CHEST Physician

PULMONARY VASCULAR AND CARDIOVASCULAR NETWORK

Cardiovascular Medicine and Surgery Section

Patients with intermediate-risk pulmonary embolism (IRPE), or those with right ventricular dysfunction without overt hemodynamic instability, represent a heterogenous population with short-term mortality ranging from 2% to 17%.¹ While systemic anticoagulation is the mainstay therapy, select individuals may benefit from more immediate reperfusion. Catheter-based therapies (CBT), including thrombus aspiration, fragmentation, or catheter-directed thrombolysis, have seen rapid uptake over the last decade, with promising retrospective data. Unfortunately, only small, randomized trials exploring surrogate outcomes are available to guide modality and patient selection.²

CHEST

To better define which patients with IRPE are best managed with which therapy, several large-scale randomized controlled trials are underway. PE-TRACT, a study funded by the National Institutes of Health, aims to randomize 500 patients with IRPE to anticoagulation alone vs one of several modalities of CBT with a focus on long-term functional outcomes, including peak oxygen consumption at 3 months and functional class at 1 year. Aspiration thrombectomy with the FlowTriever^® device is being compared with anticoagulation alone in a study of 1,200 patients examining short-term composite end points.

CHEST

References

1. Fernández C, Bova C, Sanchez O, et al. Validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism. Chest. 2015;148(1):211-218. doi:10.1378/chest.14-2551

2. Yuriditsky E, Horowitz JM. The role of the PERT in the management and therapeutic decision-making in pulmonary embolism. Eur Heart J Acute Cardiovasc Care. 2022;11(9):693-694. doi:10.1093/ehjacc/zuac102

3. National Library of Medicine (US). A Randomized Trial of Ultrasound-facilitated, Catheter-directed, Thrombolysis Versus Anticoagulation for Acute Intermediate-high Risk Pulmonary Embolism: The Higher-risk Pulmonary Embolism Thrombolysis Study. Updated July 16, 2024. https://clinicaltrials.gov/study/NCT04790370

4. National Library of Medicine (US). PEERLESS II: RCT of FlowTriever vs. Anticoagulation Alone in Pulmonary Embolism. Updated July 17, 2024. https://clinicaltrials.gov/study/NCT06055920

5. National Library of Medicine (US). A Reduced Dose of Thrombolytic Treatment for Patients With Intermediate High-risk Acute Pulmonary Embolism: a Randomized Controled Trial. Updated July 17, 2024. https://clinicaltrials.gov/study/NCT04430569

PULMONARY VASCULAR AND CARDIOVASCULAR NETWORK

Cardiovascular Medicine and Surgery Section

Patients with intermediate-risk pulmonary embolism (IRPE), or those with right ventricular dysfunction without overt hemodynamic instability, represent a heterogenous population with short-term mortality ranging from 2% to 17%.¹ While systemic anticoagulation is the mainstay therapy, select individuals may benefit from more immediate reperfusion. Catheter-based therapies (CBT), including thrombus aspiration, fragmentation, or catheter-directed thrombolysis, have seen rapid uptake over the last decade, with promising retrospective data. Unfortunately, only small, randomized trials exploring surrogate outcomes are available to guide modality and patient selection.²

CHEST

To better define which patients with IRPE are best managed with which therapy, several large-scale randomized controlled trials are underway. PE-TRACT, a study funded by the National Institutes of Health, aims to randomize 500 patients with IRPE to anticoagulation alone vs one of several modalities of CBT with a focus on long-term functional outcomes, including peak oxygen consumption at 3 months and functional class at 1 year. Aspiration thrombectomy with the FlowTriever^® device is being compared with anticoagulation alone in a study of 1,200 patients examining short-term composite end points.

CHEST

References

1. Fernández C, Bova C, Sanchez O, et al. Validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism. Chest. 2015;148(1):211-218. doi:10.1378/chest.14-2551

2. Yuriditsky E, Horowitz JM. The role of the PERT in the management and therapeutic decision-making in pulmonary embolism. Eur Heart J Acute Cardiovasc Care. 2022;11(9):693-694. doi:10.1093/ehjacc/zuac102

3. National Library of Medicine (US). A Randomized Trial of Ultrasound-facilitated, Catheter-directed, Thrombolysis Versus Anticoagulation for Acute Intermediate-high Risk Pulmonary Embolism: The Higher-risk Pulmonary Embolism Thrombolysis Study. Updated July 16, 2024. https://clinicaltrials.gov/study/NCT04790370

4. National Library of Medicine (US). PEERLESS II: RCT of FlowTriever vs. Anticoagulation Alone in Pulmonary Embolism. Updated July 17, 2024. https://clinicaltrials.gov/study/NCT06055920

5. National Library of Medicine (US). A Reduced Dose of Thrombolytic Treatment for Patients With Intermediate High-risk Acute Pulmonary Embolism: a Randomized Controled Trial. Updated July 17, 2024. https://clinicaltrials.gov/study/NCT04430569

PULMONARY VASCULAR AND CARDIOVASCULAR NETWORK

Cardiovascular Medicine and Surgery Section

Patients with intermediate-risk pulmonary embolism (IRPE), or those with right ventricular dysfunction without overt hemodynamic instability, represent a heterogenous population with short-term mortality ranging from 2% to 17%.¹ While systemic anticoagulation is the mainstay therapy, select individuals may benefit from more immediate reperfusion. Catheter-based therapies (CBT), including thrombus aspiration, fragmentation, or catheter-directed thrombolysis, have seen rapid uptake over the last decade, with promising retrospective data. Unfortunately, only small, randomized trials exploring surrogate outcomes are available to guide modality and patient selection.²

CHEST

To better define which patients with IRPE are best managed with which therapy, several large-scale randomized controlled trials are underway. PE-TRACT, a study funded by the National Institutes of Health, aims to randomize 500 patients with IRPE to anticoagulation alone vs one of several modalities of CBT with a focus on long-term functional outcomes, including peak oxygen consumption at 3 months and functional class at 1 year. Aspiration thrombectomy with the FlowTriever^® device is being compared with anticoagulation alone in a study of 1,200 patients examining short-term composite end points.

CHEST

References

1. Fernández C, Bova C, Sanchez O, et al. Validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism. Chest. 2015;148(1):211-218. doi:10.1378/chest.14-2551

2. Yuriditsky E, Horowitz JM. The role of the PERT in the management and therapeutic decision-making in pulmonary embolism. Eur Heart J Acute Cardiovasc Care. 2022;11(9):693-694. doi:10.1093/ehjacc/zuac102

3. National Library of Medicine (US). A Randomized Trial of Ultrasound-facilitated, Catheter-directed, Thrombolysis Versus Anticoagulation for Acute Intermediate-high Risk Pulmonary Embolism: The Higher-risk Pulmonary Embolism Thrombolysis Study. Updated July 16, 2024. https://clinicaltrials.gov/study/NCT04790370

4. National Library of Medicine (US). PEERLESS II: RCT of FlowTriever vs. Anticoagulation Alone in Pulmonary Embolism. Updated July 17, 2024. https://clinicaltrials.gov/study/NCT06055920

5. National Library of Medicine (US). A Reduced Dose of Thrombolytic Treatment for Patients With Intermediate High-risk Acute Pulmonary Embolism: a Randomized Controled Trial. Updated July 17, 2024. https://clinicaltrials.gov/study/NCT04430569

AIRWAYS DISORDERS NETWORK

Bronchiectasis Section

Bronchiectasis is an extremely heterogeneous airways disease, making it difficult to study. For years, the noncystic fibrosis (CF) bronchiectasis community has been trying to organize to provide better care for more than half a million adults with bronchiectasis in the United States. Internationally, the Europeans created the European Bronchiectasis Registry, which has been a powerful tool including nearly 20,000 patients, to answer important epidemiologic and management questions. We must do more for the bronchiectasis community.

Clinicaltrials.gov indicates that there are 8 international phase 3 or 4 clinical trials that are currently enrolling; 3 of those have enrollment sites in the United States. One such study from University of North Carolina at Chapel Hill is looking at the use of nebulized hypertonic saline in patients with non-CF bronchiectasis to understand the effect it has on mucociliary clearance. Emory University is looking at the use of elexacaftor/tezacaftor/ivacaftor (Trikafta) in patients with non-CF bronchiectasis; these patients have only 1 targetable mutation and a phenotype that resembles CF. This 8-week, open-label, single-center study aims to measure both clinical and biomarker outcomes after treatment with Trikafta. Finally, a phase 3 trial out of Florida, the ICoN-1 study, is examining the efficacy and safety of inhaled clofazimine in the treatment of nontuberculous mycobacteria (NTM). This double-blind, randomized trial will look at culture conversion and quality of life measures. Additionally, the COPD Foundation has created the Bronchiectasis and NTM Research Registry, an American cohort containing more than 5,000 patients and data from 22 different sites, to answer some of the most important questions for clinicians and patients.

CHEST

We have made significant progress in bronchiectasis research; however, there is still much to learn. Together, we must make a concerted effort to enroll patients in clinical trials. Doing so will allow us to define our epidemiologic profile more precisely and explore new treatments and airway clearance techniques.

AIRWAYS DISORDERS NETWORK

Bronchiectasis Section

Bronchiectasis is an extremely heterogeneous airways disease, making it difficult to study. For years, the noncystic fibrosis (CF) bronchiectasis community has been trying to organize to provide better care for more than half a million adults with bronchiectasis in the United States. Internationally, the Europeans created the European Bronchiectasis Registry, which has been a powerful tool including nearly 20,000 patients, to answer important epidemiologic and management questions. We must do more for the bronchiectasis community.

Clinicaltrials.gov indicates that there are 8 international phase 3 or 4 clinical trials that are currently enrolling; 3 of those have enrollment sites in the United States. One such study from University of North Carolina at Chapel Hill is looking at the use of nebulized hypertonic saline in patients with non-CF bronchiectasis to understand the effect it has on mucociliary clearance. Emory University is looking at the use of elexacaftor/tezacaftor/ivacaftor (Trikafta) in patients with non-CF bronchiectasis; these patients have only 1 targetable mutation and a phenotype that resembles CF. This 8-week, open-label, single-center study aims to measure both clinical and biomarker outcomes after treatment with Trikafta. Finally, a phase 3 trial out of Florida, the ICoN-1 study, is examining the efficacy and safety of inhaled clofazimine in the treatment of nontuberculous mycobacteria (NTM). This double-blind, randomized trial will look at culture conversion and quality of life measures. Additionally, the COPD Foundation has created the Bronchiectasis and NTM Research Registry, an American cohort containing more than 5,000 patients and data from 22 different sites, to answer some of the most important questions for clinicians and patients.

