Specialty Sections From CHEST® Physician

National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.¹

FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.²

Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.

The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.^3,4

LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.⁵ LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.

For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.

Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.⁶ All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.

This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.^7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
 

References

1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.

2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.

3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.

4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.

5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.

6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.

7. Global strategy for asthma management and prevention. 2020.

8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.

National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.¹

FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.²

Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.

The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.^3,4

LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.⁵ LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.

For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.

Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.⁶ All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.

This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.^7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
 

References

1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.

2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.

3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.

4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.

5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.

6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.

7. Global strategy for asthma management and prevention. 2020.

8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.

National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.¹

FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.²

Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.

The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.^3,4

LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.⁵ LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.

For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.

Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.⁶ All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.

This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.^7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
 

References

1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.

2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.

3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.

4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.

5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.

6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.

7. Global strategy for asthma management and prevention. 2020.

8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.

Patients with COPD may develop sustained hypercapnia, often defined as an awake arterial PCO2 of >45 mm Hg. Other synonymous terms include alveolar hypoventilation or chronic hypercapnic respiratory failure, noting that the specific terminology used may reflect local practice, an assessment of patient severity, or specific insurance requirements. Regardless, available data suggest that hypercapnic COPD patients are at high risk for adverse health outcomes (Yang H, et al. BMJ Open. 2015;5[12]:e008909). Moreover, there appears to have been a growing interest in this population driven by a focus on reducing COPD hospitalizations, increasing recognition of sleep disordered breathing, and progress in potential therapeutic strategies.

There are a number of factors that might drive COPD patients to develop hypercapnia. Lower airway obstruction, expiratory flow limitation and air trapping cause mechanical load on breathing, as well as a trade-off between time spent in inspiration vs prolonged expiration. The function of the diaphragm is impacted by hyperinflation leading to mal-positioning, as well as possibly by local and/or systemic myopathy. The net result is often decreased overall minute ventilation. In terms of gas exchange, increased dead space and ventilation-perfusion mismatching leads to reduced efficiency of ventilation towards CO₂ removal. Breathing changes during sleep play an important role, as evidenced by worsened hypercapnia during sleep that can drive chronic CO₂ retention (O’Donoghue FJ, et al. Eur Respir J. 2003;21[6]:977). The pathogenesis includes reduced central respiratory drive, increased upper airway resistance and/or obstructive hypopneas and apneas, and respiratory muscle atonia, particularly during REM sleep. The extent to which each of these factors contributes to hypercapnia varies across individual patients, in accordance with the known substantial heterogeneity of COPD. Regardless of underlying traits, patients with COPD who develop hypercapnia have sufficiently severe perturbations to disrupt the normally tight control over CO₂ homeostasis.

Nocturnal home noninvasive ventilation (NIV) has been examined as a potential therapeutic strategy for patients with hypercapnic COPD. While older studies have not shown consistent benefits, more recent evidence suggests that NIV can reduce hospitalizations, improve quality of life, and potentially reduce mortality among those with hypercapnic COPD. Accordingly, the American Thoracic Society recently released a clinical practice guideline regarding the use of NIV in patients with chronic stable hypercapnic COPD (Macrea M, et al. Am J Respir Crit Care Med. 2020;202[4]:e74-e87). Recommendations from the guideline included:

1) The use of nocturnal NIV for patients with chronic stable hypercapnic COPD

2) Screening for OSA before initiation of long-term NIV

3) Not using in-hospital initiation of long-term NIV after an episode of acute or chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2–4 weeks after resolution

4) Not using an in-laboratory overnight PSG to initially titrate NIV

5) Targeting normalization of PaCO₂.

Although it now seems clear that efforts should be made to use NIV in COPD to decrease chronic hypercapnia, there are a number of important questions that remain, particularly surrounding the topic of concurrent OSA, titration, and devices:

• What is the appropriate approach towards patients with suspected concurrent OSA? Most studies of NIV have excluded patients with OSA, or otherwise at higher risk of OSA. Nonetheless, such patients may be common, both based on continued high prevalence of obesity, as well as the potential role that upper airway obstructive events may play towards elevations in CO₂ (Resta O., et al. Sleep Breath. 2002;6[1]:11-8). COPD epidemiological studies indicate obesity as a risk factor for several poor outcomes, including severe COPD exacerbation (Lambert AA, et al. Chest. 2017;151[1]:68-77), while studies of COPD and OSA suggest that the presence of hypercapnia defines a high-risk group Jaoude P., Lung. 2014;192:215). Recognizing the potential importance of OSA in this group, ATS guidelines recommend that a general questionnaire-based screening be performed. If screening is positive, the implication would be to perform diagnostic polysomnography to confirm the diagnosis of OSA. However, this may be a challenge for chronically ill patients, and likely would result in delays in NIV initiation. Of note, emerging evidence suggests that home sleep apnea testing (HSAT) might have reasonable accuracy in this group, which may facilitate formal diagnosis. Other concerns in this area include the lack of questionnaire validation in COPD patients.

• Should patients with OSA be managed differently than those without OSA? A diagnosis of OSA might impact several subsequent management decisions related to appropriate NIV therapy and titration. Patients with OSA have increased upper airway collapsibility, which might necessitate higher EPAP support than the minimal EPAP used in NIV trials with non-OSA patients (often fixed at 4 cm water). Potential strategies for optimizing EPAP include use of an NIV device with auto-titrating EPAP, titration in the sleep laboratory (discussed below), or outpatient titration based on clinical parameters and subsequent device download follow-up. On the other hand, one might consider all patients to be at risk for upper airway obstruction and need for additional EPAP titration, which would obviate the need for OSA diagnostic testing.

• What is the role of the sleep laboratory towards successful titration? The inpatient hospital setting has been the traditional site to initiate home NIV in some institutions but is highly resource intensive and increasingly impractical in many health systems. On the other hand, advances in home remote device monitoring now provide the clinician with the ability to examine daily usage, estimated leak, tidal volumes, respiratory rate, and other parameters – often reported as recently as the prior night. In addition, setting changes can be made via these remote monitoring tools (for nonventilator devices), allowing titration to be performed over time on outpatients. Several studies support the effectiveness of this approach over hospital titration in neuromuscular disease and now in COPD (Duiverman ML, et al. Thorax. 2020;75[3]:244-52). Similarly, data suggest that titration under polysomnographic guidance might not be necessary (Patout M, Arbane G, Cuvelier A, Muir JF, Hart N, Murphy PB. Polysomnography versus limited respiratory monitoring and nurse-led titration to optimize non-invasive ventilation set-up: a pilot randomised clinical trial. Thorax. 2019;74:83-86).

Limitations towards the sleep lab as the site of initial titration include waiting time, cost and insurance coverage, and the need to accommodate issues such as impaired mobility or reliance on a caretaker. In addition, titration goals must be clearly outlined in protocols and via staff training specific to NIV. The sleep laboratory may be most appropriately utilized in the minority of patients in whom outpatient titration is unsuccessful. Relatively common issues that might be best addressed in the lab setting include excessive mask leaks, residual apneas and hypopneas, failure to control CO₂, or other sleep complaints. In general, studies should probably be focused primarily on titrating EPAP to alleviate upper airway obstructive events. The goals in terms of IPAP titration (or ventilation titration, in the case of “VAPS” modes) are less clear, and overly aggressive increases may complicate the picture with excessive leaks or airway obstruction due to glottic closure. Attempting to accomplish “too much” often leads to a study with limited utility. In contrast, simply performing the study in the patient’s home settings can provide useful diagnostic information regarding the problem one is trying to solve.

• When and where should one initiate NIV following a severe COPD exacerbation? In contrast to the ATS guidelines, the European Respiratory Society guidelines suggest that patients recovering from severe COPD exacerbations be initiated on NIV during that hospitalization, noting that this is a group at high risk for early rehospitalization and mortality (Ergan B, et al. Eur Respir J. 2019;54[3]:1901003). ATS guidelines had the concern of unnecessary start of NIV in those who might normalize their CO₂ after recovery, and the possibility of prolonging hospitalizations for titration. For the clinician, the decision will probably be individualized based on risk and available resources. For patients with frequent ICU admissions and/or difficulty with close outpatient follow-up, earlier NIV initiation is certainly a reasonable approach, but adherence and effectiveness remains a concern and, thus, more data are needed.

• Which patients should receive a bedside respiratory assist device (RAD, i.e., BIPAP machine) vs. a noninvasive ventilator? Two classes of devices can be used for home NIV. While both can provide similar positive pressure ventilation, ventilators are designed as life support with alarms and batteries, and may have modes not otherwise available (e.g., auto-titrating EPAP). On the other hand, RAD devices are more convenient for patients and less expensive, but difficult qualification requirements (particularly for devices capable of Bilevel ST or VAPS) have likely resulted in their underutilization. CHEST is spearheading an effort to reconsider Medicare coverage determinations (current rules are from 1998), which will hopefully better align device qualification requirements with emerging evidence regarding patient needs and preferences.

Home non-invasive ventilation can improve outcomes in these high-risk patients with hypercapnic COPD, and the new clinical practice guidelines are an important step in outlining appropriate management. Further progress is needed to delineate an individualized approach based on underlying patient pathophysiology, COPD manifestations/phenotypes, and systems-based practice considerations.

Dr. Orr is Assistant Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, UC San Diego.

Patients with COPD may develop sustained hypercapnia, often defined as an awake arterial PCO2 of >45 mm Hg. Other synonymous terms include alveolar hypoventilation or chronic hypercapnic respiratory failure, noting that the specific terminology used may reflect local practice, an assessment of patient severity, or specific insurance requirements. Regardless, available data suggest that hypercapnic COPD patients are at high risk for adverse health outcomes (Yang H, et al. BMJ Open. 2015;5[12]:e008909). Moreover, there appears to have been a growing interest in this population driven by a focus on reducing COPD hospitalizations, increasing recognition of sleep disordered breathing, and progress in potential therapeutic strategies.

There are a number of factors that might drive COPD patients to develop hypercapnia. Lower airway obstruction, expiratory flow limitation and air trapping cause mechanical load on breathing, as well as a trade-off between time spent in inspiration vs prolonged expiration. The function of the diaphragm is impacted by hyperinflation leading to mal-positioning, as well as possibly by local and/or systemic myopathy. The net result is often decreased overall minute ventilation. In terms of gas exchange, increased dead space and ventilation-perfusion mismatching leads to reduced efficiency of ventilation towards CO₂ removal. Breathing changes during sleep play an important role, as evidenced by worsened hypercapnia during sleep that can drive chronic CO₂ retention (O’Donoghue FJ, et al. Eur Respir J. 2003;21[6]:977). The pathogenesis includes reduced central respiratory drive, increased upper airway resistance and/or obstructive hypopneas and apneas, and respiratory muscle atonia, particularly during REM sleep. The extent to which each of these factors contributes to hypercapnia varies across individual patients, in accordance with the known substantial heterogeneity of COPD. Regardless of underlying traits, patients with COPD who develop hypercapnia have sufficiently severe perturbations to disrupt the normally tight control over CO₂ homeostasis.

