An observational study to understand burden and cost of care in adults diagnosed with refractory chronic cough (RCC) or unexplained chronic cough (UCC).

BACKGROUND: Refractory and unexplained chronic cough (RCC and UCC) necessitate frequent referral for specialist evaluations, but data on healthcare resource utilisation and costs are lacking. METHODS: This observational study enrolled adults with RCC or UCC attending a specialist cough clinic and included a control cohort, both from North West England, matched 1:5 for age, gender and smoking history. Primary and secondary care data were obtained for the 5 years prior to and 2 years post initial clinic visit (index). The primary endpoint was the total 5-year healthcare cost to the UK NHS pre-RCC or UCC diagnosis compared to the control cohort. RESULTS: Mean age at index for the 200 RCC or UCC consented patients was 62.2 ± 11.4 years; 71% were female, and 68% had never smoked. Mean duration of symptoms pre-diagnosis was 8.0 ± 9.4 years. Mean cough severity score was 63.7 ± 23.2 mm at index on a Visual Analog Scale, and Leicester Cough Questionnaire total score was 10.9 ± 4.1. GP data were available for 80 patients and mean total cost over the 5 years pre-diagnosis (index date) was 3.0-fold higher (95% CI 2.3, 3.9) than in the control cohort (p < 0.001). Most excess costs were related to visits and procedures carried out in secondary care. RCC- or UCC-associated costs decreased post-diagnosis, but remained higher than those of controls. CONCLUSION: Diagnosis of RCC or UCC requires significant health resource utilisation in the 5 years prior to a specialist clinic diagnosis. Resource utilisation was less after diagnosis, but remained higher than in a matched control cohort.

Patient-reported experiences with refractory or unexplained chronic cough: a qualitative analysis.

BACKGROUND: Chronic cough, defined as a cough lasting 8 or more weeks, affects up to 10% of adults. Refractory chronic cough (RCC) is a cough that is uncontrolled despite comprehensive investigation and treatment of comorbid conditions while unexplained chronic cough (UCC) is a cough with no identifiable cause despite extensive evaluation of comorbid conditions. RCC and UCC are often poorly controlled. Understanding individuals' lived experience of the symptoms and impacts of these conditions may guide therapeutic strategies. OBJECTIVES: The primary objectives of this study were to assess respondents' perceptions of the key symptoms of RCC and UCC and the impacts of RCC and UCC and their symptoms on well-being, health-related quality of life, work productivity, and social relationships. DESIGN: Qualitative study. METHODS: This study enrolled 30 adults with physician-diagnosed RCC or UCC. Two trained qualitative researchers conducted individual, in-depth telephone interviews using a semi-structured interview guide. Interviews were audio-recorded, transcribed, coded, and systematically analyzed to identify content themes. RESULTS: A total of 15 respondents with RCC and 15 with UCC were included in the study. Many respondents had RCC or UCC for a long duration (median 9 years, range: 0-24). Half of the respondents reported having a coughing episode at least once daily. Only 40% of respondents reported that medication had improved their symptoms. In over half of the respondents, RCC or UCC hindered communication, caused embarrassment, frustration, and worry, and lowered quality of life. Perceptions of meaningful treatment benefits in RCC or UCC varied widely across respondents. CONCLUSION: RCC and UCC remained poorly managed in many individuals and were associated with a wide range of symptoms and cough triggers that hindered daily activities and reduced emotional well-being. Understanding individuals' lived experiences may inform the development of RCC and UCC therapeutic strategies.

Patient-reported experiences with refractory or unexplained chronic cough: a qualitative analysisChronic cough, particularly refractory and unexplained chronic cough, remain poorly managed in many individuals and are associated with a wide range of symptoms and cough triggers that hinder daily activities and reduce emotional well-being. Currently there are no US Food and Drug Administration-approved treatments for refractory or unexplained chronic cough. Understanding the experience and treatment preferences of individuals with these conditions may help inform the development of new therapies and clarify the potential impact of such therapies on the lives of individuals with chronic cough. Using in-depth interviews, the present study comprehensively evaluated individuals' experience with refractory or unexplained chronic cough and treatment priorities, a research area that has not been well-studied. This study detailed broad-ranging physical, behavioral, and emotional impacts of chronic cough, which hindered individuals' social well-being.

Patterns of Cough Medication Prescribing among Patients with Chronic Cough in Florida: 2012-2021.