CHEST

We have made significant progress in bronchiectasis research; however, there is still much to learn. Together, we must make a concerted effort to enroll patients in clinical trials. Doing so will allow us to define our epidemiologic profile more precisely and explore new treatments and airway clearance techniques.

AIRWAYS DISORDERS NETWORK

Bronchiectasis Section

Bronchiectasis is an extremely heterogeneous airways disease, making it difficult to study. For years, the noncystic fibrosis (CF) bronchiectasis community has been trying to organize to provide better care for more than half a million adults with bronchiectasis in the United States. Internationally, the Europeans created the European Bronchiectasis Registry, which has been a powerful tool including nearly 20,000 patients, to answer important epidemiologic and management questions. We must do more for the bronchiectasis community.

Clinicaltrials.gov indicates that there are 8 international phase 3 or 4 clinical trials that are currently enrolling; 3 of those have enrollment sites in the United States. One such study from University of North Carolina at Chapel Hill is looking at the use of nebulized hypertonic saline in patients with non-CF bronchiectasis to understand the effect it has on mucociliary clearance. Emory University is looking at the use of elexacaftor/tezacaftor/ivacaftor (Trikafta) in patients with non-CF bronchiectasis; these patients have only 1 targetable mutation and a phenotype that resembles CF. This 8-week, open-label, single-center study aims to measure both clinical and biomarker outcomes after treatment with Trikafta. Finally, a phase 3 trial out of Florida, the ICoN-1 study, is examining the efficacy and safety of inhaled clofazimine in the treatment of nontuberculous mycobacteria (NTM). This double-blind, randomized trial will look at culture conversion and quality of life measures. Additionally, the COPD Foundation has created the Bronchiectasis and NTM Research Registry, an American cohort containing more than 5,000 patients and data from 22 different sites, to answer some of the most important questions for clinicians and patients.

CHEST

We have made significant progress in bronchiectasis research; however, there is still much to learn. Together, we must make a concerted effort to enroll patients in clinical trials. Doing so will allow us to define our epidemiologic profile more precisely and explore new treatments and airway clearance techniques.

CHEST

As we find ourselves in September, I cannot help but dedicate my column to the upcoming CHEST Annual Meeting quickly approaching, October 6 to 9, in Boston.

If you haven’t yet been to a CHEST Annual Meeting, it’s an unmatched experience. We have top-notch experts in the field delivering content and materials in a variety of learning formats—lectures, interactive sessions, case-based scenarios, simulations, etc—and there’s an atmosphere unlike any other that’s welcoming to any level of practice.

For those who have attended, there’s always something new to see. Every year is different, with the culture of the location guiding the way and new opportunities to network while engaging in activity. No matter how many times you have been, attending the CHEST Annual Meeting never gets old.

CHEST

CHEST

As we find ourselves in September, I cannot help but dedicate my column to the upcoming CHEST Annual Meeting quickly approaching, October 6 to 9, in Boston.

If you haven’t yet been to a CHEST Annual Meeting, it’s an unmatched experience. We have top-notch experts in the field delivering content and materials in a variety of learning formats—lectures, interactive sessions, case-based scenarios, simulations, etc—and there’s an atmosphere unlike any other that’s welcoming to any level of practice.

For those who have attended, there’s always something new to see. Every year is different, with the culture of the location guiding the way and new opportunities to network while engaging in activity. No matter how many times you have been, attending the CHEST Annual Meeting never gets old.

CHEST

CHEST

As we find ourselves in September, I cannot help but dedicate my column to the upcoming CHEST Annual Meeting quickly approaching, October 6 to 9, in Boston.

If you haven’t yet been to a CHEST Annual Meeting, it’s an unmatched experience. We have top-notch experts in the field delivering content and materials in a variety of learning formats—lectures, interactive sessions, case-based scenarios, simulations, etc—and there’s an atmosphere unlike any other that’s welcoming to any level of practice.

For those who have attended, there’s always something new to see. Every year is different, with the culture of the location guiding the way and new opportunities to network while engaging in activity. No matter how many times you have been, attending the CHEST Annual Meeting never gets old.

CHEST

CHEST

The estimated prevalence of OSA in pregnancy ranges from 4% to 27% compared with 0.7% to 6.5% in nonpregnant, reproductive-age females, with an even higher prevalence in complicated pregnancies.¹ The increased prevalence in pregnancy can be explained by physiologic changes impacting the upper airway such as increases in maternal blood volume and reductions in oncotic pressure, as well as increases in circulating levels of estrogen and progesterone. OSA in pregnancy is associated with adverse perinatal outcomes such as hypertensive disorders of pregnancy, gestational diabetes, severe maternal morbidity abnormalities in fetal growth, preterm birth, and congenital abnormalities in the offspring.^2,3 Despite this evidence, guidelines on the screening, diagnosis, and treatment of OSA in pregnancy have only recently been published and will be reviewed here.¹

CHEST

The obstetric subcommittee of the Society of Anesthesia and Sleep Medicine that produced these guidelines had expertise in obstetric anesthesiology, sleep medicine and sleep research, high-risk obstetrics, and obstetric medicine. The guideline aimed to answer 3 questions: 1) Who should be screened in pregnancy for OSA, 2) how to make a diagnosis of OSA in pregnancy and the postpartum period, and 3) what is the treatment for OSA in pregnancy and the postpartum period. Although the estimated number of annual pregnancies in the US declined between 2010 to 2019, these clinical questions remain critical considering the obesity epidemic, the ability to conceive despite advanced maternal age and chronic illnesses with the use of fertility treatments, and the crisis of severe maternal morbidity and mortality. As sleep disordered breathing (SDB) has been associated with many conditions linked to maternal mortality, better management of SDB in this population is key.
 

Screening for OSA in the pregnant population

The guideline does not support universal screening of all people who are pregnant, but rather suggests that people who are pregnant and at high risk for OSA, such as those with a body mass index (BMI) ≥30 kg/m² and those with hypertensive disorders of pregnancy, or diabetes, in the index pregnancy or a prior pregnancy, be screened for OSA in the first or second trimester.¹ Screening for OSA in pregnancy in limited populations is recommended due to the lower yield of universal screening and its potential burden on the health care system. Furthermore, screening for OSA in early pregnancy is suggested given the practical challenges of arranging testing, initiating, and allowing time for patients to become acclimated to therapy in later stages of pregnancy. However, even when timing of diagnosis may not allow for appropriate treatment of OSA during pregnancy, knowing a person’s OSA status before delivery is beneficial, particularly for patients at risk for Cesarean delivery who may require intubation and exposure to sedative medications, as well as those receiving epidural anesthesia, as OSA is a risk factor for respiratory depression.

Although screening was thought to be beneficial in specific populations, there is insufficient evidence to recommend any one screening tool. The guideline made recommendations against the use of the Berlin questionnaire, STOP-BANG questionnaire, Epworth Sleepiness Scale, or the ASA checklist.¹ These screening tools were developed and validated in nonpregnant patient populations and their pooled sensitivity and specificity to detect OSA in pregnancy is low. Individual components of these screening tools, such as prepregnancy BMI, frequency and volume of snoring, hypertension, and neck circumference ≥16 inches have, however, been associated with OSA status.

Pregnancy-specific OSA screening tools have been proposed.^4,5 The guideline suggests these pregnancy-specific tools may be considered for screening for OSA in pregnancy but still require external validation, especially in high-risk populations. The committee agreed that individuals with BMI >30kg/m², hypertension, diabetes, and those with a history of difficult intubation or Mallampati score III or IV are considered at risk for OSA in pregnancy.
 

Diagnosis of OSA in the pregnant population

In the general population, in-laboratory polysomnogram (PSG) is the gold standard diagnostic test. However, for patients in whom uncomplicated OSA is suspected with a moderate to high pretest probability, unattended home sleep apnea testing (HSAT) is a reasonable initial study. On the other hand, in-lab PSG is recommended in mission-critical workers and when coexisting respiratory sleep disorders, or nonrespiratory sleep disorders, are suspected. For individuals who are pregnant and suspected of having OSA, the guideline suggests that HSAT is a reasonable diagnostic tool, as many level III devices have demonstrated good agreement between the respiratory disturbance index (RDI) and apnea-hypopnea index (AHI) measured by PSG.⁶ Notably, most studies have examined the performance of level III devices in late pregnancy in populations with obesity; hence, the performance of these devices in early pregnancy when risk for OSA is lower, or more subtle forms of SDB may be more common, is less clear but may be an acceptable first-line test.

The guideline did not provide recommendations for next steps following an inconclusive, technically inadequate, or negative HSAT. However, recommendations to proceed with in-lab PSG in individuals with clinical suspicion for OSA and a negative HSAT is a reasonable approach, keeping in mind the time restrictions of pregnancy. The more delayed the diagnosis, the less time there will be for initiation of and acclimation to therapy to maximize potential benefits during pregnancy. HSAT is especially practical and convenient for individuals with young families. The guideline does not recommend the use of overnight oximetry for diagnostic purposes.¹

The postpartum period is usually associated with weight loss and reversal of pregnancy physiology. Generally, the decision to perform a repeat sleep study following weight loss is individualized, based on factors such as improved symptoms or sustained, significant weight loss. Though data show improvement in AHI following delivery, small studies show persistent OSA in nearly half of individuals diagnosed in pregnancy. Hence, as pregnancy increases the risk for OSA, and given that the postpartum status is not always associated with resolution of OSA, the guideline recommends considering repeat diagnostic testing in the postpartum period.¹ The decision to repeat testing also depends on whether OSA or OSA symptoms predated pregnancy, on the persistence of symptoms, and the degree of weight loss with delivery and the postpartum body habitus.
 

Treatment of OSA in the pregnant population

The guideline recommends behavior modification in OSA similarly to individuals who are not pregnant (avoidance of sedatives, smoking, and alcohol).¹ However, weight loss is not recommended in pregnancy due to the potential for harm to the fetus.