Nocturnal home noninvasive ventilation (NIV) has been examined as a potential therapeutic strategy for patients with hypercapnic COPD. While older studies have not shown consistent benefits, more recent evidence suggests that NIV can reduce hospitalizations, improve quality of life, and potentially reduce mortality among those with hypercapnic COPD. Accordingly, the American Thoracic Society recently released a clinical practice guideline regarding the use of NIV in patients with chronic stable hypercapnic COPD (Macrea M, et al. Am J Respir Crit Care Med. 2020;202[4]:e74-e87). Recommendations from the guideline included:

1) The use of nocturnal NIV for patients with chronic stable hypercapnic COPD

2) Screening for OSA before initiation of long-term NIV

3) Not using in-hospital initiation of long-term NIV after an episode of acute or chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2–4 weeks after resolution

4) Not using an in-laboratory overnight PSG to initially titrate NIV

5) Targeting normalization of PaCO₂.

Although it now seems clear that efforts should be made to use NIV in COPD to decrease chronic hypercapnia, there are a number of important questions that remain, particularly surrounding the topic of concurrent OSA, titration, and devices:

• What is the appropriate approach towards patients with suspected concurrent OSA? Most studies of NIV have excluded patients with OSA, or otherwise at higher risk of OSA. Nonetheless, such patients may be common, both based on continued high prevalence of obesity, as well as the potential role that upper airway obstructive events may play towards elevations in CO₂ (Resta O., et al. Sleep Breath. 2002;6[1]:11-8). COPD epidemiological studies indicate obesity as a risk factor for several poor outcomes, including severe COPD exacerbation (Lambert AA, et al. Chest. 2017;151[1]:68-77), while studies of COPD and OSA suggest that the presence of hypercapnia defines a high-risk group Jaoude P., Lung. 2014;192:215). Recognizing the potential importance of OSA in this group, ATS guidelines recommend that a general questionnaire-based screening be performed. If screening is positive, the implication would be to perform diagnostic polysomnography to confirm the diagnosis of OSA. However, this may be a challenge for chronically ill patients, and likely would result in delays in NIV initiation. Of note, emerging evidence suggests that home sleep apnea testing (HSAT) might have reasonable accuracy in this group, which may facilitate formal diagnosis. Other concerns in this area include the lack of questionnaire validation in COPD patients.

• Should patients with OSA be managed differently than those without OSA? A diagnosis of OSA might impact several subsequent management decisions related to appropriate NIV therapy and titration. Patients with OSA have increased upper airway collapsibility, which might necessitate higher EPAP support than the minimal EPAP used in NIV trials with non-OSA patients (often fixed at 4 cm water). Potential strategies for optimizing EPAP include use of an NIV device with auto-titrating EPAP, titration in the sleep laboratory (discussed below), or outpatient titration based on clinical parameters and subsequent device download follow-up. On the other hand, one might consider all patients to be at risk for upper airway obstruction and need for additional EPAP titration, which would obviate the need for OSA diagnostic testing.

• What is the role of the sleep laboratory towards successful titration? The inpatient hospital setting has been the traditional site to initiate home NIV in some institutions but is highly resource intensive and increasingly impractical in many health systems. On the other hand, advances in home remote device monitoring now provide the clinician with the ability to examine daily usage, estimated leak, tidal volumes, respiratory rate, and other parameters – often reported as recently as the prior night. In addition, setting changes can be made via these remote monitoring tools (for nonventilator devices), allowing titration to be performed over time on outpatients. Several studies support the effectiveness of this approach over hospital titration in neuromuscular disease and now in COPD (Duiverman ML, et al. Thorax. 2020;75[3]:244-52). Similarly, data suggest that titration under polysomnographic guidance might not be necessary (Patout M, Arbane G, Cuvelier A, Muir JF, Hart N, Murphy PB. Polysomnography versus limited respiratory monitoring and nurse-led titration to optimize non-invasive ventilation set-up: a pilot randomised clinical trial. Thorax. 2019;74:83-86).

Limitations towards the sleep lab as the site of initial titration include waiting time, cost and insurance coverage, and the need to accommodate issues such as impaired mobility or reliance on a caretaker. In addition, titration goals must be clearly outlined in protocols and via staff training specific to NIV. The sleep laboratory may be most appropriately utilized in the minority of patients in whom outpatient titration is unsuccessful. Relatively common issues that might be best addressed in the lab setting include excessive mask leaks, residual apneas and hypopneas, failure to control CO₂, or other sleep complaints. In general, studies should probably be focused primarily on titrating EPAP to alleviate upper airway obstructive events. The goals in terms of IPAP titration (or ventilation titration, in the case of “VAPS” modes) are less clear, and overly aggressive increases may complicate the picture with excessive leaks or airway obstruction due to glottic closure. Attempting to accomplish “too much” often leads to a study with limited utility. In contrast, simply performing the study in the patient’s home settings can provide useful diagnostic information regarding the problem one is trying to solve.

• When and where should one initiate NIV following a severe COPD exacerbation? In contrast to the ATS guidelines, the European Respiratory Society guidelines suggest that patients recovering from severe COPD exacerbations be initiated on NIV during that hospitalization, noting that this is a group at high risk for early rehospitalization and mortality (Ergan B, et al. Eur Respir J. 2019;54[3]:1901003). ATS guidelines had the concern of unnecessary start of NIV in those who might normalize their CO₂ after recovery, and the possibility of prolonging hospitalizations for titration. For the clinician, the decision will probably be individualized based on risk and available resources. For patients with frequent ICU admissions and/or difficulty with close outpatient follow-up, earlier NIV initiation is certainly a reasonable approach, but adherence and effectiveness remains a concern and, thus, more data are needed.

• Which patients should receive a bedside respiratory assist device (RAD, i.e., BIPAP machine) vs. a noninvasive ventilator? Two classes of devices can be used for home NIV. While both can provide similar positive pressure ventilation, ventilators are designed as life support with alarms and batteries, and may have modes not otherwise available (e.g., auto-titrating EPAP). On the other hand, RAD devices are more convenient for patients and less expensive, but difficult qualification requirements (particularly for devices capable of Bilevel ST or VAPS) have likely resulted in their underutilization. CHEST is spearheading an effort to reconsider Medicare coverage determinations (current rules are from 1998), which will hopefully better align device qualification requirements with emerging evidence regarding patient needs and preferences.

Home non-invasive ventilation can improve outcomes in these high-risk patients with hypercapnic COPD, and the new clinical practice guidelines are an important step in outlining appropriate management. Further progress is needed to delineate an individualized approach based on underlying patient pathophysiology, COPD manifestations/phenotypes, and systems-based practice considerations.

Dr. Orr is Assistant Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, UC San Diego.

Patients with COPD may develop sustained hypercapnia, often defined as an awake arterial PCO2 of >45 mm Hg. Other synonymous terms include alveolar hypoventilation or chronic hypercapnic respiratory failure, noting that the specific terminology used may reflect local practice, an assessment of patient severity, or specific insurance requirements. Regardless, available data suggest that hypercapnic COPD patients are at high risk for adverse health outcomes (Yang H, et al. BMJ Open. 2015;5[12]:e008909). Moreover, there appears to have been a growing interest in this population driven by a focus on reducing COPD hospitalizations, increasing recognition of sleep disordered breathing, and progress in potential therapeutic strategies.

There are a number of factors that might drive COPD patients to develop hypercapnia. Lower airway obstruction, expiratory flow limitation and air trapping cause mechanical load on breathing, as well as a trade-off between time spent in inspiration vs prolonged expiration. The function of the diaphragm is impacted by hyperinflation leading to mal-positioning, as well as possibly by local and/or systemic myopathy. The net result is often decreased overall minute ventilation. In terms of gas exchange, increased dead space and ventilation-perfusion mismatching leads to reduced efficiency of ventilation towards CO₂ removal. Breathing changes during sleep play an important role, as evidenced by worsened hypercapnia during sleep that can drive chronic CO₂ retention (O’Donoghue FJ, et al. Eur Respir J. 2003;21[6]:977). The pathogenesis includes reduced central respiratory drive, increased upper airway resistance and/or obstructive hypopneas and apneas, and respiratory muscle atonia, particularly during REM sleep. The extent to which each of these factors contributes to hypercapnia varies across individual patients, in accordance with the known substantial heterogeneity of COPD. Regardless of underlying traits, patients with COPD who develop hypercapnia have sufficiently severe perturbations to disrupt the normally tight control over CO₂ homeostasis.

Nocturnal home noninvasive ventilation (NIV) has been examined as a potential therapeutic strategy for patients with hypercapnic COPD. While older studies have not shown consistent benefits, more recent evidence suggests that NIV can reduce hospitalizations, improve quality of life, and potentially reduce mortality among those with hypercapnic COPD. Accordingly, the American Thoracic Society recently released a clinical practice guideline regarding the use of NIV in patients with chronic stable hypercapnic COPD (Macrea M, et al. Am J Respir Crit Care Med. 2020;202[4]:e74-e87). Recommendations from the guideline included:

1) The use of nocturnal NIV for patients with chronic stable hypercapnic COPD

2) Screening for OSA before initiation of long-term NIV

3) Not using in-hospital initiation of long-term NIV after an episode of acute or chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2–4 weeks after resolution

4) Not using an in-laboratory overnight PSG to initially titrate NIV

5) Targeting normalization of PaCO₂.

Although it now seems clear that efforts should be made to use NIV in COPD to decrease chronic hypercapnia, there are a number of important questions that remain, particularly surrounding the topic of concurrent OSA, titration, and devices:

• What is the appropriate approach towards patients with suspected concurrent OSA? Most studies of NIV have excluded patients with OSA, or otherwise at higher risk of OSA. Nonetheless, such patients may be common, both based on continued high prevalence of obesity, as well as the potential role that upper airway obstructive events may play towards elevations in CO₂ (Resta O., et al. Sleep Breath. 2002;6[1]:11-8). COPD epidemiological studies indicate obesity as a risk factor for several poor outcomes, including severe COPD exacerbation (Lambert AA, et al. Chest. 2017;151[1]:68-77), while studies of COPD and OSA suggest that the presence of hypercapnia defines a high-risk group Jaoude P., Lung. 2014;192:215). Recognizing the potential importance of OSA in this group, ATS guidelines recommend that a general questionnaire-based screening be performed. If screening is positive, the implication would be to perform diagnostic polysomnography to confirm the diagnosis of OSA. However, this may be a challenge for chronically ill patients, and likely would result in delays in NIV initiation. Of note, emerging evidence suggests that home sleep apnea testing (HSAT) might have reasonable accuracy in this group, which may facilitate formal diagnosis. Other concerns in this area include the lack of questionnaire validation in COPD patients.

