Objectives: To determine whether viral infection status and CRP (C-reactive protein) can classify subphenotypes of PEx that differ in outcomes and biomarker profiles. Methods: Patients were recruited at time of admission for a PEx. Nasal swabs and sputum samples were collected and processed using the respiratory panel of the FilmArray multiplex polymerase chain reaction (PCR). Serum and plasma biomarkers were measured. PEx were classified using serum CRP and viral PCR: "pauci-inflammatory" if CRP < 5 mg/L, "non-viral with systemic inflammation" if CRP ⩾ 5 mg/L and no viral infection detected by PCR and "viral with systemic inflammation" if CRP ⩾ 5 mg/L and viral infection detected by PCR. Results: Discovery cohort (n = 59) subphenotype frequencies were 1) pauci-inflammatory (37%); 2) non-viral with systemic inflammation (41%); and 3) viral with systemic inflammation (22%). Immunoglobulin G, immunoglobulin M, interleukin-10, interleukin-13, serum calprotectin, and CRP levels differed across phenotypes. Reduction from baseline in forced expiratory volume in 1 second as percent predicted (FEV1pp) at onset of exacerbation differed between non-viral with systemic inflammation and viral with systemic inflammation (-6.73 ± 1.78 vs. -13.5 ± 2.32%; P = 0.025). Non-viral with systemic inflammation PEx had a trend toward longer duration of intravenous antibiotics versus pauci-inflammation (18.1 ± 1.17 vs. 14.8 ± 1.19 days, P = 0.057). There were no differences in percent with lung function recovery to <10% of baseline FEV1pp. Similar results were seen in local and external validation cohorts comparing a pauci-inflammatory to viral/non-viral inflammatory exacerbation phenotypes. Conclusions: Subphenotypes of CF PEx exist with differences in biomarker profile, clinical presentation, and outcomes.