The gold standard treatment for people who are pregnant and have OSA is continuous positive airway pressure (CPAP). Treatment of OSA in pregnancy is complicated by the fact that very few women are referred to sleep practices due to time restrictions and logistical reasons, and that data demonstrating improved pregnancy outcomes with CPAP are scarce, limiting the prioritization of OSA management. However, expert consensus considers a theoretical benefit in the context of lack of current evidence of harm from treatment. Hence, at this point, the guideline recommends counseling around CPAP therapy be aimed at improvement in symptoms, AHI, and quality of life, rather than pregnancy-specific outcomes.¹ This recommendation was based on observations from small case series that demonstrated improved breathing parameters during sleep and symptoms, and small randomized controlled trials (RCT), limited by short-term exposure to the intervention. However, since the publication of this guideline, a large RCT that randomized pregnant women with SDB to CPAP or usual care has demonstrated significantly lower diastolic blood pressure, an altered diastolic blood pressure trajectory, and a lower rate of preeclampsia in the group treated with CPAP compared with usual care.⁷

This guideline provides helpful insight on who to screen and how to manage OSA in pregnancy but additional research is needed to elucidate benefits of treatment and its effects on maternal and neonatal outcomes. Multidisciplinary collaborations between obstetric and sleep teams are necessary to ensure that screening and diagnostic strategies result in management change for improved outcomes.

References

1. Dominguez JE, Cantrell S, Habib AS, et al. Society of Anesthesia and Sleep Medicine and the Society for Obstetric Anesthesia and Perinatology Consensus Guideline on the screening, diagnosis and treatment of obstructive sleep apnea in pregnancy. Obstet Gynecol. 2023;142(2):403-423.

2. Bourjeily, G, Danilack C, Bublitz M, Muri J, Rosene-Montella K, Lipkind H. Maternal obstructive sleep apnea and neonatal birth outcomes in a population based sample. Sleep Med. 2000;66:233-240.

3. Malhamé I, Bublitz MH, Wilson D, Sanapo L, Rochin E, Bourjeily G. Sleep disordered breathing and the risk of severe maternal morbidity in women with preeclampsia: a population-based study. Pregnancy Hypertens. 2022;30:215-220.

4. Izci-Balserak B, Zhu B, Gurubhagavatula I, Keenan BT, Pien GW. A screening algorithm for obstructive sleep apnea in pregnancy. Ann Am Thorac Soc. 2019;16(10):1286-1294.

5. Louis J, Koch MA, Reddy UM, et al. Predictors of sleep-disordered breathing in pregnancy. Am J Obstet Gynecol. 2018;218(5):521.e1.e12.

6. Sharkey K, Waters K, Millman R, Moore R, Martin SM, Bourjeily. Validation of the Apnea Risk Evaluation System (ARES) device against laboratory polysomnogram in pregnant women at risk for obstructive sleep apnea syndrome. J Clin Sleep Med. 2014;10(5):497-502.

7. Tantrakul V, Ingsathit A, Liamsombut S, et al. Treatment of obstructive sleep apnea in high-risk pregnancy: a multicenter randomized controlled trial. Respir Res. 2023;24(1):171.

CHEST

The estimated prevalence of OSA in pregnancy ranges from 4% to 27% compared with 0.7% to 6.5% in nonpregnant, reproductive-age females, with an even higher prevalence in complicated pregnancies.¹ The increased prevalence in pregnancy can be explained by physiologic changes impacting the upper airway such as increases in maternal blood volume and reductions in oncotic pressure, as well as increases in circulating levels of estrogen and progesterone. OSA in pregnancy is associated with adverse perinatal outcomes such as hypertensive disorders of pregnancy, gestational diabetes, severe maternal morbidity abnormalities in fetal growth, preterm birth, and congenital abnormalities in the offspring.^2,3 Despite this evidence, guidelines on the screening, diagnosis, and treatment of OSA in pregnancy have only recently been published and will be reviewed here.¹

CHEST

The obstetric subcommittee of the Society of Anesthesia and Sleep Medicine that produced these guidelines had expertise in obstetric anesthesiology, sleep medicine and sleep research, high-risk obstetrics, and obstetric medicine. The guideline aimed to answer 3 questions: 1) Who should be screened in pregnancy for OSA, 2) how to make a diagnosis of OSA in pregnancy and the postpartum period, and 3) what is the treatment for OSA in pregnancy and the postpartum period. Although the estimated number of annual pregnancies in the US declined between 2010 to 2019, these clinical questions remain critical considering the obesity epidemic, the ability to conceive despite advanced maternal age and chronic illnesses with the use of fertility treatments, and the crisis of severe maternal morbidity and mortality. As sleep disordered breathing (SDB) has been associated with many conditions linked to maternal mortality, better management of SDB in this population is key.
 

Screening for OSA in the pregnant population

The guideline does not support universal screening of all people who are pregnant, but rather suggests that people who are pregnant and at high risk for OSA, such as those with a body mass index (BMI) ≥30 kg/m² and those with hypertensive disorders of pregnancy, or diabetes, in the index pregnancy or a prior pregnancy, be screened for OSA in the first or second trimester.¹ Screening for OSA in pregnancy in limited populations is recommended due to the lower yield of universal screening and its potential burden on the health care system. Furthermore, screening for OSA in early pregnancy is suggested given the practical challenges of arranging testing, initiating, and allowing time for patients to become acclimated to therapy in later stages of pregnancy. However, even when timing of diagnosis may not allow for appropriate treatment of OSA during pregnancy, knowing a person’s OSA status before delivery is beneficial, particularly for patients at risk for Cesarean delivery who may require intubation and exposure to sedative medications, as well as those receiving epidural anesthesia, as OSA is a risk factor for respiratory depression.

Although screening was thought to be beneficial in specific populations, there is insufficient evidence to recommend any one screening tool. The guideline made recommendations against the use of the Berlin questionnaire, STOP-BANG questionnaire, Epworth Sleepiness Scale, or the ASA checklist.¹ These screening tools were developed and validated in nonpregnant patient populations and their pooled sensitivity and specificity to detect OSA in pregnancy is low. Individual components of these screening tools, such as prepregnancy BMI, frequency and volume of snoring, hypertension, and neck circumference ≥16 inches have, however, been associated with OSA status.

Pregnancy-specific OSA screening tools have been proposed.^4,5 The guideline suggests these pregnancy-specific tools may be considered for screening for OSA in pregnancy but still require external validation, especially in high-risk populations. The committee agreed that individuals with BMI >30kg/m², hypertension, diabetes, and those with a history of difficult intubation or Mallampati score III or IV are considered at risk for OSA in pregnancy.
 

Diagnosis of OSA in the pregnant population

In the general population, in-laboratory polysomnogram (PSG) is the gold standard diagnostic test. However, for patients in whom uncomplicated OSA is suspected with a moderate to high pretest probability, unattended home sleep apnea testing (HSAT) is a reasonable initial study. On the other hand, in-lab PSG is recommended in mission-critical workers and when coexisting respiratory sleep disorders, or nonrespiratory sleep disorders, are suspected. For individuals who are pregnant and suspected of having OSA, the guideline suggests that HSAT is a reasonable diagnostic tool, as many level III devices have demonstrated good agreement between the respiratory disturbance index (RDI) and apnea-hypopnea index (AHI) measured by PSG.⁶ Notably, most studies have examined the performance of level III devices in late pregnancy in populations with obesity; hence, the performance of these devices in early pregnancy when risk for OSA is lower, or more subtle forms of SDB may be more common, is less clear but may be an acceptable first-line test.

The guideline did not provide recommendations for next steps following an inconclusive, technically inadequate, or negative HSAT. However, recommendations to proceed with in-lab PSG in individuals with clinical suspicion for OSA and a negative HSAT is a reasonable approach, keeping in mind the time restrictions of pregnancy. The more delayed the diagnosis, the less time there will be for initiation of and acclimation to therapy to maximize potential benefits during pregnancy. HSAT is especially practical and convenient for individuals with young families. The guideline does not recommend the use of overnight oximetry for diagnostic purposes.¹

The postpartum period is usually associated with weight loss and reversal of pregnancy physiology. Generally, the decision to perform a repeat sleep study following weight loss is individualized, based on factors such as improved symptoms or sustained, significant weight loss. Though data show improvement in AHI following delivery, small studies show persistent OSA in nearly half of individuals diagnosed in pregnancy. Hence, as pregnancy increases the risk for OSA, and given that the postpartum status is not always associated with resolution of OSA, the guideline recommends considering repeat diagnostic testing in the postpartum period.¹ The decision to repeat testing also depends on whether OSA or OSA symptoms predated pregnancy, on the persistence of symptoms, and the degree of weight loss with delivery and the postpartum body habitus.
 

Treatment of OSA in the pregnant population

The guideline recommends behavior modification in OSA similarly to individuals who are not pregnant (avoidance of sedatives, smoking, and alcohol).¹ However, weight loss is not recommended in pregnancy due to the potential for harm to the fetus.

The gold standard treatment for people who are pregnant and have OSA is continuous positive airway pressure (CPAP). Treatment of OSA in pregnancy is complicated by the fact that very few women are referred to sleep practices due to time restrictions and logistical reasons, and that data demonstrating improved pregnancy outcomes with CPAP are scarce, limiting the prioritization of OSA management. However, expert consensus considers a theoretical benefit in the context of lack of current evidence of harm from treatment. Hence, at this point, the guideline recommends counseling around CPAP therapy be aimed at improvement in symptoms, AHI, and quality of life, rather than pregnancy-specific outcomes.¹ This recommendation was based on observations from small case series that demonstrated improved breathing parameters during sleep and symptoms, and small randomized controlled trials (RCT), limited by short-term exposure to the intervention. However, since the publication of this guideline, a large RCT that randomized pregnant women with SDB to CPAP or usual care has demonstrated significantly lower diastolic blood pressure, an altered diastolic blood pressure trajectory, and a lower rate of preeclampsia in the group treated with CPAP compared with usual care.⁷

This guideline provides helpful insight on who to screen and how to manage OSA in pregnancy but additional research is needed to elucidate benefits of treatment and its effects on maternal and neonatal outcomes. Multidisciplinary collaborations between obstetric and sleep teams are necessary to ensure that screening and diagnostic strategies result in management change for improved outcomes.

References

1. Dominguez JE, Cantrell S, Habib AS, et al. Society of Anesthesia and Sleep Medicine and the Society for Obstetric Anesthesia and Perinatology Consensus Guideline on the screening, diagnosis and treatment of obstructive sleep apnea in pregnancy. Obstet Gynecol. 2023;142(2):403-423.

2. Bourjeily, G, Danilack C, Bublitz M, Muri J, Rosene-Montella K, Lipkind H. Maternal obstructive sleep apnea and neonatal birth outcomes in a population based sample. Sleep Med. 2000;66:233-240.