• Should patients with OSA be managed differently than those without OSA? A diagnosis of OSA might impact several subsequent management decisions related to appropriate NIV therapy and titration. Patients with OSA have increased upper airway collapsibility, which might necessitate higher EPAP support than the minimal EPAP used in NIV trials with non-OSA patients (often fixed at 4 cm water). Potential strategies for optimizing EPAP include use of an NIV device with auto-titrating EPAP, titration in the sleep laboratory (discussed below), or outpatient titration based on clinical parameters and subsequent device download follow-up. On the other hand, one might consider all patients to be at risk for upper airway obstruction and need for additional EPAP titration, which would obviate the need for OSA diagnostic testing.

• What is the role of the sleep laboratory towards successful titration? The inpatient hospital setting has been the traditional site to initiate home NIV in some institutions but is highly resource intensive and increasingly impractical in many health systems. On the other hand, advances in home remote device monitoring now provide the clinician with the ability to examine daily usage, estimated leak, tidal volumes, respiratory rate, and other parameters – often reported as recently as the prior night. In addition, setting changes can be made via these remote monitoring tools (for nonventilator devices), allowing titration to be performed over time on outpatients. Several studies support the effectiveness of this approach over hospital titration in neuromuscular disease and now in COPD (Duiverman ML, et al. Thorax. 2020;75[3]:244-52). Similarly, data suggest that titration under polysomnographic guidance might not be necessary (Patout M, Arbane G, Cuvelier A, Muir JF, Hart N, Murphy PB. Polysomnography versus limited respiratory monitoring and nurse-led titration to optimize non-invasive ventilation set-up: a pilot randomised clinical trial. Thorax. 2019;74:83-86).

Limitations towards the sleep lab as the site of initial titration include waiting time, cost and insurance coverage, and the need to accommodate issues such as impaired mobility or reliance on a caretaker. In addition, titration goals must be clearly outlined in protocols and via staff training specific to NIV. The sleep laboratory may be most appropriately utilized in the minority of patients in whom outpatient titration is unsuccessful. Relatively common issues that might be best addressed in the lab setting include excessive mask leaks, residual apneas and hypopneas, failure to control CO₂, or other sleep complaints. In general, studies should probably be focused primarily on titrating EPAP to alleviate upper airway obstructive events. The goals in terms of IPAP titration (or ventilation titration, in the case of “VAPS” modes) are less clear, and overly aggressive increases may complicate the picture with excessive leaks or airway obstruction due to glottic closure. Attempting to accomplish “too much” often leads to a study with limited utility. In contrast, simply performing the study in the patient’s home settings can provide useful diagnostic information regarding the problem one is trying to solve.

• When and where should one initiate NIV following a severe COPD exacerbation? In contrast to the ATS guidelines, the European Respiratory Society guidelines suggest that patients recovering from severe COPD exacerbations be initiated on NIV during that hospitalization, noting that this is a group at high risk for early rehospitalization and mortality (Ergan B, et al. Eur Respir J. 2019;54[3]:1901003). ATS guidelines had the concern of unnecessary start of NIV in those who might normalize their CO₂ after recovery, and the possibility of prolonging hospitalizations for titration. For the clinician, the decision will probably be individualized based on risk and available resources. For patients with frequent ICU admissions and/or difficulty with close outpatient follow-up, earlier NIV initiation is certainly a reasonable approach, but adherence and effectiveness remains a concern and, thus, more data are needed.

• Which patients should receive a bedside respiratory assist device (RAD, i.e., BIPAP machine) vs. a noninvasive ventilator? Two classes of devices can be used for home NIV. While both can provide similar positive pressure ventilation, ventilators are designed as life support with alarms and batteries, and may have modes not otherwise available (e.g., auto-titrating EPAP). On the other hand, RAD devices are more convenient for patients and less expensive, but difficult qualification requirements (particularly for devices capable of Bilevel ST or VAPS) have likely resulted in their underutilization. CHEST is spearheading an effort to reconsider Medicare coverage determinations (current rules are from 1998), which will hopefully better align device qualification requirements with emerging evidence regarding patient needs and preferences.

Home non-invasive ventilation can improve outcomes in these high-risk patients with hypercapnic COPD, and the new clinical practice guidelines are an important step in outlining appropriate management. Further progress is needed to delineate an individualized approach based on underlying patient pathophysiology, COPD manifestations/phenotypes, and systems-based practice considerations.

Dr. Orr is Assistant Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, UC San Diego.

What’s in a name?

Bronchiolitis, a group of diseases also referred to as “small airways diseases,” is characterized by inflammation and/or fibrosis in airways less than 2 mm in diameter. In pediatric patients, it is most commonly related to acute viral infections, while in adults, it is often associated with chronic diseases. Bronchiolitis is a well-recognized complication in a significant number of patients who have undergone lung or stem cell transplantation. Common associations also include connective tissue diseases, environmental or occupational inhalation exposures, aspiration, drug toxicity, and infections. Diagnosing bronchiolitis can be challenging for clinicians, and few treatment options exist apart from treating identifiable underlying etiologies. More research is needed into noninvasive diagnostic techniques and treatment modalities.

The terminology used to describe bronchiolitis has evolved over time. Bronchiolitis is now used to describe conditions where the primary pathologic condition is damage to the bronchiolar epithelium not attributable to a larger parenchymal disease (such as hypersensitivity pneumonitis). This change in nomenclature explains why the condition formerly known as “bronchiolitis obliterans organizing pneumonia” (BOOP) is now simply recognized as “organizing pneumonia.” Despite several proposed classification schemes focusing on histopathology, there is no consensus regarding the different subtypes of bronchiolitis, leading to confusion in some cases. Recently, authors have attempted to distinguish cases based on three main histologic patterns (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

• Obliterative/constrictive bronchiolitis (OB) – the terms “obliterative” and “constrictive” are used interchangeably throughout pulmonary literature. It is characterized by fibroblast-rich tissue accumulation in the sub-epithelium of bronchioles leading to progressive narrowing of the lumen. In addition to the transplant setting, it is often seen in patients with rheumatoid arthritis or other connective tissue diseases, inhalational exposures, or acute respiratory infections. More recently, clinicians have recognized diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) as a rare condition causing OB with potentially effective treatment.
• Follicular bronchiolitis (FB) – features peribronchiolar inflammation with subepithelial lymphoid deposits leading to luminal obstruction. FB is chiefly associated with conditions of impaired immunity or chronic airway infection, such as autoimmune connective tissues diseases (especially rheumatoid arthritis and Sjogren’s), severe combined immunodeficiency, HIV, cystic fibrosis, and primary ciliary dyskinesia. 
• Diffuse panbronchiolitis (DBP) – features bilateral bronchiolar lesions with lymphocytic inflammation of the bronchiolar wall, as well as peribronchiolar inflammation and accumulation of interstitial foamy macrophages. Patients afflicted with DBP may suffer repeated bacterial colonization or infection. There is a higher prevalence of DBP in Asia where it was first identified in the 1960s, potentially due to several HLA alleles that are more common in Asia. 

In addition to the above terminology, the transplant-setting diagnosis “bronchiolitis obliterans syndrome” (BOS) is used to denote progressive obstructive lung disease for which there is not another cause aside from chronic graft rejection. For these patients, clinicians assume the underlying disease entity is OB, but they often lack histopathologic confirmation. 
 

Diagnosis is challenging

Symptoms of bronchiolitis are typically dyspnea and cough, and patients may often be diagnosed with asthma or COPD initially. Pulmonary function testing may show signs of obstruction, restriction, or mixed disease with or without a reduction in Dlco. Chest radiography often appears normal, but high-resolution CT may show expiratory air trapping and centrilobular nodules. Advanced imaging modalities may augment or replace CT imaging in diagnosing bronchiolitis: investigators are evaluating pulmonary MRI and fluoroscopy with computerized ventilation analysis in clinical trials (NCT04080232).

Currently, open or thoracoscopic lung biopsy is typically required to make a definitive diagnosis. Because bronchiolitis is a patchy and heterogeneous process, transbronchial biopsy may provide insufficient yield, with a sensitivity of 29% to 70% reported in lung transplant literature (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

Recent studies have demonstrated transbronchial cryobiopsy to be a promising alternative to surgical biopsy, owing to larger tissue samples than conventional transbronchial lung biopsies. For example, in a recent case series four patients underwent transbronchial cryobiopsy. The procedure yielded adequate tissue for diagnosis of a chronic bronchiolitis in each case (Yamakawa H, et al. Internal Med Advance Publication. doi: 10.2169/internalmedicine.6028-20.
 

Treatment options are growing

Evidence for treatment of bronchiolitis remains limited. Options are extrapolated from lung transplant patients, where incidence of BOS ranges from 50% at 5 years to 76% at 10 years post transplant. Guidelines recommend a 3-month minimum trial of azithromycin, which has been shown to slow or reverse decline of lung function in some patients. Modification of immunosuppression is also recommended. In patients who have continued lung function decline, a systematic review concluded that extracorporeal photopheresis had the most robust evidence for efficacy with stabilized lung function and improved overall survival (Benden C, et al. J Heart Lung Transplant. 2017;36[9]:921). Other salvage therapies that have lower-quality evidence of benefit include total lymphoid irradiation, montelukast, and aerosolized cyclosporine.

In patients who have undergone hematopoietic stem cell transplant, steroids are typically the first line treatment for OB as it is thought to be a form of chronic graft-vs-host disease (GVHD). Ruxolitinib, a selective JAK1/2 inhibitor, demonstrated significant improvement overall in patients with steroid-refractory acute GVHD in a recent randomized clinical trial, although the trial did not examine its effect on pulmonary manifestations (Zeiser R, et al. N Engl J Med. 2020;382[19]:1800). To date, retrospective observational studies of ruxolitinib in patients with lung GVHD have shown conflicting results regarding benefit. Investigators are currently studying ruxolitinib in a phase II trial for patients with BOS following stem cell transplant (NCT03674047).

DIPNECH is unique from other bronchiolitis entities, as small airways dysfunction develops as a result of neuroendocrine cell proliferation in the airway mucosa, ultimately leading to bronchial narrowing. It most commonly presents in middle-aged nonsmoking women with years of chronic cough and dyspnea. While it has an indolent course in many patients, some patients develop progressive symptoms and obstructive lung disease. DIPNECH is considered a precursor to other pulmonary neuroendocrine tumors. The lesions demonstrate somatostatin receptor expression in many cases, prompting the use of somatostatin analogues as treatment. In the largest published case series, 42 patients from three different institutions were identified who were treated with somatostatin analogues for a mean of 38.8 months at the time of review. Symptomatic improvement was seen in 33 of the 42 (79%), and of the 15 with posttreatment PFT data, 14 (93%) showed improvement in PFTs (Al-Toubah, T, et al. Chest. 2020;158[1]:401). Other small studies have demonstrated varying results with symptomatic improvement in 29% to 76% of patients and improvement or stability of PFTs in 50% to 100% of patients (Samhouri BF, et al. ERJ Open Res. 2020;6[4]:527).

For patients who have not undergone lung transplant, and who do not have an identifiable exposure or underlying rheumatologic condition, a similar 3-month minimum trial of macrolide antibiotics is reasonable. Macrolides have been shown to double long-term survival rates to over 90% in patients with DPB. Evidence in this patient population is quite limited, and further research is needed to determine effective therapies for patients.
 