Among patients with chronic cough (CC) in the 2012-2021 statewide OneFlorida Clinical Research Consortium database, we examined trends in cough medication (CM) prescribing prevalence over time in repeated cross-sectional analyses and identified distinct CM utilization trajectories using group-based trajectory modeling (GBTM) in a retrospective cohort study. Among eligible adults (≥18 years) without cancer/benign respiratory tumor diagnoses, we identified CC patients and non-CC patients with any cough-related diagnosis. In the GBTM analysis, we calculated the number of monthly prescriptions for any CMs (excluding gabapentinoids) during the 12 months from the first qualifying cough event to identify distinct utilization trajectories. From 2012 to 2021, benzonatate (9.6% to 26.1%), dextromethorphan (5.2% to 8.6%), and gabapentinoid (5.3% to 14.4%) use increased among CC patients, while opioid antitussive use increased from 2012 to 2015 and decreased thereafter (8.4% in 2012, 14.7% in 2015, 6.7% in 2021; all p < 0.001). Of 15,566 CC patients and 655,250 non-CC patients identified in the GBTM analysis, CC patients had substantial burdens of respiratory/non-respiratory comorbidities and healthcare service and concomitant medication use compared to non-CC patients. Among CC patients, GBTM identified three distinct CM utilization trajectories: (1) no CM use (n = 11,222; 72.1%); (2) declining CM use (n = 4105; 26.4%); and (3) chronic CM use (n = 239; 1.5%). CC patients in Florida had limited CM use with increasing trends in use of benzonatate, dextromethorphan, and gabapentinoids and a decreasing trend in opioid antitussive use. CC patients, particularly with chronic prescription CM use, experienced substantial disease burden.

Burden of chronic cough in the UK: results from the 2018 National Health and Wellness Survey.

Background: Chronic cough, defined as daily cough for at least 8 weeks, negatively affects quality of life and work productivity and increases healthcare resource utilisation. We aimed to determine the prevalence and burden of chronic cough in the UK. Methods: Study participants were general population respondents to the 2018 UK National Health and Wellness Survey (NHWS). Respondents completed survey questions relating to health, quality of life, work productivity and activity impairment, and use of healthcare resources. Prevalence estimates were projected to the UK population using post-stratification sampling weights to adjust for sampling bias. The population with chronic cough was matched 1:3 with a group without chronic cough, using propensity score matchingon age, sex and the modified Charlson Comorbidity Index. Results: Of 15 000 NHWS respondents, 715 reported chronic cough in the previous 12 months and 918 during their lifetime. Weighted to the UK adult population, the 12-month prevalence of chronic cough was 4.9% and lifetime prevalence was 6.2%. Prevalence of chronic cough was higher among older respondents and those with smoking histories. Chronic cough respondents experienced higher rates of severe anxiety and depression in the past 2 weeks than matched controls. Poor sleep quality and loss of work productivity were also observed. More chronic cough respondents visited a healthcare provider in the past 6 months than respondents without chronic cough with a mean of 5.8 and 3.7 visits per respondent, respectively. Conclusion: Adults with chronic cough report lower quality of life, reduced work productivity and greater healthcare resource utilisation than matched controls without chronic cough.

Demographic, clinical, and patient-reported outcome data from 2 global, phase 3 trials of chronic cough.

BACKGROUND: The current characterization of patients with refractory or unexplained chronic cough (RCC and UCC, respectively) primarily stems from relatively small clinical studies. OBJECTIVE: To report the baseline medical history and clinical characteristics of individuals with RCC or UCC who were enrolled in COUGH-1 and COUGH-2, 2 large, global, phase 3 trials of gefapixant, a P2 × 3-receptor antagonist. METHODS: Adults with a chronic cough lasting for more than 1 year, diagnosis of RCC or UCC, and score greater than 40 mm on a 100-mm cough severity visual analog scale at both screening and baseline were eligible for enrollment. Demographics, medical history, and cough characteristics were collected at baseline. Cough-related measures included objective cough frequency, cough severity visual analog scale, Leicester Cough Questionnaire, and Hull Airway Reflux Questionnaire. The data were summarized using descriptive statistics. RESULTS: Of 2044 participants, 75% were women; mean age was 58 years, and mean cough duration was approximately 11 years. Among all participants, 73% were previously diagnosed with asthma, gastroesophageal reflux disease, or upper airway cough syndrome. The mean Leicester Cough Questionnaire total score was 10.4, with domain scores reflecting impaired cough-specific quality of life across physical, psychological, and social domains. The mean Hull Airway Reflux Questionnaire score was 39.6, with some of the most burdensome reported items being consistent with features of cough-reflex hypersensitivity. Participant characteristics and cough burden were comparable across geographic regions. CONCLUSION: Participants with RCC or UCC had characteristics consistent with published demographics associated with chronic cough. These data reflect a global population with burdensome cough of long duration and substantial impairment to quality of life. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: COUGH-1, NCT03449134 (https://www. CLINICALTRIALS: gov/ct2/show/NCT03449134); COUGH-2, NCT03449147 (https://clinicaltrials.gov/ct2/show/NCT03449147).