3. Malhamé I, Bublitz MH, Wilson D, Sanapo L, Rochin E, Bourjeily G. Sleep disordered breathing and the risk of severe maternal morbidity in women with preeclampsia: a population-based study. Pregnancy Hypertens. 2022;30:215-220.

4. Izci-Balserak B, Zhu B, Gurubhagavatula I, Keenan BT, Pien GW. A screening algorithm for obstructive sleep apnea in pregnancy. Ann Am Thorac Soc. 2019;16(10):1286-1294.

5. Louis J, Koch MA, Reddy UM, et al. Predictors of sleep-disordered breathing in pregnancy. Am J Obstet Gynecol. 2018;218(5):521.e1.e12.

6. Sharkey K, Waters K, Millman R, Moore R, Martin SM, Bourjeily. Validation of the Apnea Risk Evaluation System (ARES) device against laboratory polysomnogram in pregnant women at risk for obstructive sleep apnea syndrome. J Clin Sleep Med. 2014;10(5):497-502.

7. Tantrakul V, Ingsathit A, Liamsombut S, et al. Treatment of obstructive sleep apnea in high-risk pregnancy: a multicenter randomized controlled trial. Respir Res. 2023;24(1):171.

CHEST

The estimated prevalence of OSA in pregnancy ranges from 4% to 27% compared with 0.7% to 6.5% in nonpregnant, reproductive-age females, with an even higher prevalence in complicated pregnancies.¹ The increased prevalence in pregnancy can be explained by physiologic changes impacting the upper airway such as increases in maternal blood volume and reductions in oncotic pressure, as well as increases in circulating levels of estrogen and progesterone. OSA in pregnancy is associated with adverse perinatal outcomes such as hypertensive disorders of pregnancy, gestational diabetes, severe maternal morbidity abnormalities in fetal growth, preterm birth, and congenital abnormalities in the offspring.^2,3 Despite this evidence, guidelines on the screening, diagnosis, and treatment of OSA in pregnancy have only recently been published and will be reviewed here.¹

CHEST

The obstetric subcommittee of the Society of Anesthesia and Sleep Medicine that produced these guidelines had expertise in obstetric anesthesiology, sleep medicine and sleep research, high-risk obstetrics, and obstetric medicine. The guideline aimed to answer 3 questions: 1) Who should be screened in pregnancy for OSA, 2) how to make a diagnosis of OSA in pregnancy and the postpartum period, and 3) what is the treatment for OSA in pregnancy and the postpartum period. Although the estimated number of annual pregnancies in the US declined between 2010 to 2019, these clinical questions remain critical considering the obesity epidemic, the ability to conceive despite advanced maternal age and chronic illnesses with the use of fertility treatments, and the crisis of severe maternal morbidity and mortality. As sleep disordered breathing (SDB) has been associated with many conditions linked to maternal mortality, better management of SDB in this population is key.
 

Screening for OSA in the pregnant population

The guideline does not support universal screening of all people who are pregnant, but rather suggests that people who are pregnant and at high risk for OSA, such as those with a body mass index (BMI) ≥30 kg/m² and those with hypertensive disorders of pregnancy, or diabetes, in the index pregnancy or a prior pregnancy, be screened for OSA in the first or second trimester.¹ Screening for OSA in pregnancy in limited populations is recommended due to the lower yield of universal screening and its potential burden on the health care system. Furthermore, screening for OSA in early pregnancy is suggested given the practical challenges of arranging testing, initiating, and allowing time for patients to become acclimated to therapy in later stages of pregnancy. However, even when timing of diagnosis may not allow for appropriate treatment of OSA during pregnancy, knowing a person’s OSA status before delivery is beneficial, particularly for patients at risk for Cesarean delivery who may require intubation and exposure to sedative medications, as well as those receiving epidural anesthesia, as OSA is a risk factor for respiratory depression.

Although screening was thought to be beneficial in specific populations, there is insufficient evidence to recommend any one screening tool. The guideline made recommendations against the use of the Berlin questionnaire, STOP-BANG questionnaire, Epworth Sleepiness Scale, or the ASA checklist.¹ These screening tools were developed and validated in nonpregnant patient populations and their pooled sensitivity and specificity to detect OSA in pregnancy is low. Individual components of these screening tools, such as prepregnancy BMI, frequency and volume of snoring, hypertension, and neck circumference ≥16 inches have, however, been associated with OSA status.

Pregnancy-specific OSA screening tools have been proposed.^4,5 The guideline suggests these pregnancy-specific tools may be considered for screening for OSA in pregnancy but still require external validation, especially in high-risk populations. The committee agreed that individuals with BMI >30kg/m², hypertension, diabetes, and those with a history of difficult intubation or Mallampati score III or IV are considered at risk for OSA in pregnancy.
 

Diagnosis of OSA in the pregnant population

In the general population, in-laboratory polysomnogram (PSG) is the gold standard diagnostic test. However, for patients in whom uncomplicated OSA is suspected with a moderate to high pretest probability, unattended home sleep apnea testing (HSAT) is a reasonable initial study. On the other hand, in-lab PSG is recommended in mission-critical workers and when coexisting respiratory sleep disorders, or nonrespiratory sleep disorders, are suspected. For individuals who are pregnant and suspected of having OSA, the guideline suggests that HSAT is a reasonable diagnostic tool, as many level III devices have demonstrated good agreement between the respiratory disturbance index (RDI) and apnea-hypopnea index (AHI) measured by PSG.⁶ Notably, most studies have examined the performance of level III devices in late pregnancy in populations with obesity; hence, the performance of these devices in early pregnancy when risk for OSA is lower, or more subtle forms of SDB may be more common, is less clear but may be an acceptable first-line test.

The guideline did not provide recommendations for next steps following an inconclusive, technically inadequate, or negative HSAT. However, recommendations to proceed with in-lab PSG in individuals with clinical suspicion for OSA and a negative HSAT is a reasonable approach, keeping in mind the time restrictions of pregnancy. The more delayed the diagnosis, the less time there will be for initiation of and acclimation to therapy to maximize potential benefits during pregnancy. HSAT is especially practical and convenient for individuals with young families. The guideline does not recommend the use of overnight oximetry for diagnostic purposes.¹

The postpartum period is usually associated with weight loss and reversal of pregnancy physiology. Generally, the decision to perform a repeat sleep study following weight loss is individualized, based on factors such as improved symptoms or sustained, significant weight loss. Though data show improvement in AHI following delivery, small studies show persistent OSA in nearly half of individuals diagnosed in pregnancy. Hence, as pregnancy increases the risk for OSA, and given that the postpartum status is not always associated with resolution of OSA, the guideline recommends considering repeat diagnostic testing in the postpartum period.¹ The decision to repeat testing also depends on whether OSA or OSA symptoms predated pregnancy, on the persistence of symptoms, and the degree of weight loss with delivery and the postpartum body habitus.
 

Treatment of OSA in the pregnant population

The guideline recommends behavior modification in OSA similarly to individuals who are not pregnant (avoidance of sedatives, smoking, and alcohol).¹ However, weight loss is not recommended in pregnancy due to the potential for harm to the fetus.

The gold standard treatment for people who are pregnant and have OSA is continuous positive airway pressure (CPAP). Treatment of OSA in pregnancy is complicated by the fact that very few women are referred to sleep practices due to time restrictions and logistical reasons, and that data demonstrating improved pregnancy outcomes with CPAP are scarce, limiting the prioritization of OSA management. However, expert consensus considers a theoretical benefit in the context of lack of current evidence of harm from treatment. Hence, at this point, the guideline recommends counseling around CPAP therapy be aimed at improvement in symptoms, AHI, and quality of life, rather than pregnancy-specific outcomes.¹ This recommendation was based on observations from small case series that demonstrated improved breathing parameters during sleep and symptoms, and small randomized controlled trials (RCT), limited by short-term exposure to the intervention. However, since the publication of this guideline, a large RCT that randomized pregnant women with SDB to CPAP or usual care has demonstrated significantly lower diastolic blood pressure, an altered diastolic blood pressure trajectory, and a lower rate of preeclampsia in the group treated with CPAP compared with usual care.⁷

This guideline provides helpful insight on who to screen and how to manage OSA in pregnancy but additional research is needed to elucidate benefits of treatment and its effects on maternal and neonatal outcomes. Multidisciplinary collaborations between obstetric and sleep teams are necessary to ensure that screening and diagnostic strategies result in management change for improved outcomes.

References

1. Dominguez JE, Cantrell S, Habib AS, et al. Society of Anesthesia and Sleep Medicine and the Society for Obstetric Anesthesia and Perinatology Consensus Guideline on the screening, diagnosis and treatment of obstructive sleep apnea in pregnancy. Obstet Gynecol. 2023;142(2):403-423.

2. Bourjeily, G, Danilack C, Bublitz M, Muri J, Rosene-Montella K, Lipkind H. Maternal obstructive sleep apnea and neonatal birth outcomes in a population based sample. Sleep Med. 2000;66:233-240.

3. Malhamé I, Bublitz MH, Wilson D, Sanapo L, Rochin E, Bourjeily G. Sleep disordered breathing and the risk of severe maternal morbidity in women with preeclampsia: a population-based study. Pregnancy Hypertens. 2022;30:215-220.

4. Izci-Balserak B, Zhu B, Gurubhagavatula I, Keenan BT, Pien GW. A screening algorithm for obstructive sleep apnea in pregnancy. Ann Am Thorac Soc. 2019;16(10):1286-1294.

5. Louis J, Koch MA, Reddy UM, et al. Predictors of sleep-disordered breathing in pregnancy. Am J Obstet Gynecol. 2018;218(5):521.e1.e12.

6. Sharkey K, Waters K, Millman R, Moore R, Martin SM, Bourjeily. Validation of the Apnea Risk Evaluation System (ARES) device against laboratory polysomnogram in pregnant women at risk for obstructive sleep apnea syndrome. J Clin Sleep Med. 2014;10(5):497-502.

7. Tantrakul V, Ingsathit A, Liamsombut S, et al. Treatment of obstructive sleep apnea in high-risk pregnancy: a multicenter randomized controlled trial. Respir Res. 2023;24(1):171.

After Rena Barrow-Wells, an African American mother, fought mightily to prevent a repeat of her experience of two decades earlier when her first child’s cystic fibrosis (CF) took 4 years to diagnose, her story became the subject of a New York Times feature covering disparities in diagnostic CF screening. The article highlighted not only her struggles, but also the utter transformation of the CF landscape since the introduction of small molecule mutation-specific drugs. These drugs restore function to defective CF transmembrane conductance regulator (CFTR) proteins. By the time Ms. Barrow-Wells’ young son was treated, lung and pancreatic scarring were already significant. So when the 39-mutation variant screening test available in Ms. Barrow-Wells’ Lawrenceville, Georgia, clinic turned out negative for CF, her pediatrician told her to stop worrying despite her new son’s inherent genetic risk, telltale salty skin, foul-smelling diapers, and her pleas to test for sweat chloride. It still took 3 months for a confirmed diagnosis and the initiation of treatment.