What’s next for bronchiolitis

While clinicians currently have few tools for diagnosing and treating these uncommon diseases, in the coming years, we should learn whether novel imaging modalities or less invasive procedures can aid in the diagnosis. Physicians hope these advances will preclude the need for invasive biopsies in more patients going forward. We should also learn whether newer, targeted agents like ruxolitinib are effective for BOS in patients with stem cell transplant. If so, this finding may open it and similar agents to investigation in other forms of bronchiolitis.
 

Dr. Poole and Dr. Callahan are with University of Utah Health, Salt Lake City, Utah.

What’s in a name?

Bronchiolitis, a group of diseases also referred to as “small airways diseases,” is characterized by inflammation and/or fibrosis in airways less than 2 mm in diameter. In pediatric patients, it is most commonly related to acute viral infections, while in adults, it is often associated with chronic diseases. Bronchiolitis is a well-recognized complication in a significant number of patients who have undergone lung or stem cell transplantation. Common associations also include connective tissue diseases, environmental or occupational inhalation exposures, aspiration, drug toxicity, and infections. Diagnosing bronchiolitis can be challenging for clinicians, and few treatment options exist apart from treating identifiable underlying etiologies. More research is needed into noninvasive diagnostic techniques and treatment modalities.

The terminology used to describe bronchiolitis has evolved over time. Bronchiolitis is now used to describe conditions where the primary pathologic condition is damage to the bronchiolar epithelium not attributable to a larger parenchymal disease (such as hypersensitivity pneumonitis). This change in nomenclature explains why the condition formerly known as “bronchiolitis obliterans organizing pneumonia” (BOOP) is now simply recognized as “organizing pneumonia.” Despite several proposed classification schemes focusing on histopathology, there is no consensus regarding the different subtypes of bronchiolitis, leading to confusion in some cases. Recently, authors have attempted to distinguish cases based on three main histologic patterns (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

• Obliterative/constrictive bronchiolitis (OB) – the terms “obliterative” and “constrictive” are used interchangeably throughout pulmonary literature. It is characterized by fibroblast-rich tissue accumulation in the sub-epithelium of bronchioles leading to progressive narrowing of the lumen. In addition to the transplant setting, it is often seen in patients with rheumatoid arthritis or other connective tissue diseases, inhalational exposures, or acute respiratory infections. More recently, clinicians have recognized diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) as a rare condition causing OB with potentially effective treatment.
• Follicular bronchiolitis (FB) – features peribronchiolar inflammation with subepithelial lymphoid deposits leading to luminal obstruction. FB is chiefly associated with conditions of impaired immunity or chronic airway infection, such as autoimmune connective tissues diseases (especially rheumatoid arthritis and Sjogren’s), severe combined immunodeficiency, HIV, cystic fibrosis, and primary ciliary dyskinesia. 
• Diffuse panbronchiolitis (DBP) – features bilateral bronchiolar lesions with lymphocytic inflammation of the bronchiolar wall, as well as peribronchiolar inflammation and accumulation of interstitial foamy macrophages. Patients afflicted with DBP may suffer repeated bacterial colonization or infection. There is a higher prevalence of DBP in Asia where it was first identified in the 1960s, potentially due to several HLA alleles that are more common in Asia. 

In addition to the above terminology, the transplant-setting diagnosis “bronchiolitis obliterans syndrome” (BOS) is used to denote progressive obstructive lung disease for which there is not another cause aside from chronic graft rejection. For these patients, clinicians assume the underlying disease entity is OB, but they often lack histopathologic confirmation. 
 

Diagnosis is challenging

Symptoms of bronchiolitis are typically dyspnea and cough, and patients may often be diagnosed with asthma or COPD initially. Pulmonary function testing may show signs of obstruction, restriction, or mixed disease with or without a reduction in Dlco. Chest radiography often appears normal, but high-resolution CT may show expiratory air trapping and centrilobular nodules. Advanced imaging modalities may augment or replace CT imaging in diagnosing bronchiolitis: investigators are evaluating pulmonary MRI and fluoroscopy with computerized ventilation analysis in clinical trials (NCT04080232).

Currently, open or thoracoscopic lung biopsy is typically required to make a definitive diagnosis. Because bronchiolitis is a patchy and heterogeneous process, transbronchial biopsy may provide insufficient yield, with a sensitivity of 29% to 70% reported in lung transplant literature (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

Recent studies have demonstrated transbronchial cryobiopsy to be a promising alternative to surgical biopsy, owing to larger tissue samples than conventional transbronchial lung biopsies. For example, in a recent case series four patients underwent transbronchial cryobiopsy. The procedure yielded adequate tissue for diagnosis of a chronic bronchiolitis in each case (Yamakawa H, et al. Internal Med Advance Publication. doi: 10.2169/internalmedicine.6028-20.
 

Treatment options are growing

Evidence for treatment of bronchiolitis remains limited. Options are extrapolated from lung transplant patients, where incidence of BOS ranges from 50% at 5 years to 76% at 10 years post transplant. Guidelines recommend a 3-month minimum trial of azithromycin, which has been shown to slow or reverse decline of lung function in some patients. Modification of immunosuppression is also recommended. In patients who have continued lung function decline, a systematic review concluded that extracorporeal photopheresis had the most robust evidence for efficacy with stabilized lung function and improved overall survival (Benden C, et al. J Heart Lung Transplant. 2017;36[9]:921). Other salvage therapies that have lower-quality evidence of benefit include total lymphoid irradiation, montelukast, and aerosolized cyclosporine.

In patients who have undergone hematopoietic stem cell transplant, steroids are typically the first line treatment for OB as it is thought to be a form of chronic graft-vs-host disease (GVHD). Ruxolitinib, a selective JAK1/2 inhibitor, demonstrated significant improvement overall in patients with steroid-refractory acute GVHD in a recent randomized clinical trial, although the trial did not examine its effect on pulmonary manifestations (Zeiser R, et al. N Engl J Med. 2020;382[19]:1800). To date, retrospective observational studies of ruxolitinib in patients with lung GVHD have shown conflicting results regarding benefit. Investigators are currently studying ruxolitinib in a phase II trial for patients with BOS following stem cell transplant (NCT03674047).

DIPNECH is unique from other bronchiolitis entities, as small airways dysfunction develops as a result of neuroendocrine cell proliferation in the airway mucosa, ultimately leading to bronchial narrowing. It most commonly presents in middle-aged nonsmoking women with years of chronic cough and dyspnea. While it has an indolent course in many patients, some patients develop progressive symptoms and obstructive lung disease. DIPNECH is considered a precursor to other pulmonary neuroendocrine tumors. The lesions demonstrate somatostatin receptor expression in many cases, prompting the use of somatostatin analogues as treatment. In the largest published case series, 42 patients from three different institutions were identified who were treated with somatostatin analogues for a mean of 38.8 months at the time of review. Symptomatic improvement was seen in 33 of the 42 (79%), and of the 15 with posttreatment PFT data, 14 (93%) showed improvement in PFTs (Al-Toubah, T, et al. Chest. 2020;158[1]:401). Other small studies have demonstrated varying results with symptomatic improvement in 29% to 76% of patients and improvement or stability of PFTs in 50% to 100% of patients (Samhouri BF, et al. ERJ Open Res. 2020;6[4]:527).

For patients who have not undergone lung transplant, and who do not have an identifiable exposure or underlying rheumatologic condition, a similar 3-month minimum trial of macrolide antibiotics is reasonable. Macrolides have been shown to double long-term survival rates to over 90% in patients with DPB. Evidence in this patient population is quite limited, and further research is needed to determine effective therapies for patients.
 

What’s next for bronchiolitis

While clinicians currently have few tools for diagnosing and treating these uncommon diseases, in the coming years, we should learn whether novel imaging modalities or less invasive procedures can aid in the diagnosis. Physicians hope these advances will preclude the need for invasive biopsies in more patients going forward. We should also learn whether newer, targeted agents like ruxolitinib are effective for BOS in patients with stem cell transplant. If so, this finding may open it and similar agents to investigation in other forms of bronchiolitis.
 

Dr. Poole and Dr. Callahan are with University of Utah Health, Salt Lake City, Utah.

What’s in a name?

Bronchiolitis, a group of diseases also referred to as “small airways diseases,” is characterized by inflammation and/or fibrosis in airways less than 2 mm in diameter. In pediatric patients, it is most commonly related to acute viral infections, while in adults, it is often associated with chronic diseases. Bronchiolitis is a well-recognized complication in a significant number of patients who have undergone lung or stem cell transplantation. Common associations also include connective tissue diseases, environmental or occupational inhalation exposures, aspiration, drug toxicity, and infections. Diagnosing bronchiolitis can be challenging for clinicians, and few treatment options exist apart from treating identifiable underlying etiologies. More research is needed into noninvasive diagnostic techniques and treatment modalities.

The terminology used to describe bronchiolitis has evolved over time. Bronchiolitis is now used to describe conditions where the primary pathologic condition is damage to the bronchiolar epithelium not attributable to a larger parenchymal disease (such as hypersensitivity pneumonitis). This change in nomenclature explains why the condition formerly known as “bronchiolitis obliterans organizing pneumonia” (BOOP) is now simply recognized as “organizing pneumonia.” Despite several proposed classification schemes focusing on histopathology, there is no consensus regarding the different subtypes of bronchiolitis, leading to confusion in some cases. Recently, authors have attempted to distinguish cases based on three main histologic patterns (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

• Obliterative/constrictive bronchiolitis (OB) – the terms “obliterative” and “constrictive” are used interchangeably throughout pulmonary literature. It is characterized by fibroblast-rich tissue accumulation in the sub-epithelium of bronchioles leading to progressive narrowing of the lumen. In addition to the transplant setting, it is often seen in patients with rheumatoid arthritis or other connective tissue diseases, inhalational exposures, or acute respiratory infections. More recently, clinicians have recognized diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) as a rare condition causing OB with potentially effective treatment.
• Follicular bronchiolitis (FB) – features peribronchiolar inflammation with subepithelial lymphoid deposits leading to luminal obstruction. FB is chiefly associated with conditions of impaired immunity or chronic airway infection, such as autoimmune connective tissues diseases (especially rheumatoid arthritis and Sjogren’s), severe combined immunodeficiency, HIV, cystic fibrosis, and primary ciliary dyskinesia. 
• Diffuse panbronchiolitis (DBP) – features bilateral bronchiolar lesions with lymphocytic inflammation of the bronchiolar wall, as well as peribronchiolar inflammation and accumulation of interstitial foamy macrophages. Patients afflicted with DBP may suffer repeated bacterial colonization or infection. There is a higher prevalence of DBP in Asia where it was first identified in the 1960s, potentially due to several HLA alleles that are more common in Asia. 