Validation and Meaningful Change Thresholds for an Objective Cough Frequency Measurement in Chronic Cough.

PURPOSE: Objective cough frequency is used to assess efficacy of chronic cough (CC) treatments. The objective of this study was to explore the relationship between objective cough frequency and cough-specific patient-reported outcomes (PROs) and estimate a clinically meaningful change threshold (MCT) for objective cough frequency. METHODS: Data collected in a phase 2b study in participants with refractory or unexplained CC were used to investigate the relationship between 24-h cough frequency (measured using an ambulatory cough monitor) and cough-specific PROs (i.e., cough severity visual analog scale, cough severity diary, Leicester Cough Questionnaire). Convergent validity was assessed using Spearman ρ. An MCT for 24-h cough frequency was estimated using the patient global impression of change (PGIC) scale as an anchor. RESULTS: Correlations between 24-h cough frequency and cough-specific PROs at baseline, Week 4, and Week 12 were significant (P < 0.0001) but low to moderate in strength (ρ = 0.30-0.58). Participants categorized as very much improved/much improved (i.e., PGIC of 1 or 2) or minimally improved (i.e., PGIC of 3) had mean 24-h cough frequency reductions of 55% and 30%, respectively. Receiver operating characteristic curve analysis suggested that a 24-h cough frequency reduction of 38% optimizes sensitivity and specificity for predicting a PGIC score of 1-3. CONCLUSION: Objective 24-h cough frequency is significantly associated with cough-specific PROs, but cough frequency and PROs most likely capture distinct aspects of CC. A ≥ 30% reduction in 24-h cough frequency is a reasonable MCT to define treatment response in CC clinical trials.

Evaluation of Cough Medication Use Patterns in Ambulatory Care Settings in the United States: 2003-2018.

Using 2003−2018 National Ambulatory Medical Care Survey data for office-based visits and 2003−2018 National Hospital Ambulatory Medical Care Survey data for emergency department (ED) visits, we conducted cross-sectional analyses to examine cough medication (CM) use trends in the United States (US) ambulatory care settings. We included adult (≥18 years) patient visits with respiratory-infection-related or non-infection-related cough as reason-for-visit or diagnosis without malignant cancer or benign respiratory tumor diagnoses. Using multivariable logistic regressions, we examined opioid antitussive, benzonatate, dextromethorphan-containing antitussive, and gabapentinoid use trends. From 2003−2005 to 2015−2018, opioid antitussive use decreased in office-based visits (8.8% to 6.4%, Ptrend = 0.03) but remained stable in ED visits (6.3% to 5.9%, Ptrend = 0.99). In both settings, hydrocodone-containing antitussive use declined over 50%. Benzonatate use more than tripled (office-based:1.6% to 4.8%; ED:1.5% to 8.0%; both Ptrend < 0.001). Dextromethorphan-containing antitussive use increased in ED visits (1.8% to 2.6%, Ptrend = 0.003) but stayed unchanged in office-based visits (3.8% to 2.7%; Ptrend = 0.60). Gabapentinoid use doubled in office-based visits (1.1% in 2006−2008 to 2.4% in 2015−2018, Ptrend < 0.001) but was negligible in ED visits. In US office-based and ED ambulatory care settings, hydrocodone-containing antitussive use substantially declined from 2003 to 2018, while benzonatate use more than tripled, and dextromethorphan-containing antitussive and gabapentinoid use remained low (<3%).

Improvements in Objective and Subjective Measures of Chronic Cough with Gefapixant: A Pooled Phase 3 Efficacy Analysis of Predefined Subgroups.