Current genetic tests, based largely on older clinical trials that enrolled mostly white children, are highly accurate for identifying CF in white babies (95%), but often fail to identify substantial percentages of mutations originating in Africa, Asia, and Latin America. They miss CF in Asian (44%), Black (22%), and Hispanic, Native American and Alaskan Native babies (14%), the Times article stated. In the United States, the number of CF variants tested for falls into a wide range: from the one variant found mostly in White populations in Mississippi (with a 38% Black populace) to 689 variants in Wisconsin.

Callista Images/Image Source/Getty Images

Today’s CF challenges

Beyond refinements in screening instruments and policies that broaden access leading to the earliest possible diagnoses, ongoing research needs include finding treatments for other variants, and caring for adult populations living with treated CF and the disease’s multisystem manifestations. “As people with CF live longer, we need to be very focused on optimized adult medical care for this population,” Marc A. Sala, MD, assistant professor of medicine, Adult CF Program, Northwestern University Feinberg School of Medicine, Chicago, said in an interview. “For example, we need higher vigilance for liver, microvascular, coronary artery disease, and various cancer screenings. We do not know exactly how these will manifest differently from the way they do in non-CF populations, so this is where more work needs to be done.”

Northwestern University Feinberg School of Medicine

Emphasis on monitoring

The authors of “Future therapies for cystic fibrosis” (Allen et al. Nature Communications, 2023 Feb 8), after citing the ongoing transformative change for people with CF since the introduction of CFTR drugs, gave voice to important cautions. “Disease will progress, albeit more slowly, and will be more challenging to monitor. Effective CFTR modulators will likely slow or, at best, halt disease progression, but will not reverse a disease that has already become fixed.” They cited pancreatic destruction in the majority, bronchiectasis, and absence of the vas deferens, with still recurring (although less frequently) pulmonary exacerbations along with chronic infections and persistent airway inflammation. “It is essential that we do not become complacent about disease progression in this population,” the researchers stated. They cautioned also that effective surveillance for infection is critical in asymptomatic patients, emphasizing that it underpins the management of young healthy children with CF who demonstrate disease progression despite a lack of symptoms.

Among the ~90% for whom Trikafta is suitable and approved (those with least one copy of F508del or specific other responsive mutations), improvements include increased percent predicted FEV₁ by 10%-15% or more, decreased exacerbations, and improved quality of life,” Dr. Sala said. “Subsequent ‘real world’ experience shows dramatic reductions in sputum production and decreased frequency of lung transplant.”
 

Mutation agnostic therapy

Unfortunately, CF mutants, outside the population eligible for Trikafta, are prodigious in number and do not fall into just a few major groups. “Furthermore, although CF is a monogenic disease, it has variable phenotypes even for two individuals with the same mutations,” Dr. Sala said. “Current CFTR modulators act on the dysfunctional CFTR protein (either as channel gating potentiators or molecular chaperones to improve misfolding). That leaves about 10% of the CF population, those with little to no protein production (such as in nonsense mutations) ineligible for treatment with CFTR modulators. “The ideal for efficacy and equity, given that some CFTR mutations only exist in a handful of people, would be to develop a ‘mutation agnostic’ strategy — such as with mRNA or gene delivery. Here you could imagine that regardless of the type of mutation, a patient would then be able to receive the technology to increase CFTR channel function,” Dr. Sala said. Many modifiable factors, including host immunity and non-CFTR genes that impact CFTR indirectly, may underlie the fact that one person has a worse trajectory than another. “New therapies may also be found in this area of research,” Dr. Sala said.

Strategies in testing phases

“For patients with class I (nonsense) mutations there is hope that small molecules will be identified that can facilitate premature truncation codon (PTC) read-through and/or impede mRNA decay allowing for clinically relevant levels of functional CFTR,” the researchers noted. While the most extensively developed, ataluren, an oxadiazole, failed in phase 3 trials after initial promise, other ribosomal read-through drugs are in preclinical and early phase clinical trials. Also, early encouraging results support an alternative strategy, engineered transfer RNAs (tRNAs) that introduce an amino acid to an elongating peptide in place of the termination codon.

While these will address specific mutations, DNA or mRNA replacement strategies would be “mutation agnostic,” the researchers stated. The major challenge: delivery to the respiratory epithelium. Approaches currently in early testing include an inhaled aerosolized, lipid-based nanoparticle carrier for mRNA delivery, viral and non-viral DNA transfer, lipid-mediated CFTR gene transfer, pseudotyped lentiviral vector and adeno-associated vector transfer of CFTR DNA.
 

Adult CF care

“Adult CF care in general is a completely new frontier,” Meilinh Thi, DO, director of the adult cystic fibrosis program and assistant professor at University of Texas Health at San Antonio, said in an interview. “It’s fairly new to have separate pediatric and adult CF centers. There’s been a shift,” she said. “We’re encountering diseases in CF that we have not in the past had to deal with: diabetes that has features of both type 1 and type 2, increased colon cancer risk, bone disease, and mental health issues. Also, while pregnancy was previously discouraged for women with CF because of lung disease, now many are giving birth without complications and living normal lives,” Dr. Thi said.

University of Texas Health at San Antonio

“We do encourage our patients to talk to us before becoming pregnant so we can discuss the risk of passing on the gene. And, we do encourage their significant others to get testing. Some patients and their others, however, do decline to get tested,” she added.

The lifetime health issues conferred by CF, Dr. Thi noted, include lung disease with chronic inflammation, infection, respiratory failure (still the most common cause of death), gastrointestinal disorders (including of the pancreas) , colon obstruction and colon cancer, sinus disease, and reproductive system effects. Their permanence, she said, depends on how far their disease has progressed. “So the earlier you can provide these newer therapies — the modulators, for example, or the gene therapy whenever that comes out, then the less damage these organ systems will have, and the patients, we hope, will then do better.”

After Rena Barrow-Wells, an African American mother, fought mightily to prevent a repeat of her experience of two decades earlier when her first child’s cystic fibrosis (CF) took 4 years to diagnose, her story became the subject of a New York Times feature covering disparities in diagnostic CF screening. The article highlighted not only her struggles, but also the utter transformation of the CF landscape since the introduction of small molecule mutation-specific drugs. These drugs restore function to defective CF transmembrane conductance regulator (CFTR) proteins. By the time Ms. Barrow-Wells’ young son was treated, lung and pancreatic scarring were already significant. So when the 39-mutation variant screening test available in Ms. Barrow-Wells’ Lawrenceville, Georgia, clinic turned out negative for CF, her pediatrician told her to stop worrying despite her new son’s inherent genetic risk, telltale salty skin, foul-smelling diapers, and her pleas to test for sweat chloride. It still took 3 months for a confirmed diagnosis and the initiation of treatment.

Current genetic tests, based largely on older clinical trials that enrolled mostly white children, are highly accurate for identifying CF in white babies (95%), but often fail to identify substantial percentages of mutations originating in Africa, Asia, and Latin America. They miss CF in Asian (44%), Black (22%), and Hispanic, Native American and Alaskan Native babies (14%), the Times article stated. In the United States, the number of CF variants tested for falls into a wide range: from the one variant found mostly in White populations in Mississippi (with a 38% Black populace) to 689 variants in Wisconsin.

Callista Images/Image Source/Getty Images

Today’s CF challenges

Beyond refinements in screening instruments and policies that broaden access leading to the earliest possible diagnoses, ongoing research needs include finding treatments for other variants, and caring for adult populations living with treated CF and the disease’s multisystem manifestations. “As people with CF live longer, we need to be very focused on optimized adult medical care for this population,” Marc A. Sala, MD, assistant professor of medicine, Adult CF Program, Northwestern University Feinberg School of Medicine, Chicago, said in an interview. “For example, we need higher vigilance for liver, microvascular, coronary artery disease, and various cancer screenings. We do not know exactly how these will manifest differently from the way they do in non-CF populations, so this is where more work needs to be done.”

Northwestern University Feinberg School of Medicine

Emphasis on monitoring

The authors of “Future therapies for cystic fibrosis” (Allen et al. Nature Communications, 2023 Feb 8), after citing the ongoing transformative change for people with CF since the introduction of CFTR drugs, gave voice to important cautions. “Disease will progress, albeit more slowly, and will be more challenging to monitor. Effective CFTR modulators will likely slow or, at best, halt disease progression, but will not reverse a disease that has already become fixed.” They cited pancreatic destruction in the majority, bronchiectasis, and absence of the vas deferens, with still recurring (although less frequently) pulmonary exacerbations along with chronic infections and persistent airway inflammation. “It is essential that we do not become complacent about disease progression in this population,” the researchers stated. They cautioned also that effective surveillance for infection is critical in asymptomatic patients, emphasizing that it underpins the management of young healthy children with CF who demonstrate disease progression despite a lack of symptoms.

Among the ~90% for whom Trikafta is suitable and approved (those with least one copy of F508del or specific other responsive mutations), improvements include increased percent predicted FEV₁ by 10%-15% or more, decreased exacerbations, and improved quality of life,” Dr. Sala said. “Subsequent ‘real world’ experience shows dramatic reductions in sputum production and decreased frequency of lung transplant.”
 

Mutation agnostic therapy

Unfortunately, CF mutants, outside the population eligible for Trikafta, are prodigious in number and do not fall into just a few major groups. “Furthermore, although CF is a monogenic disease, it has variable phenotypes even for two individuals with the same mutations,” Dr. Sala said. “Current CFTR modulators act on the dysfunctional CFTR protein (either as channel gating potentiators or molecular chaperones to improve misfolding). That leaves about 10% of the CF population, those with little to no protein production (such as in nonsense mutations) ineligible for treatment with CFTR modulators. “The ideal for efficacy and equity, given that some CFTR mutations only exist in a handful of people, would be to develop a ‘mutation agnostic’ strategy — such as with mRNA or gene delivery. Here you could imagine that regardless of the type of mutation, a patient would then be able to receive the technology to increase CFTR channel function,” Dr. Sala said. Many modifiable factors, including host immunity and non-CFTR genes that impact CFTR indirectly, may underlie the fact that one person has a worse trajectory than another. “New therapies may also be found in this area of research,” Dr. Sala said.