In addition to the above terminology, the transplant-setting diagnosis “bronchiolitis obliterans syndrome” (BOS) is used to denote progressive obstructive lung disease for which there is not another cause aside from chronic graft rejection. For these patients, clinicians assume the underlying disease entity is OB, but they often lack histopathologic confirmation. 
 

Diagnosis is challenging

Symptoms of bronchiolitis are typically dyspnea and cough, and patients may often be diagnosed with asthma or COPD initially. Pulmonary function testing may show signs of obstruction, restriction, or mixed disease with or without a reduction in Dlco. Chest radiography often appears normal, but high-resolution CT may show expiratory air trapping and centrilobular nodules. Advanced imaging modalities may augment or replace CT imaging in diagnosing bronchiolitis: investigators are evaluating pulmonary MRI and fluoroscopy with computerized ventilation analysis in clinical trials (NCT04080232).

Currently, open or thoracoscopic lung biopsy is typically required to make a definitive diagnosis. Because bronchiolitis is a patchy and heterogeneous process, transbronchial biopsy may provide insufficient yield, with a sensitivity of 29% to 70% reported in lung transplant literature (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

Recent studies have demonstrated transbronchial cryobiopsy to be a promising alternative to surgical biopsy, owing to larger tissue samples than conventional transbronchial lung biopsies. For example, in a recent case series four patients underwent transbronchial cryobiopsy. The procedure yielded adequate tissue for diagnosis of a chronic bronchiolitis in each case (Yamakawa H, et al. Internal Med Advance Publication. doi: 10.2169/internalmedicine.6028-20.
 

Treatment options are growing

Evidence for treatment of bronchiolitis remains limited. Options are extrapolated from lung transplant patients, where incidence of BOS ranges from 50% at 5 years to 76% at 10 years post transplant. Guidelines recommend a 3-month minimum trial of azithromycin, which has been shown to slow or reverse decline of lung function in some patients. Modification of immunosuppression is also recommended. In patients who have continued lung function decline, a systematic review concluded that extracorporeal photopheresis had the most robust evidence for efficacy with stabilized lung function and improved overall survival (Benden C, et al. J Heart Lung Transplant. 2017;36[9]:921). Other salvage therapies that have lower-quality evidence of benefit include total lymphoid irradiation, montelukast, and aerosolized cyclosporine.

In patients who have undergone hematopoietic stem cell transplant, steroids are typically the first line treatment for OB as it is thought to be a form of chronic graft-vs-host disease (GVHD). Ruxolitinib, a selective JAK1/2 inhibitor, demonstrated significant improvement overall in patients with steroid-refractory acute GVHD in a recent randomized clinical trial, although the trial did not examine its effect on pulmonary manifestations (Zeiser R, et al. N Engl J Med. 2020;382[19]:1800). To date, retrospective observational studies of ruxolitinib in patients with lung GVHD have shown conflicting results regarding benefit. Investigators are currently studying ruxolitinib in a phase II trial for patients with BOS following stem cell transplant (NCT03674047).

DIPNECH is unique from other bronchiolitis entities, as small airways dysfunction develops as a result of neuroendocrine cell proliferation in the airway mucosa, ultimately leading to bronchial narrowing. It most commonly presents in middle-aged nonsmoking women with years of chronic cough and dyspnea. While it has an indolent course in many patients, some patients develop progressive symptoms and obstructive lung disease. DIPNECH is considered a precursor to other pulmonary neuroendocrine tumors. The lesions demonstrate somatostatin receptor expression in many cases, prompting the use of somatostatin analogues as treatment. In the largest published case series, 42 patients from three different institutions were identified who were treated with somatostatin analogues for a mean of 38.8 months at the time of review. Symptomatic improvement was seen in 33 of the 42 (79%), and of the 15 with posttreatment PFT data, 14 (93%) showed improvement in PFTs (Al-Toubah, T, et al. Chest. 2020;158[1]:401). Other small studies have demonstrated varying results with symptomatic improvement in 29% to 76% of patients and improvement or stability of PFTs in 50% to 100% of patients (Samhouri BF, et al. ERJ Open Res. 2020;6[4]:527).

For patients who have not undergone lung transplant, and who do not have an identifiable exposure or underlying rheumatologic condition, a similar 3-month minimum trial of macrolide antibiotics is reasonable. Macrolides have been shown to double long-term survival rates to over 90% in patients with DPB. Evidence in this patient population is quite limited, and further research is needed to determine effective therapies for patients.
 

What’s next for bronchiolitis

While clinicians currently have few tools for diagnosing and treating these uncommon diseases, in the coming years, we should learn whether novel imaging modalities or less invasive procedures can aid in the diagnosis. Physicians hope these advances will preclude the need for invasive biopsies in more patients going forward. We should also learn whether newer, targeted agents like ruxolitinib are effective for BOS in patients with stem cell transplant. If so, this finding may open it and similar agents to investigation in other forms of bronchiolitis.
 

Dr. Poole and Dr. Callahan are with University of Utah Health, Salt Lake City, Utah.

Although the United States has observed daylight saving time (DST) continuously, in some form, for the last 5 decades (Table), the twice a year switches have never been less popular. In 2019, an American Academy of Sleep Medicine (AASM) survey of more than 2,000 US adults found that 63% support the elimination of seasonal time changes in favor of a national, fixed, year-round time, and only 11% oppose it. Indeed, multiple states have pending legislations to adopt year-round daylight saving time or year-round standard time (Updated September 30, 2020, Congressional Research Service. https://crsreports.congress.gov. R45208 Daylight Saving Time. Accessed Dec 14, 2020). Adjacent states, to limit confusion to interstate travel and commerce, tend to lobby for similar changes together. Most importantly, because of the scientific evidence of detrimental health effects to the public and safety concerns, the American Academy of Sleep Medicine has issued a position statement for year-round standard time (Rishi MA, et al. Daylight saving time: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2020;16(10):1781).

Railroad industry successfully lobbied the US government for consistent time in the United States to keep transportation schedules uniform in 1883; standard time was implemented. When war efforts were over, DST was dropped. Some regions, such as New York and Chicago, maintained DST, but no national standard was applied. Retailers and the recreational activity industry advocated for DST to increase business after work in the afternoon and evenings. In 1966, Congress passed the Uniform Time Act of 1966 to implement 6 months of DST and 6 months of standard time (Waxman OB. The real reason why daylight saving time is a thing. https://time.com/4549397/daylight-saving-time-history-politics/; November 1, 2017. Accessed Dec 14, 2020). Local jurisdictions can opt out of DST, but it requires an act of congress to enforce perennial DST.

When the OPEC embargo occurred, the Emergency Daylight Saving Time Energy Conservation Act was enacted in 1973, but it was quickly ended in October 1974 due to its unpopularity. The dairy industry was opposed to earlier rise time that disrupted the animals’ feeding schedules and their farm operations (Feldman R. Five myths about daylight saving time. https://www.washingtonpost.com/opinions/five-myths-about-daylight-saving-time/2015/03/06/970092d4-c2c1-11e4-9271-610273846239_story.html. Accessed Dec 14, 2020.). Public safety was raised as a concern as early as 1975. The Department of Transportation found increased fatalities of school-aged children in the mornings from January to April of 1974 as compared with 1973. However, the National Bureau of Standards, that performed a review subsequently, stated that other factors might also be at play. Further extension of DST from 6 months of the year to the subsequent 7, and then 8 months per year were enacted in 1986 and 2005, respectively (The reasoning behind changing daylight saving. https://www.npr.org/templates/story/story.php?storyId=7779869. NPR. Accessed Nov 1, 2020.)

An exemption of a state from DST is allowable under existing law, but to establish permanent DST will require an act of Congress. Since then, Arizona and Hawaii, as well as US territories, such as Puerto Rico, Guam, American Samoa and Northern Mariana Islands, and US Virgin Islands, have all opted out of DST by state exemption. Because of Hawaii’s proximity to the equator, the timing of sunrise and sunset were fairly constant throughout the year that made DST unnecessary. The Navajo Nation in Arizona, because of its extension into adjacent New Mexico and Utah, participates in DST. Most of the countries along the tropics, parts of Australia, China, Japan, South Korea, India, and majority of African countries do not observe DST. The European Union has voted to abolish twice yearly change in time in 2021; and individual member states will be able to decide whether they wish to remain on permanent standard time or DST. Since 2015, more than 45 states have proposed legislation to change their observance of DST.

The human biological rhythm is most consistent with standard time (Antle M. Circadian rhythm expert argues against permanent daylight saving time. https://www.ucalgary.ca/news/circadian-rhythm-expert-argues-against-permanent-daylight-saving-time. Accessed Dec 14, 2020.). Since the biological clock for most individuals is not exactly 24 hours long, zeitgebers such as sunlight, exercise, and feeding behaviors are important time cues to foster a regular rhythm. Acutely, the adjustment to 1 hour’s sleep loss at the spring switch from standard time to DST generally requires several days to adapt (Kalidindi A. Daylight saving time is bad for your health. https://massivesci.com/articles/daylight-saving-savings-time-dst-november-standard-time. Accessed Dec 14, 2020.). During this adjustment period, the internal bodily functions are disrupted. The sense of sleepiness and fatigue are increased with earlier morning awakenings, and the inability to fall asleep earlier leads to symptoms of insomnia and poor sleep quality.

Timeline for DST
 

1784 Benjamin Franklin advocated to rise earlier so as to burn fewer candles in the evenings.

1883 Railroads need standard time for operations.

1890 Merchants and retailers (clothing, cigars) advocated for longer shopping hours.

1916 Germany conserves energy.

1918 DST: fuel conservation during World War I.

1942 DST during World War II.

1963 “Chaos of clocks” needs uniform time for commerce.

1966 Uniform Time Act: DST 6 months per year.

1973 Emergency DST Energy Conservation Act: Arab oil embargo to extend DST to 8 months; ended prematurely in October 1974.

1986 Extended start date from last Sunday of April to first Sunday of November.

2005 Energy Act of 2005: 2nd week of March.
 

Dr. Yuen is Assistant Professor, UCSF Department of Internal Medicine-Pulmonary Department, and Adjunct Clinical Assistant Professor at Department of Psychiatry & Behavioral Sciences at Stanford (Calif.) University. Dr. Rishi is Consultant – Pulmonary, Critical Care and Sleep Medicine, Mayo Clinic Health System, Eau Claire, WI; and Assistant Professor of Medicine, Alix School of Medicine, Mayo Clinic, Rochester, MN.

Correction 3/16/21: A photo caption in an earlier version of this article misstated Dr. Kin Yuen's name.






 

Although the United States has observed daylight saving time (DST) continuously, in some form, for the last 5 decades (Table), the twice a year switches have never been less popular. In 2019, an American Academy of Sleep Medicine (AASM) survey of more than 2,000 US adults found that 63% support the elimination of seasonal time changes in favor of a national, fixed, year-round time, and only 11% oppose it. Indeed, multiple states have pending legislations to adopt year-round daylight saving time or year-round standard time (Updated September 30, 2020, Congressional Research Service. https://crsreports.congress.gov. R45208 Daylight Saving Time. Accessed Dec 14, 2020). Adjacent states, to limit confusion to interstate travel and commerce, tend to lobby for similar changes together. Most importantly, because of the scientific evidence of detrimental health effects to the public and safety concerns, the American Academy of Sleep Medicine has issued a position statement for year-round standard time (Rishi MA, et al. Daylight saving time: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2020;16(10):1781).