INTRODUCTION: In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). METHODS: Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., ≥ 1.3-point improvement) at Week 24 were assessed. RESULTS: Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; ≥ 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. CONCLUSION: These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC.

Leicester Cough Questionnaire validation and clinically important thresholds for change in refractory or unexplained chronic cough.

INTRODUCTION: The Leicester Cough Questionnaire (LCQ), a cough-specific quality-of-life measure, evaluates the impact of cough across physical, psychological, and social domains in patients with chronic cough (CC). This study assessed the psychometric properties of the LCQ. METHODS: Data from a phase IIb, randomized controlled trial of the P2X3-receptor antagonist gefapixant were analyzed (NCT02612610). Subjective [Cough Severity Diary, cough severity visual analogue scale, and patient global impression of change (PGIC)] and objective (awake and 24-h cough frequency) data were used to validate the LCQ for use in patients with refractory or unexplained CC (RCC and UCC, respectively). Psychometric analyses included confirmatory factor analyses, internal consistency and test-retest reliability, validity, responsiveness, and estimated within-patient thresholds for clinically meaningful change. RESULTS: Model-fit values for the proposed three-factor LCQ domains and most individual items were acceptable. Analyses suggest that a mean improvement ranging from 1.3 to 2.3 points for the LCQ total and ⩾0.8, ⩾0.9, and ⩾0.8 points for physical, psychological, and social domain scores, respectively, had the best sensitivity and/or specificity for predicting patient ratings of improvement on the PGIC. CONCLUSIONS: The LCQ is a valid and reliable measure to evaluate cough-specific quality of life and is a fit-for-purpose measure for use in patients with RCC or UCC. Although a single threshold for defining clinically meaningful change depends on the context of use, the results can help guide both treatment decisions and drug development. Therefore, clinicians may consider a ⩾1.3-point increase in the LCQ total score as clinically meaningful.

Cost-effectiveness analysis of cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplant recipients from a US payer perspective.

To evaluate the cost-effectiveness of letermovir versus no prophylaxis for the prevention of cytomegalovirus infection and disease in adult cytomegalovirus-seropositive allogeneic hematopoietic cell transplantation (allo-HCT) recipients. A decision model for 100 patients was developed to estimate the probabilities of cytomegalovirus infection, cytomegalovirus disease, various other complications, and death in patients receiving letermovir versus no prophylaxis. The probabilities of clinical outcomes were based on the pivotal phase 3 trial of letermovir use for cytomegalovirus prophylaxis versus placebo in adult cytomegalovirus-seropositive recipients of an allo-HCT. Costs of prophylaxis with letermovir and of each clinical outcome were derived from published sources or the trial clinical study reports. Incremental cost-effectiveness ratios (ICERs) in terms of cost per quality-adjusted life year (QALY) gained were used in the model. One-way and probabilistic sensitivity analyses were conducted to explore uncertainty around the base-case analysis. In this model, the use of letermovir prophylaxis would lead to an increase of QALYs (619) and direct medical cost ($1 733 794) compared with no prophylaxis (578 QALYs; $710 300) in cytomegalovirus-seropositive recipients of an allo-HCT. Letermovir use for cytomegalovirus prophylaxis was a cost-effective option versus no prophylaxis with base-case analysis ICER $25 046/QALY gained. One-way sensitivity analysis showed the most influential parameter was mortality rate. The probabilistic sensitivity analysis showed a 92% probability of letermovir producing an ICER below the commonly accepted willingness-to-pay threshold of $100 000/QALY gained. Based on this model, letermovir use for cytomegalovirus prophylaxis was a cost-effective option in adult cytomegalovirus-seropositive recipients of an allo-HCT.

Impact of cytomegalovirus complications on resource utilization and costs following hematopoietic stem cell transplant.