Strategies in testing phases

“For patients with class I (nonsense) mutations there is hope that small molecules will be identified that can facilitate premature truncation codon (PTC) read-through and/or impede mRNA decay allowing for clinically relevant levels of functional CFTR,” the researchers noted. While the most extensively developed, ataluren, an oxadiazole, failed in phase 3 trials after initial promise, other ribosomal read-through drugs are in preclinical and early phase clinical trials. Also, early encouraging results support an alternative strategy, engineered transfer RNAs (tRNAs) that introduce an amino acid to an elongating peptide in place of the termination codon.

While these will address specific mutations, DNA or mRNA replacement strategies would be “mutation agnostic,” the researchers stated. The major challenge: delivery to the respiratory epithelium. Approaches currently in early testing include an inhaled aerosolized, lipid-based nanoparticle carrier for mRNA delivery, viral and non-viral DNA transfer, lipid-mediated CFTR gene transfer, pseudotyped lentiviral vector and adeno-associated vector transfer of CFTR DNA.
 

Adult CF care

“Adult CF care in general is a completely new frontier,” Meilinh Thi, DO, director of the adult cystic fibrosis program and assistant professor at University of Texas Health at San Antonio, said in an interview. “It’s fairly new to have separate pediatric and adult CF centers. There’s been a shift,” she said. “We’re encountering diseases in CF that we have not in the past had to deal with: diabetes that has features of both type 1 and type 2, increased colon cancer risk, bone disease, and mental health issues. Also, while pregnancy was previously discouraged for women with CF because of lung disease, now many are giving birth without complications and living normal lives,” Dr. Thi said.

University of Texas Health at San Antonio

“We do encourage our patients to talk to us before becoming pregnant so we can discuss the risk of passing on the gene. And, we do encourage their significant others to get testing. Some patients and their others, however, do decline to get tested,” she added.

The lifetime health issues conferred by CF, Dr. Thi noted, include lung disease with chronic inflammation, infection, respiratory failure (still the most common cause of death), gastrointestinal disorders (including of the pancreas) , colon obstruction and colon cancer, sinus disease, and reproductive system effects. Their permanence, she said, depends on how far their disease has progressed. “So the earlier you can provide these newer therapies — the modulators, for example, or the gene therapy whenever that comes out, then the less damage these organ systems will have, and the patients, we hope, will then do better.”

After Rena Barrow-Wells, an African American mother, fought mightily to prevent a repeat of her experience of two decades earlier when her first child’s cystic fibrosis (CF) took 4 years to diagnose, her story became the subject of a New York Times feature covering disparities in diagnostic CF screening. The article highlighted not only her struggles, but also the utter transformation of the CF landscape since the introduction of small molecule mutation-specific drugs. These drugs restore function to defective CF transmembrane conductance regulator (CFTR) proteins. By the time Ms. Barrow-Wells’ young son was treated, lung and pancreatic scarring were already significant. So when the 39-mutation variant screening test available in Ms. Barrow-Wells’ Lawrenceville, Georgia, clinic turned out negative for CF, her pediatrician told her to stop worrying despite her new son’s inherent genetic risk, telltale salty skin, foul-smelling diapers, and her pleas to test for sweat chloride. It still took 3 months for a confirmed diagnosis and the initiation of treatment.

Current genetic tests, based largely on older clinical trials that enrolled mostly white children, are highly accurate for identifying CF in white babies (95%), but often fail to identify substantial percentages of mutations originating in Africa, Asia, and Latin America. They miss CF in Asian (44%), Black (22%), and Hispanic, Native American and Alaskan Native babies (14%), the Times article stated. In the United States, the number of CF variants tested for falls into a wide range: from the one variant found mostly in White populations in Mississippi (with a 38% Black populace) to 689 variants in Wisconsin.

Callista Images/Image Source/Getty Images

Today’s CF challenges

Beyond refinements in screening instruments and policies that broaden access leading to the earliest possible diagnoses, ongoing research needs include finding treatments for other variants, and caring for adult populations living with treated CF and the disease’s multisystem manifestations. “As people with CF live longer, we need to be very focused on optimized adult medical care for this population,” Marc A. Sala, MD, assistant professor of medicine, Adult CF Program, Northwestern University Feinberg School of Medicine, Chicago, said in an interview. “For example, we need higher vigilance for liver, microvascular, coronary artery disease, and various cancer screenings. We do not know exactly how these will manifest differently from the way they do in non-CF populations, so this is where more work needs to be done.”

Northwestern University Feinberg School of Medicine

Emphasis on monitoring

The authors of “Future therapies for cystic fibrosis” (Allen et al. Nature Communications, 2023 Feb 8), after citing the ongoing transformative change for people with CF since the introduction of CFTR drugs, gave voice to important cautions. “Disease will progress, albeit more slowly, and will be more challenging to monitor. Effective CFTR modulators will likely slow or, at best, halt disease progression, but will not reverse a disease that has already become fixed.” They cited pancreatic destruction in the majority, bronchiectasis, and absence of the vas deferens, with still recurring (although less frequently) pulmonary exacerbations along with chronic infections and persistent airway inflammation. “It is essential that we do not become complacent about disease progression in this population,” the researchers stated. They cautioned also that effective surveillance for infection is critical in asymptomatic patients, emphasizing that it underpins the management of young healthy children with CF who demonstrate disease progression despite a lack of symptoms.

Among the ~90% for whom Trikafta is suitable and approved (those with least one copy of F508del or specific other responsive mutations), improvements include increased percent predicted FEV₁ by 10%-15% or more, decreased exacerbations, and improved quality of life,” Dr. Sala said. “Subsequent ‘real world’ experience shows dramatic reductions in sputum production and decreased frequency of lung transplant.”
 

Mutation agnostic therapy

Unfortunately, CF mutants, outside the population eligible for Trikafta, are prodigious in number and do not fall into just a few major groups. “Furthermore, although CF is a monogenic disease, it has variable phenotypes even for two individuals with the same mutations,” Dr. Sala said. “Current CFTR modulators act on the dysfunctional CFTR protein (either as channel gating potentiators or molecular chaperones to improve misfolding). That leaves about 10% of the CF population, those with little to no protein production (such as in nonsense mutations) ineligible for treatment with CFTR modulators. “The ideal for efficacy and equity, given that some CFTR mutations only exist in a handful of people, would be to develop a ‘mutation agnostic’ strategy — such as with mRNA or gene delivery. Here you could imagine that regardless of the type of mutation, a patient would then be able to receive the technology to increase CFTR channel function,” Dr. Sala said. Many modifiable factors, including host immunity and non-CFTR genes that impact CFTR indirectly, may underlie the fact that one person has a worse trajectory than another. “New therapies may also be found in this area of research,” Dr. Sala said.

Strategies in testing phases

“For patients with class I (nonsense) mutations there is hope that small molecules will be identified that can facilitate premature truncation codon (PTC) read-through and/or impede mRNA decay allowing for clinically relevant levels of functional CFTR,” the researchers noted. While the most extensively developed, ataluren, an oxadiazole, failed in phase 3 trials after initial promise, other ribosomal read-through drugs are in preclinical and early phase clinical trials. Also, early encouraging results support an alternative strategy, engineered transfer RNAs (tRNAs) that introduce an amino acid to an elongating peptide in place of the termination codon.

While these will address specific mutations, DNA or mRNA replacement strategies would be “mutation agnostic,” the researchers stated. The major challenge: delivery to the respiratory epithelium. Approaches currently in early testing include an inhaled aerosolized, lipid-based nanoparticle carrier for mRNA delivery, viral and non-viral DNA transfer, lipid-mediated CFTR gene transfer, pseudotyped lentiviral vector and adeno-associated vector transfer of CFTR DNA.
 

Adult CF care

“Adult CF care in general is a completely new frontier,” Meilinh Thi, DO, director of the adult cystic fibrosis program and assistant professor at University of Texas Health at San Antonio, said in an interview. “It’s fairly new to have separate pediatric and adult CF centers. There’s been a shift,” she said. “We’re encountering diseases in CF that we have not in the past had to deal with: diabetes that has features of both type 1 and type 2, increased colon cancer risk, bone disease, and mental health issues. Also, while pregnancy was previously discouraged for women with CF because of lung disease, now many are giving birth without complications and living normal lives,” Dr. Thi said.

University of Texas Health at San Antonio

“We do encourage our patients to talk to us before becoming pregnant so we can discuss the risk of passing on the gene. And, we do encourage their significant others to get testing. Some patients and their others, however, do decline to get tested,” she added.

The lifetime health issues conferred by CF, Dr. Thi noted, include lung disease with chronic inflammation, infection, respiratory failure (still the most common cause of death), gastrointestinal disorders (including of the pancreas) , colon obstruction and colon cancer, sinus disease, and reproductive system effects. Their permanence, she said, depends on how far their disease has progressed. “So the earlier you can provide these newer therapies — the modulators, for example, or the gene therapy whenever that comes out, then the less damage these organ systems will have, and the patients, we hope, will then do better.”

Journal CHEST^®

The Clinical Frailty Scale for Risk Stratification in Patients With Fibrotic Interstitial Lung Disease 

By Guler, MD, and colleagues

Life expectancy is a very important factor for patients with interstitial lung disease (ILD) and their caregivers. The discussion surrounding prognosis is often wrought with uncertainty and is inherently painful for both patients and clinicians when faced with nonmodifiable traits. This study illustrates the significance of employing a method that succinctly and systematically communicates the degree of functional impairment in patients with fibrotic lung disease. The authors have highlighted the importance of identifying and improving health factors associated with frailty to enhance the survival and quality of life of patients with chronic noncurable fibrotic lung disease. It also presents hope that interventions aimed at improving functional capacity may improve frailty and thus modify prognosis. In the future, longitudinal trends of frailty assessments following interventions aimed at improving both exercise and functional capacity, like pulmonary rehab, should be explored.