Railroad industry successfully lobbied the US government for consistent time in the United States to keep transportation schedules uniform in 1883; standard time was implemented. When war efforts were over, DST was dropped. Some regions, such as New York and Chicago, maintained DST, but no national standard was applied. Retailers and the recreational activity industry advocated for DST to increase business after work in the afternoon and evenings. In 1966, Congress passed the Uniform Time Act of 1966 to implement 6 months of DST and 6 months of standard time (Waxman OB. The real reason why daylight saving time is a thing. https://time.com/4549397/daylight-saving-time-history-politics/; November 1, 2017. Accessed Dec 14, 2020). Local jurisdictions can opt out of DST, but it requires an act of congress to enforce perennial DST.

When the OPEC embargo occurred, the Emergency Daylight Saving Time Energy Conservation Act was enacted in 1973, but it was quickly ended in October 1974 due to its unpopularity. The dairy industry was opposed to earlier rise time that disrupted the animals’ feeding schedules and their farm operations (Feldman R. Five myths about daylight saving time. https://www.washingtonpost.com/opinions/five-myths-about-daylight-saving-time/2015/03/06/970092d4-c2c1-11e4-9271-610273846239_story.html. Accessed Dec 14, 2020.). Public safety was raised as a concern as early as 1975. The Department of Transportation found increased fatalities of school-aged children in the mornings from January to April of 1974 as compared with 1973. However, the National Bureau of Standards, that performed a review subsequently, stated that other factors might also be at play. Further extension of DST from 6 months of the year to the subsequent 7, and then 8 months per year were enacted in 1986 and 2005, respectively (The reasoning behind changing daylight saving. https://www.npr.org/templates/story/story.php?storyId=7779869. NPR. Accessed Nov 1, 2020.)

An exemption of a state from DST is allowable under existing law, but to establish permanent DST will require an act of Congress. Since then, Arizona and Hawaii, as well as US territories, such as Puerto Rico, Guam, American Samoa and Northern Mariana Islands, and US Virgin Islands, have all opted out of DST by state exemption. Because of Hawaii’s proximity to the equator, the timing of sunrise and sunset were fairly constant throughout the year that made DST unnecessary. The Navajo Nation in Arizona, because of its extension into adjacent New Mexico and Utah, participates in DST. Most of the countries along the tropics, parts of Australia, China, Japan, South Korea, India, and majority of African countries do not observe DST. The European Union has voted to abolish twice yearly change in time in 2021; and individual member states will be able to decide whether they wish to remain on permanent standard time or DST. Since 2015, more than 45 states have proposed legislation to change their observance of DST.

The human biological rhythm is most consistent with standard time (Antle M. Circadian rhythm expert argues against permanent daylight saving time. https://www.ucalgary.ca/news/circadian-rhythm-expert-argues-against-permanent-daylight-saving-time. Accessed Dec 14, 2020.). Since the biological clock for most individuals is not exactly 24 hours long, zeitgebers such as sunlight, exercise, and feeding behaviors are important time cues to foster a regular rhythm. Acutely, the adjustment to 1 hour’s sleep loss at the spring switch from standard time to DST generally requires several days to adapt (Kalidindi A. Daylight saving time is bad for your health. https://massivesci.com/articles/daylight-saving-savings-time-dst-november-standard-time. Accessed Dec 14, 2020.). During this adjustment period, the internal bodily functions are disrupted. The sense of sleepiness and fatigue are increased with earlier morning awakenings, and the inability to fall asleep earlier leads to symptoms of insomnia and poor sleep quality.

Timeline for DST
 

1784 Benjamin Franklin advocated to rise earlier so as to burn fewer candles in the evenings.

1883 Railroads need standard time for operations.

1890 Merchants and retailers (clothing, cigars) advocated for longer shopping hours.

1916 Germany conserves energy.

1918 DST: fuel conservation during World War I.

1942 DST during World War II.

1963 “Chaos of clocks” needs uniform time for commerce.

1966 Uniform Time Act: DST 6 months per year.

1973 Emergency DST Energy Conservation Act: Arab oil embargo to extend DST to 8 months; ended prematurely in October 1974.

1986 Extended start date from last Sunday of April to first Sunday of November.

2005 Energy Act of 2005: 2nd week of March.
 

Dr. Yuen is Assistant Professor, UCSF Department of Internal Medicine-Pulmonary Department, and Adjunct Clinical Assistant Professor at Department of Psychiatry & Behavioral Sciences at Stanford (Calif.) University. Dr. Rishi is Consultant – Pulmonary, Critical Care and Sleep Medicine, Mayo Clinic Health System, Eau Claire, WI; and Assistant Professor of Medicine, Alix School of Medicine, Mayo Clinic, Rochester, MN.

Correction 3/16/21: A photo caption in an earlier version of this article misstated Dr. Kin Yuen's name.






 

Although the United States has observed daylight saving time (DST) continuously, in some form, for the last 5 decades (Table), the twice a year switches have never been less popular. In 2019, an American Academy of Sleep Medicine (AASM) survey of more than 2,000 US adults found that 63% support the elimination of seasonal time changes in favor of a national, fixed, year-round time, and only 11% oppose it. Indeed, multiple states have pending legislations to adopt year-round daylight saving time or year-round standard time (Updated September 30, 2020, Congressional Research Service. https://crsreports.congress.gov. R45208 Daylight Saving Time. Accessed Dec 14, 2020). Adjacent states, to limit confusion to interstate travel and commerce, tend to lobby for similar changes together. Most importantly, because of the scientific evidence of detrimental health effects to the public and safety concerns, the American Academy of Sleep Medicine has issued a position statement for year-round standard time (Rishi MA, et al. Daylight saving time: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2020;16(10):1781).

Railroad industry successfully lobbied the US government for consistent time in the United States to keep transportation schedules uniform in 1883; standard time was implemented. When war efforts were over, DST was dropped. Some regions, such as New York and Chicago, maintained DST, but no national standard was applied. Retailers and the recreational activity industry advocated for DST to increase business after work in the afternoon and evenings. In 1966, Congress passed the Uniform Time Act of 1966 to implement 6 months of DST and 6 months of standard time (Waxman OB. The real reason why daylight saving time is a thing. https://time.com/4549397/daylight-saving-time-history-politics/; November 1, 2017. Accessed Dec 14, 2020). Local jurisdictions can opt out of DST, but it requires an act of congress to enforce perennial DST.

When the OPEC embargo occurred, the Emergency Daylight Saving Time Energy Conservation Act was enacted in 1973, but it was quickly ended in October 1974 due to its unpopularity. The dairy industry was opposed to earlier rise time that disrupted the animals’ feeding schedules and their farm operations (Feldman R. Five myths about daylight saving time. https://www.washingtonpost.com/opinions/five-myths-about-daylight-saving-time/2015/03/06/970092d4-c2c1-11e4-9271-610273846239_story.html. Accessed Dec 14, 2020.). Public safety was raised as a concern as early as 1975. The Department of Transportation found increased fatalities of school-aged children in the mornings from January to April of 1974 as compared with 1973. However, the National Bureau of Standards, that performed a review subsequently, stated that other factors might also be at play. Further extension of DST from 6 months of the year to the subsequent 7, and then 8 months per year were enacted in 1986 and 2005, respectively (The reasoning behind changing daylight saving. https://www.npr.org/templates/story/story.php?storyId=7779869. NPR. Accessed Nov 1, 2020.)

An exemption of a state from DST is allowable under existing law, but to establish permanent DST will require an act of Congress. Since then, Arizona and Hawaii, as well as US territories, such as Puerto Rico, Guam, American Samoa and Northern Mariana Islands, and US Virgin Islands, have all opted out of DST by state exemption. Because of Hawaii’s proximity to the equator, the timing of sunrise and sunset were fairly constant throughout the year that made DST unnecessary. The Navajo Nation in Arizona, because of its extension into adjacent New Mexico and Utah, participates in DST. Most of the countries along the tropics, parts of Australia, China, Japan, South Korea, India, and majority of African countries do not observe DST. The European Union has voted to abolish twice yearly change in time in 2021; and individual member states will be able to decide whether they wish to remain on permanent standard time or DST. Since 2015, more than 45 states have proposed legislation to change their observance of DST.

The human biological rhythm is most consistent with standard time (Antle M. Circadian rhythm expert argues against permanent daylight saving time. https://www.ucalgary.ca/news/circadian-rhythm-expert-argues-against-permanent-daylight-saving-time. Accessed Dec 14, 2020.). Since the biological clock for most individuals is not exactly 24 hours long, zeitgebers such as sunlight, exercise, and feeding behaviors are important time cues to foster a regular rhythm. Acutely, the adjustment to 1 hour’s sleep loss at the spring switch from standard time to DST generally requires several days to adapt (Kalidindi A. Daylight saving time is bad for your health. https://massivesci.com/articles/daylight-saving-savings-time-dst-november-standard-time. Accessed Dec 14, 2020.). During this adjustment period, the internal bodily functions are disrupted. The sense of sleepiness and fatigue are increased with earlier morning awakenings, and the inability to fall asleep earlier leads to symptoms of insomnia and poor sleep quality.

Timeline for DST
 

1784 Benjamin Franklin advocated to rise earlier so as to burn fewer candles in the evenings.

1883 Railroads need standard time for operations.

1890 Merchants and retailers (clothing, cigars) advocated for longer shopping hours.

1916 Germany conserves energy.

1918 DST: fuel conservation during World War I.

1942 DST during World War II.

1963 “Chaos of clocks” needs uniform time for commerce.

1966 Uniform Time Act: DST 6 months per year.

1973 Emergency DST Energy Conservation Act: Arab oil embargo to extend DST to 8 months; ended prematurely in October 1974.

1986 Extended start date from last Sunday of April to first Sunday of November.

2005 Energy Act of 2005: 2nd week of March.
 

Dr. Yuen is Assistant Professor, UCSF Department of Internal Medicine-Pulmonary Department, and Adjunct Clinical Assistant Professor at Department of Psychiatry & Behavioral Sciences at Stanford (Calif.) University. Dr. Rishi is Consultant – Pulmonary, Critical Care and Sleep Medicine, Mayo Clinic Health System, Eau Claire, WI; and Assistant Professor of Medicine, Alix School of Medicine, Mayo Clinic, Rochester, MN.

Correction 3/16/21: A photo caption in an earlier version of this article misstated Dr. Kin Yuen's name.






 

Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.

The phases of COVID 19

COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).

The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.

The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.

The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.

The tools in our toolbox: Timing is paramount

Remdesivir

The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.


Convalescent plasma

 Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).

The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.


Corticosteroids

Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.


Self-proning

Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change. 
 