Objective: The impact of cytomegalovirus (CMV) infection on healthcare resource utilization (HCRU) and costs post-allogeneic hematopoietic stem cell transplant (allo-HSCT) has not been well studied in the US. This retrospective, observational cohort study examined such outcomes in the first year following allo-HSCT.Methods: The IBM MarketScan administrative claims database was used to identify adults who underwent a first allo-HSCT between 1 January 2010 and 30 April 2015. Patients were required to have continuous medical and pharmacy enrollment for ≥12 months before and after the allo-HSCT. HCRU and medical costs (2016 US$) were compared by the presence or absence of CMV infection over 1-year follow-up.Results: A total of 1825 adults met the inclusion criteria (57.5% male; mean age 50.8 years). During the follow-up period, 410 (22.5%) patients had a CMV-related claim. Patients with CMV infection were significantly more likely to have a 60-day-(31.2 vs. 19.4%), 100-day-(50.0 vs. 30.5%) or 365-day readmission (78.0 vs. 57.8%) compared to those without a CMV-related event (all p < .001). During follow-up, patients with CMV infection had significantly greater mean total costs, reflecting higher inpatient costs ($677,240 vs. $462,562), outpatient costs ($141,366 vs. $94,312) and prescription drug costs ($27,391 vs. $22,082) (all p < .001). Valganciclovir (59.8%) and ganciclovir (33.7%) were the most commonly utilized anti-viral agents in patients with CMV.Conclusions: CMV infection was associated with significantly higher healthcare resource utilization and costs during the first year post-allo-HSCT. Additional research is warranted to further evaluate the consequences of post-HSCT CMV infection, as well as cost-effective measures to minimize its occurrence.

Cytomegalovirus infection and associated hospitalization and costs among individuals undergoing allogeneic hematopoietic stem cell transplant.

Objective: This study utilized a large, national US database to explore the impact of Cytomegalovirus (CMV) infection on hospital services utilization and costs during the first 100 days following allogeneic hematopoietic stem cell transplant (allo-HSCT).Methods: This retrospective, observational cohort study used data from the Premier Healthcare database to identify patients undergoing their first (index) allo-HSCT procedure between 1 January 2006 and 31 March 2015. Three subgroups were analyzed according to CMV-related readmissions during the 100-day follow-up (0, 1, or 2+ readmissions) to compare healthcare utilization and costs.Results: A total of 1610 patients (mean age, 50.5 years; 56.9% male) from 52 US hospitals met the inclusion criteria. During follow-up, 212 (13.2%) patients had 1 (n = 161; 10.0%) or 2+ (n = 51; 3.2%) CMV-related readmissions. The mean ± SD number of all follow-up encounters (inpatient admissions and hospital-based outpatient visits) was similar for the no CMV (3.9 ± 3.9), 1 CMV (3.7 ± 3.9), and 2+ CMV (4.5 ± 3.8) readmission groups (p = .439). Mean total costs of hospital-based healthcare encounters (inpatient admissions and hospital-based outpatient visits) during follow-up were significantly greater in patients who had a CMV readmission ($111,729 [1 CMV readmission]; $184,021 [2+ CMV readmissions]) compared to those without a CMV readmission ($46,064; p < .001]. 100-day follow-up mortality was higher in the CMV vs. non-CMV readmission groups (30.2 vs. 8.2%; p < .001).Conclusions: This large, national database study revealed significantly higher healthcare utilization and costs, as well as mortality, among patients with CMV-related re-hospitalization during the first 100 days post-transplant as compared to patients without CMV-related hospitalization.

Clinical and economic burden of pre-emptive therapy of cytomegalovirus infection in hospitalized allogeneic hematopoietic cell transplant recipients.

Cytomegalovirus (CMV) infection remains a major complication after allogeneic hematopoietic cell transplantation (allo-HCT). We conducted a retrospective study to determine the clinical and economic burden of pre-emptive therapy (PET) for CMV infection in 100 consecutive hospitalized adult CMV positive serostatus allo-HCT recipients and compared their hospitalization cost with allo-HCT recipients hospitalized with graft vs host disease without CMV infection (control group) and across 19 US cancer centers for hospitalized patients with CMV infection between 2012 and 2015 (Vizient database). A total of 192 CMV episodes of PET for CMV infection occurred within 1 year post-HCT. PET consisted of ganciclovir (41% of episodes), foscarnet (40%), and valganciclovir (38%) with the longest average length of stay in foscarnet-treated patients (41 days). The average direct cost per patient admitted for PET was $116 976 (range: $7866-$641 841) compared with $12 496 (range: $2004-$43 069) in the control group (P < .0001). The total direct cost per encounter was significantly higher in patients treated with foscarnet and had nephrotoxicity ($284 006) compared with those who did not ($112 195). The average cost amongst the 19 US cancer centers, including our institution, was $42 327 with major disparities in cost and clinical outcomes. PET for CMV infection is associated with high economic burden in allo-HCT recipients.