CHEST

– Commentary by Priya Balakrishnan, MD, MS, FCCP, Member of the CHEST Physician Editorial Board
 

CHEST® Pulmonary

The Diagnostic Yield of Cone Beam CT Combined With Radial-Endobronchial Ultrasound for the Diagnosis of Peripheral Pulmonary Nodules

By Michael V. Brown, MD, and colleagues

Brown and colleagues provide a systemic review and meta-analysis of the diagnostic yield of cone beam computed tomography (CBCT) scan combined with radial-endobronchial ultrasound (r-EBUS) for the diagnosis of peripheral pulmonary nodules. They included 14 studies (865 patients with 882 lesions) with pooled diagnostic yield from CBCT scan and r-EBUS for peripheral pulmonary nodules of 80% (95% CI, 76% to 84%) with complication rates of 2.01% for pneumothorax and 1.08% for bleeding. Amongst the studies selected, confounders (including study design, definition of diagnostic yield, use of ROSE, additional equipment, etc) existed. The important takeaway is that 3D imaging guidance with CBCT scan can corroborate “tool in lesion” and thus potentially improve the outcomes of the different bronchoscopic modalities utilized to diagnose peripheral pulmonary nodules. Future prospective investigations with less heterogeneity in study design and outcomes, as well as comparison with newer technologies such as robotic bronchoscopy, are necessary to corroborate these findings.

CHEST

CHEST® Critical Care

Platelet Bioenergetics and Associations With Delirium and Coma in Patients With Sepsis 

By Chukwudi A. Onyemekwu, DO, and colleagues

The study by Onyemekwu and colleagues explores the link between platelet mitochondrial function and acute brain dysfunction (delirium and coma) in patients with sepsis. The investigators measured various parameters of platelet mitochondrial respiratory bioenergetics and found that increased spare respiratory capacity was significantly associated with coma but not delirium. These findings suggest that systemic mitochondrial function could influence brain health and indicate a potential link between mitochondrial bioenergetics and coma during sepsis. The study did not find a significant association between platelet bioenergetics and delirium, suggesting that coma and delirium may have different underlying pathophysiologic mechanisms. We must interpret the results with caution, as the associations identified in this observational study do not prove causation. It is possible that the changes seen in platelet mitochondria may be a result of coma rather than a mechanism. Nonetheless, the study provides a foundation for future research to explore the mechanistic role of mitochondria in acute brain dysfunction during sepsis and the potential for developing mitochondrial-targeted therapies as a possible treatment approach for patients with sepsis-induced coma.

CHEST

– Commentary by Angel O. Coz, MD, FCCP, Editor in Chief of CHEST Physician
 

Journal CHEST^®

The Clinical Frailty Scale for Risk Stratification in Patients With Fibrotic Interstitial Lung Disease 

By Guler, MD, and colleagues

Life expectancy is a very important factor for patients with interstitial lung disease (ILD) and their caregivers. The discussion surrounding prognosis is often wrought with uncertainty and is inherently painful for both patients and clinicians when faced with nonmodifiable traits. This study illustrates the significance of employing a method that succinctly and systematically communicates the degree of functional impairment in patients with fibrotic lung disease. The authors have highlighted the importance of identifying and improving health factors associated with frailty to enhance the survival and quality of life of patients with chronic noncurable fibrotic lung disease. It also presents hope that interventions aimed at improving functional capacity may improve frailty and thus modify prognosis. In the future, longitudinal trends of frailty assessments following interventions aimed at improving both exercise and functional capacity, like pulmonary rehab, should be explored.

CHEST

– Commentary by Priya Balakrishnan, MD, MS, FCCP, Member of the CHEST Physician Editorial Board
 

CHEST® Pulmonary

The Diagnostic Yield of Cone Beam CT Combined With Radial-Endobronchial Ultrasound for the Diagnosis of Peripheral Pulmonary Nodules

By Michael V. Brown, MD, and colleagues

Brown and colleagues provide a systemic review and meta-analysis of the diagnostic yield of cone beam computed tomography (CBCT) scan combined with radial-endobronchial ultrasound (r-EBUS) for the diagnosis of peripheral pulmonary nodules. They included 14 studies (865 patients with 882 lesions) with pooled diagnostic yield from CBCT scan and r-EBUS for peripheral pulmonary nodules of 80% (95% CI, 76% to 84%) with complication rates of 2.01% for pneumothorax and 1.08% for bleeding. Amongst the studies selected, confounders (including study design, definition of diagnostic yield, use of ROSE, additional equipment, etc) existed. The important takeaway is that 3D imaging guidance with CBCT scan can corroborate “tool in lesion” and thus potentially improve the outcomes of the different bronchoscopic modalities utilized to diagnose peripheral pulmonary nodules. Future prospective investigations with less heterogeneity in study design and outcomes, as well as comparison with newer technologies such as robotic bronchoscopy, are necessary to corroborate these findings.

CHEST

CHEST® Critical Care

Platelet Bioenergetics and Associations With Delirium and Coma in Patients With Sepsis 

By Chukwudi A. Onyemekwu, DO, and colleagues

The study by Onyemekwu and colleagues explores the link between platelet mitochondrial function and acute brain dysfunction (delirium and coma) in patients with sepsis. The investigators measured various parameters of platelet mitochondrial respiratory bioenergetics and found that increased spare respiratory capacity was significantly associated with coma but not delirium. These findings suggest that systemic mitochondrial function could influence brain health and indicate a potential link between mitochondrial bioenergetics and coma during sepsis. The study did not find a significant association between platelet bioenergetics and delirium, suggesting that coma and delirium may have different underlying pathophysiologic mechanisms. We must interpret the results with caution, as the associations identified in this observational study do not prove causation. It is possible that the changes seen in platelet mitochondria may be a result of coma rather than a mechanism. Nonetheless, the study provides a foundation for future research to explore the mechanistic role of mitochondria in acute brain dysfunction during sepsis and the potential for developing mitochondrial-targeted therapies as a possible treatment approach for patients with sepsis-induced coma.

CHEST

– Commentary by Angel O. Coz, MD, FCCP, Editor in Chief of CHEST Physician
 

Journal CHEST^®

The Clinical Frailty Scale for Risk Stratification in Patients With Fibrotic Interstitial Lung Disease 

By Guler, MD, and colleagues

Life expectancy is a very important factor for patients with interstitial lung disease (ILD) and their caregivers. The discussion surrounding prognosis is often wrought with uncertainty and is inherently painful for both patients and clinicians when faced with nonmodifiable traits. This study illustrates the significance of employing a method that succinctly and systematically communicates the degree of functional impairment in patients with fibrotic lung disease. The authors have highlighted the importance of identifying and improving health factors associated with frailty to enhance the survival and quality of life of patients with chronic noncurable fibrotic lung disease. It also presents hope that interventions aimed at improving functional capacity may improve frailty and thus modify prognosis. In the future, longitudinal trends of frailty assessments following interventions aimed at improving both exercise and functional capacity, like pulmonary rehab, should be explored.

CHEST

– Commentary by Priya Balakrishnan, MD, MS, FCCP, Member of the CHEST Physician Editorial Board
 

CHEST® Pulmonary

The Diagnostic Yield of Cone Beam CT Combined With Radial-Endobronchial Ultrasound for the Diagnosis of Peripheral Pulmonary Nodules

By Michael V. Brown, MD, and colleagues

Brown and colleagues provide a systemic review and meta-analysis of the diagnostic yield of cone beam computed tomography (CBCT) scan combined with radial-endobronchial ultrasound (r-EBUS) for the diagnosis of peripheral pulmonary nodules. They included 14 studies (865 patients with 882 lesions) with pooled diagnostic yield from CBCT scan and r-EBUS for peripheral pulmonary nodules of 80% (95% CI, 76% to 84%) with complication rates of 2.01% for pneumothorax and 1.08% for bleeding. Amongst the studies selected, confounders (including study design, definition of diagnostic yield, use of ROSE, additional equipment, etc) existed. The important takeaway is that 3D imaging guidance with CBCT scan can corroborate “tool in lesion” and thus potentially improve the outcomes of the different bronchoscopic modalities utilized to diagnose peripheral pulmonary nodules. Future prospective investigations with less heterogeneity in study design and outcomes, as well as comparison with newer technologies such as robotic bronchoscopy, are necessary to corroborate these findings.

CHEST

CHEST® Critical Care

Platelet Bioenergetics and Associations With Delirium and Coma in Patients With Sepsis 

By Chukwudi A. Onyemekwu, DO, and colleagues

The study by Onyemekwu and colleagues explores the link between platelet mitochondrial function and acute brain dysfunction (delirium and coma) in patients with sepsis. The investigators measured various parameters of platelet mitochondrial respiratory bioenergetics and found that increased spare respiratory capacity was significantly associated with coma but not delirium. These findings suggest that systemic mitochondrial function could influence brain health and indicate a potential link between mitochondrial bioenergetics and coma during sepsis. The study did not find a significant association between platelet bioenergetics and delirium, suggesting that coma and delirium may have different underlying pathophysiologic mechanisms. We must interpret the results with caution, as the associations identified in this observational study do not prove causation. It is possible that the changes seen in platelet mitochondria may be a result of coma rather than a mechanism. Nonetheless, the study provides a foundation for future research to explore the mechanistic role of mitochondria in acute brain dysfunction during sepsis and the potential for developing mitochondrial-targeted therapies as a possible treatment approach for patients with sepsis-induced coma.

CHEST

– Commentary by Angel O. Coz, MD, FCCP, Editor in Chief of CHEST Physician
 

Ensifentrine (Ohtuvayre), a novel medication for the treatment of chronic obstructive pulmonary disease (COPD) recently approved by the Food and Drug Administration, has been shown to reduce COPD exacerbations and may improve the quality of life for patients, but these potential benefits come at an unreasonably high annual cost, authors of a cost and effectiveness analysis say.

Ensifentrine is a first-in-class selective dual inhibitor of both phosphodiesterase 3 (PDE-3) and PDE-4, combining both bronchodilator and nonsteroidal anti-inflammatory effects in a single molecule. The drug is delivered through a standard jet nebulizer.

In the phase 3 ENHANCE 1 and 2 trials, ensifentrine significantly improved lung function based on the primary outcome of average forced expiratory volume in 1 second within 0-12 hours of administration, compared with placebo. In addition, patients were reported to tolerate the inhaled treatment well, with similar proportions of ensifentrine- and placebo-assigned patients reporting treatment-emergent adverse events. The most common treatment-emergent adverse events were nasopharyngitis, hypertension, and back pain, reported in < 3% of the ensifentrine group.
 

High cost barrier

But as authors of the analysis from the Boston, Massachusetts–based Institute for Clinical and Economic Review (ICER) found, the therapeutic edge offered by ensifentrine is outweighed by the annual wholesale acquisition cost that its maker, Vernona Pharma, has established: $35,400, which far exceeds the estimated health-benefit price of $7,500-$12,700, according to ICER. ICER is an independent, nonprofit research institute that conducts evidence-based reviews of healthcare interventions, including prescription drugs, other treatments, and diagnostic tests.