What about thromboembolic events?

Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.

Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.

Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.

The phases of COVID 19

COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).

The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.

The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.

The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.

The tools in our toolbox: Timing is paramount

Remdesivir

The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.


Convalescent plasma

 Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).

The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.


Corticosteroids

Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.


Self-proning

Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change. 
 

What about thromboembolic events?

Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.

Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.

Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.

The phases of COVID 19

COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).

The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.

The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.

The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.

The tools in our toolbox: Timing is paramount

Remdesivir

The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.


Convalescent plasma

 Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).

The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.


Corticosteroids

Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.


Self-proning

Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change. 
 

What about thromboembolic events?

Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.

Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Sleep-disordered breathing (SDB) is a common sleep disturbance in neuromuscular disease (NMD) affecting 36% to 53% of diagnosed adults (Arens R, et al. Paediatr Respir Rev. 2010;11[1]:24). Disturbances in sleep may serve as the earliest sign of muscle weakness in these patients, at times being detected before their underlying neuromuscular disease is diagnosed. This is of paramount importance to sleep medicine and pulmonary physicians who may be among the first specialists to evaluate these patients and can play a vital role in the recognition and diagnosis of neuromuscular disease. Herein, we will provide a guide to aid the reader in recognizing the early signs and symptoms of NMD as it pertains to sleep, as earlier diagnosis may lead to improved quality of life or possibly even survival, in some cases.

Pathophysiology

To begin, it is important to understand the pathophysiology of NMD and how it is altered during the sleep state. Sleep-related physiologic changes in healthy humans include reduction in upper airway muscle tone, blunting of chemoreceptors associated with pharyngeal dilator augmentation, and sleep stage-specific changes in skeletal muscle tone. In patients with NMD, these changes may not be adequately compensated for, leading to sleep-disordered breathing that can present as sleep apnea, hypoventilation, or hypoxia (Govindarajan R, et al. Sleep Issues in Neuromuscular Disorders: A Clinical Guide. Springer International Publishing AG, Springer Nature 2018).

Central respiratory control

The respiratory centers in the pons and medulla are generally spared from the primary effects of most NMD; however, over time, they may be affected secondarily. Similar to obesity hypoventilation syndrome (OHS), untreated chronic sleep-related hypoventilation from NMD can impair the sensitivity of respiratory chemoreceptors leading to worsening hypoventilation.
 

Upper airway resistance

Pharyngeal muscle tone is key to maintaining a patent airway during sleep. In some NMD, bulbar muscle weakness with pharyngeal dilator muscle hypotonia leads to increased upper airway resistance, especially during REM sleep, which can result in obstructive sleep apnea (OSA). In addition to weakness affecting the upper airway musculature, anatomical changes may also contribute to sleep-disordered breathing. In Pompe disease, for example, macroglossia and fibro-fatty replacement of tongue muscles may occur, leading to the development of OSA.
 

Diaphragm weakness

In NMD that affects the diaphragm, there is an increased reliance on the skeletal muscles of respiration to maintain adequate ventilation as the underlying disease progresses. Generally, weakness of the diaphragm will cause disturbances in REM sleep first as, during REM, ventilation predominately depends on the diaphragm and patients lose the assistance of their skeletal muscles. However, over time, the progressive weakening of the diaphragm will progress to involve NREM sleep as well, clinically manifesting with frank sleep apnea, hypoventilation, and, ultimately, chronic hypercapnic respiratory failure.
 

Inspiratory muscle weakness

As noted above, there are many other muscles used in inspiration in addition to the diaphragm. Other primary muscles include the intercostal and scalene muscles, and accessory muscles include the sternocleidomastoid, pectoralis, latissimus dorsi, erector spinae, and trapezius muscles. While sleep and breathing problems may begin early in the course of a neuromuscular disease, the complex restrictive lung disease pattern that we see in these patients may not develop until the respiratory muscles of the chest wall are involved. This restriction, which corresponds to lower lung volumes, leads to a fall in the caudal traction force of the airways which can lead to reduction in the pharyngeal airway cross section. Because these issues are worsened in the supine position, their pathophysiologic effects on respiration are most notable during sleep, putting patients at higher risk of OSA.
 

Cardiac abnormalities

Lastly, it should be noted that diseases such as the muscular dystrophies, myotonic dystrophy, mitochondriopathies, and nemaline myopathy can be associated with a cardiomyopathy ,which can lead to central sleep apnea in the form of Cheyne-Stokes breathing.
 

Sleep-disordered breathing in specific NMDs

In amyotrophic lateral sclerosis (ALS), up to 75% of patients may have SDB, the majority of which is central sleep apnea (CSA) and hypoventilation although they still have a higher prevalence of obstructive sleep apnea (OSA) than the general population. Whether the diaphragm or the pharyngeal muscles are predominantly affected may have something to do with the type of apnea a patient experiences; however, studies have shown that even in bulbar ALS, CSA is most common. It should be noted, that this is not Cheyne-Stokes CSA, but rather lack of chest wall and abdominal movement due to weakness. (David WS, et al. J Neurol Sci. 1997;152[suppl 1]:S29-35).

In myasthenia gravis (MG), about 40% to 60% of patients have SDB, and about 30% develop overt respiratory weakness, generally late in the course of their disease. Many of these patients report excessive daytime sleepiness, often attributed to myasthenic fatigue requiring treatment with corticosteroids. It is important to evaluate for sleep apnea, given that if diagnosed and treated, their generalized fatigue may improve and the need for steroids may be reduced or eliminated altogether. It is also important to note that the respiratory and sleep issues MG patients face may not correlate with the severity of their overall disease, such that patients well-controlled on medications from a generalized weakness standpoint may still require home noninvasive ventilation (NIV) for chronic respiratory failure due to weakness of the respiratory system muscles.

Duchenne muscular dystrophy (DMD), an X-linked disease associated with dysfunction of dystrophin synthesis, is often diagnosed in early childhood and gradually progresses over years. Their initial sleep and respiratory symptoms can be subtle and may start with increased nighttime awakenings and daytime somnolence. Generally, these patients will develop OSA in the first decade of life and progress to hypoventilation in their second decade and beyond. These patients are especially important to recognize, as studies have shown appropriate NIV therapy may significantly prolong their life (Finder JD, et al; American Thoracic Society. Am J Respir Crit Care Med. 2004(Aug 15);170[4]:456-465).

In addition to the well-known motor neuron and neuromuscular diseases mentioned above, neuropathic diseases can lead to sleep disturbances, as well. In Charcot-Marie-Tooth (CMT), pharyngeal and laryngeal neuropathy, as well as hypoglossal nerve dysfunction, lead to OSA. Similar to ALS and MG, there is a significant amount of CSA and hypoventilation, likely related to phrenic neuropathy. In contrast to MG, in CMT, the severity of neuropathic disease does correlate to the severity of sleep apnea.
 

Testing

Testing can range from overnight oximetry to polysomnogram (PSG) with CO₂ monitoring. Generally, all patients with a rapidly progressive neuromuscular disease should get pulmonary function testing (PFT) (upright and supine) to evaluate forced vital capacity (FVC) every 3 to 6 months to monitor for respiratory failure. Laboratory studies that can be helpful in assessing for SDB are the PaCO₂ (> 45 mm Hg) measured on an arterial blood gas and serum bicarbonate levels (>27 mmol/L or a base excess >4 mmol/L). Patients can qualify for NIV with an overnight SaO₂ less than or equal to 88% for greater than or equal to 5 minutes in a 2-hour recording period, PaCO₂ greater than or equal to 45 mm Hg, forced vital capacity (FVC) < 50% of predicted, or maximal inspiratory pressure (MIP) <60 cm H₂O. For ALS specifically, sniff nasal pressure < 40 cm H₂O and orthopnea are additional criteria that can be used. It is worth noting that a PSG is not required for NIV qualification in neuromuscular respiratory insufficiency. However, PSG is beneficial in patients with preserved PFTs but suspected of having early nocturnal respiratory impairment.
 

Therapy

NIV is the mainstay of therapy for SDB in patients with NMD and has been associated with a slower decline in FVC and improved survival in some cases, as demonstrated in studies of patients with DMD or ALS. Generally, a bi-level PAP mode is preferred; the expiratory positive airway pressure prevents micro-atelectasis and improves V/Q matching and the inspiratory positive airway pressure reduces inspiratory muscle load and optimizes ventilation. As weakness progresses, patients may have difficulty creating enough negative force to initiate a spontaneous breath, thus a mode with a set respiratory rate is preferred that can be implemented in bi-level PAP or more advanced modes such as volume-assured pressure support (VAPS) modality. For patients who are unable to tolerate NIV, particularly those with severe bulbar disease and difficult to manage respiratory secretions, tracheostomy with mechanical ventilation may ultimately be needed. This decision should be made as part of a multidisciplinary shared decision-making conversation with the patient, their family, and their team of providers.
 

Summary

Sleep is a particularly vulnerable state for patients with NMD, and in many patients, disturbances in sleep may be the first clue to their ultimate diagnosis. It is important that sleep medicine and pulmonary specialists understand the pathophysiology and management of NMD as they can play a vital role in the interdisciplinary care of these patients.
 

Dr. Greer is a Sleep Medicine Fellow, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine; Dr. Collop is Professor of Medicine and Neurology, Director, Emory Sleep Center; Emory University, Atlanta, Georgia.

Sleep-disordered breathing (SDB) is a common sleep disturbance in neuromuscular disease (NMD) affecting 36% to 53% of diagnosed adults (Arens R, et al. Paediatr Respir Rev. 2010;11[1]:24). Disturbances in sleep may serve as the earliest sign of muscle weakness in these patients, at times being detected before their underlying neuromuscular disease is diagnosed. This is of paramount importance to sleep medicine and pulmonary physicians who may be among the first specialists to evaluate these patients and can play a vital role in the recognition and diagnosis of neuromuscular disease. Herein, we will provide a guide to aid the reader in recognizing the early signs and symptoms of NMD as it pertains to sleep, as earlier diagnosis may lead to improved quality of life or possibly even survival, in some cases.

Pathophysiology

To begin, it is important to understand the pathophysiology of NMD and how it is altered during the sleep state. Sleep-related physiologic changes in healthy humans include reduction in upper airway muscle tone, blunting of chemoreceptors associated with pharyngeal dilator augmentation, and sleep stage-specific changes in skeletal muscle tone. In patients with NMD, these changes may not be adequately compensated for, leading to sleep-disordered breathing that can present as sleep apnea, hypoventilation, or hypoxia (Govindarajan R, et al. Sleep Issues in Neuromuscular Disorders: A Clinical Guide. Springer International Publishing AG, Springer Nature 2018).

Central respiratory control

The respiratory centers in the pons and medulla are generally spared from the primary effects of most NMD; however, over time, they may be affected secondarily. Similar to obesity hypoventilation syndrome (OHS), untreated chronic sleep-related hypoventilation from NMD can impair the sensitivity of respiratory chemoreceptors leading to worsening hypoventilation.
 