“Current evidence shows that ensifentrine decreases COPD exacerbations when used in combination with some current inhaled therapies, but there are uncertainties about how much benefit it may add to unstudied combinations of inhaled treatments,” said David Rind, MD, chief medical officer of ICER in a statement.

In an interview, Dr. Rind noted that the high price of ensifentrine may lead payers to restrict access to an otherwise promising new therapy. “Obviously many drugs in the US are overpriced, and this one, too, looks like it is overpriced. That causes ongoing financial toxicity for individual patients and it causes problems for the entire US health system, because when we pay too much for drugs we don’t have money for other things. So I’m worried about the fact that this price is too high compared to the benefit it provides.”

As previously reported, as many as one in six persons with COPD in the United States miss or delay COPD medication doses because of high drug costs. “I think that the pricing they chose is going to cause lots of barriers to people getting access and that insurance companies will throw up barriers. Primary care physicians like me won’t even try to get approval for a drug like this given the hoops we will be made to jump through, and so fewer people will get this drug,” Dr. Rind said. He pointed out that a lower wholesale acquisition cost could encourage higher-volume sales, affording the drugmaker a comparable profit with the higher-cost but lower-volume option.
 

Good drug, high price

An independent appraisal committee for ICER determined that “current evidence is adequate to demonstrate a net health benefit for ensifentrine added to maintenance therapy when compared to maintenance therapy alone.”

But ICER also issued an access and affordability alert “to signal to stakeholders and policymakers that the amount of added healthcare costs associated with a new service may be difficult for the health system to absorb over the short term without displacing other needed services.” ICER recommends that payers should include coverage for smoking cessation therapies, and that drug manufacturers “set prices that will foster affordability and good access for all patients by aligning prices with the patient-centered therapeutic value of their treatments.”

“This looks like a pretty good drug,” Dr. Rind said. “It looks quite safe and I think there will be a lot of patients, particularly those who are having frequent exacerbations, who this would be appropriate for, particularly once they’ve maxed out existing therapies, but maybe even earlier than that. And if the price comes down to the point that patients can really access this and providers can access it, people really should look at this as a potential therapy.”
 

Drug not yet available?

However, providers have not yet had direct experience with the new medication. “We haven’t been able to prescribe it yet,” said Corinne Young, MSN, FNP-C, FCCP, director of Advance Practice Provider and Clinical Services for Colorado Springs Pulmonary Consultants, president and founder of the Association of Pulmonary Advance Practice Providers, and a member of the CHEST Physician Editorial Board.

CHEST

Ensifentrine (Ohtuvayre), a novel medication for the treatment of chronic obstructive pulmonary disease (COPD) recently approved by the Food and Drug Administration, has been shown to reduce COPD exacerbations and may improve the quality of life for patients, but these potential benefits come at an unreasonably high annual cost, authors of a cost and effectiveness analysis say.

Ensifentrine is a first-in-class selective dual inhibitor of both phosphodiesterase 3 (PDE-3) and PDE-4, combining both bronchodilator and nonsteroidal anti-inflammatory effects in a single molecule. The drug is delivered through a standard jet nebulizer.

In the phase 3 ENHANCE 1 and 2 trials, ensifentrine significantly improved lung function based on the primary outcome of average forced expiratory volume in 1 second within 0-12 hours of administration, compared with placebo. In addition, patients were reported to tolerate the inhaled treatment well, with similar proportions of ensifentrine- and placebo-assigned patients reporting treatment-emergent adverse events. The most common treatment-emergent adverse events were nasopharyngitis, hypertension, and back pain, reported in < 3% of the ensifentrine group.
 

High cost barrier

But as authors of the analysis from the Boston, Massachusetts–based Institute for Clinical and Economic Review (ICER) found, the therapeutic edge offered by ensifentrine is outweighed by the annual wholesale acquisition cost that its maker, Vernona Pharma, has established: $35,400, which far exceeds the estimated health-benefit price of $7,500-$12,700, according to ICER. ICER is an independent, nonprofit research institute that conducts evidence-based reviews of healthcare interventions, including prescription drugs, other treatments, and diagnostic tests.

“Current evidence shows that ensifentrine decreases COPD exacerbations when used in combination with some current inhaled therapies, but there are uncertainties about how much benefit it may add to unstudied combinations of inhaled treatments,” said David Rind, MD, chief medical officer of ICER in a statement.

In an interview, Dr. Rind noted that the high price of ensifentrine may lead payers to restrict access to an otherwise promising new therapy. “Obviously many drugs in the US are overpriced, and this one, too, looks like it is overpriced. That causes ongoing financial toxicity for individual patients and it causes problems for the entire US health system, because when we pay too much for drugs we don’t have money for other things. So I’m worried about the fact that this price is too high compared to the benefit it provides.”

As previously reported, as many as one in six persons with COPD in the United States miss or delay COPD medication doses because of high drug costs. “I think that the pricing they chose is going to cause lots of barriers to people getting access and that insurance companies will throw up barriers. Primary care physicians like me won’t even try to get approval for a drug like this given the hoops we will be made to jump through, and so fewer people will get this drug,” Dr. Rind said. He pointed out that a lower wholesale acquisition cost could encourage higher-volume sales, affording the drugmaker a comparable profit with the higher-cost but lower-volume option.
 

Good drug, high price

An independent appraisal committee for ICER determined that “current evidence is adequate to demonstrate a net health benefit for ensifentrine added to maintenance therapy when compared to maintenance therapy alone.”

But ICER also issued an access and affordability alert “to signal to stakeholders and policymakers that the amount of added healthcare costs associated with a new service may be difficult for the health system to absorb over the short term without displacing other needed services.” ICER recommends that payers should include coverage for smoking cessation therapies, and that drug manufacturers “set prices that will foster affordability and good access for all patients by aligning prices with the patient-centered therapeutic value of their treatments.”

“This looks like a pretty good drug,” Dr. Rind said. “It looks quite safe and I think there will be a lot of patients, particularly those who are having frequent exacerbations, who this would be appropriate for, particularly once they’ve maxed out existing therapies, but maybe even earlier than that. And if the price comes down to the point that patients can really access this and providers can access it, people really should look at this as a potential therapy.”
 

Drug not yet available?

However, providers have not yet had direct experience with the new medication. “We haven’t been able to prescribe it yet,” said Corinne Young, MSN, FNP-C, FCCP, director of Advance Practice Provider and Clinical Services for Colorado Springs Pulmonary Consultants, president and founder of the Association of Pulmonary Advance Practice Providers, and a member of the CHEST Physician Editorial Board.

CHEST

Ensifentrine (Ohtuvayre), a novel medication for the treatment of chronic obstructive pulmonary disease (COPD) recently approved by the Food and Drug Administration, has been shown to reduce COPD exacerbations and may improve the quality of life for patients, but these potential benefits come at an unreasonably high annual cost, authors of a cost and effectiveness analysis say.

Ensifentrine is a first-in-class selective dual inhibitor of both phosphodiesterase 3 (PDE-3) and PDE-4, combining both bronchodilator and nonsteroidal anti-inflammatory effects in a single molecule. The drug is delivered through a standard jet nebulizer.

In the phase 3 ENHANCE 1 and 2 trials, ensifentrine significantly improved lung function based on the primary outcome of average forced expiratory volume in 1 second within 0-12 hours of administration, compared with placebo. In addition, patients were reported to tolerate the inhaled treatment well, with similar proportions of ensifentrine- and placebo-assigned patients reporting treatment-emergent adverse events. The most common treatment-emergent adverse events were nasopharyngitis, hypertension, and back pain, reported in < 3% of the ensifentrine group.
 

High cost barrier

But as authors of the analysis from the Boston, Massachusetts–based Institute for Clinical and Economic Review (ICER) found, the therapeutic edge offered by ensifentrine is outweighed by the annual wholesale acquisition cost that its maker, Vernona Pharma, has established: $35,400, which far exceeds the estimated health-benefit price of $7,500-$12,700, according to ICER. ICER is an independent, nonprofit research institute that conducts evidence-based reviews of healthcare interventions, including prescription drugs, other treatments, and diagnostic tests.

“Current evidence shows that ensifentrine decreases COPD exacerbations when used in combination with some current inhaled therapies, but there are uncertainties about how much benefit it may add to unstudied combinations of inhaled treatments,” said David Rind, MD, chief medical officer of ICER in a statement.

In an interview, Dr. Rind noted that the high price of ensifentrine may lead payers to restrict access to an otherwise promising new therapy. “Obviously many drugs in the US are overpriced, and this one, too, looks like it is overpriced. That causes ongoing financial toxicity for individual patients and it causes problems for the entire US health system, because when we pay too much for drugs we don’t have money for other things. So I’m worried about the fact that this price is too high compared to the benefit it provides.”

As previously reported, as many as one in six persons with COPD in the United States miss or delay COPD medication doses because of high drug costs. “I think that the pricing they chose is going to cause lots of barriers to people getting access and that insurance companies will throw up barriers. Primary care physicians like me won’t even try to get approval for a drug like this given the hoops we will be made to jump through, and so fewer people will get this drug,” Dr. Rind said. He pointed out that a lower wholesale acquisition cost could encourage higher-volume sales, affording the drugmaker a comparable profit with the higher-cost but lower-volume option.
 

Good drug, high price

An independent appraisal committee for ICER determined that “current evidence is adequate to demonstrate a net health benefit for ensifentrine added to maintenance therapy when compared to maintenance therapy alone.”

But ICER also issued an access and affordability alert “to signal to stakeholders and policymakers that the amount of added healthcare costs associated with a new service may be difficult for the health system to absorb over the short term without displacing other needed services.” ICER recommends that payers should include coverage for smoking cessation therapies, and that drug manufacturers “set prices that will foster affordability and good access for all patients by aligning prices with the patient-centered therapeutic value of their treatments.”

“This looks like a pretty good drug,” Dr. Rind said. “It looks quite safe and I think there will be a lot of patients, particularly those who are having frequent exacerbations, who this would be appropriate for, particularly once they’ve maxed out existing therapies, but maybe even earlier than that. And if the price comes down to the point that patients can really access this and providers can access it, people really should look at this as a potential therapy.”
 

Drug not yet available?

However, providers have not yet had direct experience with the new medication. “We haven’t been able to prescribe it yet,” said Corinne Young, MSN, FNP-C, FCCP, director of Advance Practice Provider and Clinical Services for Colorado Springs Pulmonary Consultants, president and founder of the Association of Pulmonary Advance Practice Providers, and a member of the CHEST Physician Editorial Board.

CHEST