Upper airway resistance

Pharyngeal muscle tone is key to maintaining a patent airway during sleep. In some NMD, bulbar muscle weakness with pharyngeal dilator muscle hypotonia leads to increased upper airway resistance, especially during REM sleep, which can result in obstructive sleep apnea (OSA). In addition to weakness affecting the upper airway musculature, anatomical changes may also contribute to sleep-disordered breathing. In Pompe disease, for example, macroglossia and fibro-fatty replacement of tongue muscles may occur, leading to the development of OSA.
 

Diaphragm weakness

In NMD that affects the diaphragm, there is an increased reliance on the skeletal muscles of respiration to maintain adequate ventilation as the underlying disease progresses. Generally, weakness of the diaphragm will cause disturbances in REM sleep first as, during REM, ventilation predominately depends on the diaphragm and patients lose the assistance of their skeletal muscles. However, over time, the progressive weakening of the diaphragm will progress to involve NREM sleep as well, clinically manifesting with frank sleep apnea, hypoventilation, and, ultimately, chronic hypercapnic respiratory failure.
 

Inspiratory muscle weakness

As noted above, there are many other muscles used in inspiration in addition to the diaphragm. Other primary muscles include the intercostal and scalene muscles, and accessory muscles include the sternocleidomastoid, pectoralis, latissimus dorsi, erector spinae, and trapezius muscles. While sleep and breathing problems may begin early in the course of a neuromuscular disease, the complex restrictive lung disease pattern that we see in these patients may not develop until the respiratory muscles of the chest wall are involved. This restriction, which corresponds to lower lung volumes, leads to a fall in the caudal traction force of the airways which can lead to reduction in the pharyngeal airway cross section. Because these issues are worsened in the supine position, their pathophysiologic effects on respiration are most notable during sleep, putting patients at higher risk of OSA.
 

Cardiac abnormalities

Lastly, it should be noted that diseases such as the muscular dystrophies, myotonic dystrophy, mitochondriopathies, and nemaline myopathy can be associated with a cardiomyopathy ,which can lead to central sleep apnea in the form of Cheyne-Stokes breathing.
 

Sleep-disordered breathing in specific NMDs

In amyotrophic lateral sclerosis (ALS), up to 75% of patients may have SDB, the majority of which is central sleep apnea (CSA) and hypoventilation although they still have a higher prevalence of obstructive sleep apnea (OSA) than the general population. Whether the diaphragm or the pharyngeal muscles are predominantly affected may have something to do with the type of apnea a patient experiences; however, studies have shown that even in bulbar ALS, CSA is most common. It should be noted, that this is not Cheyne-Stokes CSA, but rather lack of chest wall and abdominal movement due to weakness. (David WS, et al. J Neurol Sci. 1997;152[suppl 1]:S29-35).

In myasthenia gravis (MG), about 40% to 60% of patients have SDB, and about 30% develop overt respiratory weakness, generally late in the course of their disease. Many of these patients report excessive daytime sleepiness, often attributed to myasthenic fatigue requiring treatment with corticosteroids. It is important to evaluate for sleep apnea, given that if diagnosed and treated, their generalized fatigue may improve and the need for steroids may be reduced or eliminated altogether. It is also important to note that the respiratory and sleep issues MG patients face may not correlate with the severity of their overall disease, such that patients well-controlled on medications from a generalized weakness standpoint may still require home noninvasive ventilation (NIV) for chronic respiratory failure due to weakness of the respiratory system muscles.

Duchenne muscular dystrophy (DMD), an X-linked disease associated with dysfunction of dystrophin synthesis, is often diagnosed in early childhood and gradually progresses over years. Their initial sleep and respiratory symptoms can be subtle and may start with increased nighttime awakenings and daytime somnolence. Generally, these patients will develop OSA in the first decade of life and progress to hypoventilation in their second decade and beyond. These patients are especially important to recognize, as studies have shown appropriate NIV therapy may significantly prolong their life (Finder JD, et al; American Thoracic Society. Am J Respir Crit Care Med. 2004(Aug 15);170[4]:456-465).

In addition to the well-known motor neuron and neuromuscular diseases mentioned above, neuropathic diseases can lead to sleep disturbances, as well. In Charcot-Marie-Tooth (CMT), pharyngeal and laryngeal neuropathy, as well as hypoglossal nerve dysfunction, lead to OSA. Similar to ALS and MG, there is a significant amount of CSA and hypoventilation, likely related to phrenic neuropathy. In contrast to MG, in CMT, the severity of neuropathic disease does correlate to the severity of sleep apnea.
 

Testing

Testing can range from overnight oximetry to polysomnogram (PSG) with CO₂ monitoring. Generally, all patients with a rapidly progressive neuromuscular disease should get pulmonary function testing (PFT) (upright and supine) to evaluate forced vital capacity (FVC) every 3 to 6 months to monitor for respiratory failure. Laboratory studies that can be helpful in assessing for SDB are the PaCO₂ (> 45 mm Hg) measured on an arterial blood gas and serum bicarbonate levels (>27 mmol/L or a base excess >4 mmol/L). Patients can qualify for NIV with an overnight SaO₂ less than or equal to 88% for greater than or equal to 5 minutes in a 2-hour recording period, PaCO₂ greater than or equal to 45 mm Hg, forced vital capacity (FVC) < 50% of predicted, or maximal inspiratory pressure (MIP) <60 cm H₂O. For ALS specifically, sniff nasal pressure < 40 cm H₂O and orthopnea are additional criteria that can be used. It is worth noting that a PSG is not required for NIV qualification in neuromuscular respiratory insufficiency. However, PSG is beneficial in patients with preserved PFTs but suspected of having early nocturnal respiratory impairment.
 

Therapy

NIV is the mainstay of therapy for SDB in patients with NMD and has been associated with a slower decline in FVC and improved survival in some cases, as demonstrated in studies of patients with DMD or ALS. Generally, a bi-level PAP mode is preferred; the expiratory positive airway pressure prevents micro-atelectasis and improves V/Q matching and the inspiratory positive airway pressure reduces inspiratory muscle load and optimizes ventilation. As weakness progresses, patients may have difficulty creating enough negative force to initiate a spontaneous breath, thus a mode with a set respiratory rate is preferred that can be implemented in bi-level PAP or more advanced modes such as volume-assured pressure support (VAPS) modality. For patients who are unable to tolerate NIV, particularly those with severe bulbar disease and difficult to manage respiratory secretions, tracheostomy with mechanical ventilation may ultimately be needed. This decision should be made as part of a multidisciplinary shared decision-making conversation with the patient, their family, and their team of providers.
 

Summary

Sleep is a particularly vulnerable state for patients with NMD, and in many patients, disturbances in sleep may be the first clue to their ultimate diagnosis. It is important that sleep medicine and pulmonary specialists understand the pathophysiology and management of NMD as they can play a vital role in the interdisciplinary care of these patients.
 

Dr. Greer is a Sleep Medicine Fellow, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine; Dr. Collop is Professor of Medicine and Neurology, Director, Emory Sleep Center; Emory University, Atlanta, Georgia.

Sleep-disordered breathing (SDB) is a common sleep disturbance in neuromuscular disease (NMD) affecting 36% to 53% of diagnosed adults (Arens R, et al. Paediatr Respir Rev. 2010;11[1]:24). Disturbances in sleep may serve as the earliest sign of muscle weakness in these patients, at times being detected before their underlying neuromuscular disease is diagnosed. This is of paramount importance to sleep medicine and pulmonary physicians who may be among the first specialists to evaluate these patients and can play a vital role in the recognition and diagnosis of neuromuscular disease. Herein, we will provide a guide to aid the reader in recognizing the early signs and symptoms of NMD as it pertains to sleep, as earlier diagnosis may lead to improved quality of life or possibly even survival, in some cases.

Pathophysiology

To begin, it is important to understand the pathophysiology of NMD and how it is altered during the sleep state. Sleep-related physiologic changes in healthy humans include reduction in upper airway muscle tone, blunting of chemoreceptors associated with pharyngeal dilator augmentation, and sleep stage-specific changes in skeletal muscle tone. In patients with NMD, these changes may not be adequately compensated for, leading to sleep-disordered breathing that can present as sleep apnea, hypoventilation, or hypoxia (Govindarajan R, et al. Sleep Issues in Neuromuscular Disorders: A Clinical Guide. Springer International Publishing AG, Springer Nature 2018).

Central respiratory control

The respiratory centers in the pons and medulla are generally spared from the primary effects of most NMD; however, over time, they may be affected secondarily. Similar to obesity hypoventilation syndrome (OHS), untreated chronic sleep-related hypoventilation from NMD can impair the sensitivity of respiratory chemoreceptors leading to worsening hypoventilation.
 

Upper airway resistance

Pharyngeal muscle tone is key to maintaining a patent airway during sleep. In some NMD, bulbar muscle weakness with pharyngeal dilator muscle hypotonia leads to increased upper airway resistance, especially during REM sleep, which can result in obstructive sleep apnea (OSA). In addition to weakness affecting the upper airway musculature, anatomical changes may also contribute to sleep-disordered breathing. In Pompe disease, for example, macroglossia and fibro-fatty replacement of tongue muscles may occur, leading to the development of OSA.
 

Diaphragm weakness

In NMD that affects the diaphragm, there is an increased reliance on the skeletal muscles of respiration to maintain adequate ventilation as the underlying disease progresses. Generally, weakness of the diaphragm will cause disturbances in REM sleep first as, during REM, ventilation predominately depends on the diaphragm and patients lose the assistance of their skeletal muscles. However, over time, the progressive weakening of the diaphragm will progress to involve NREM sleep as well, clinically manifesting with frank sleep apnea, hypoventilation, and, ultimately, chronic hypercapnic respiratory failure.
 

Inspiratory muscle weakness

As noted above, there are many other muscles used in inspiration in addition to the diaphragm. Other primary muscles include the intercostal and scalene muscles, and accessory muscles include the sternocleidomastoid, pectoralis, latissimus dorsi, erector spinae, and trapezius muscles. While sleep and breathing problems may begin early in the course of a neuromuscular disease, the complex restrictive lung disease pattern that we see in these patients may not develop until the respiratory muscles of the chest wall are involved. This restriction, which corresponds to lower lung volumes, leads to a fall in the caudal traction force of the airways which can lead to reduction in the pharyngeal airway cross section. Because these issues are worsened in the supine position, their pathophysiologic effects on respiration are most notable during sleep, putting patients at higher risk of OSA.
 

Cardiac abnormalities

Lastly, it should be noted that diseases such as the muscular dystrophies, myotonic dystrophy, mitochondriopathies, and nemaline myopathy can be associated with a cardiomyopathy ,which can lead to central sleep apnea in the form of Cheyne-Stokes breathing.
 

Sleep-disordered breathing in specific NMDs

In amyotrophic lateral sclerosis (ALS), up to 75% of patients may have SDB, the majority of which is central sleep apnea (CSA) and hypoventilation although they still have a higher prevalence of obstructive sleep apnea (OSA) than the general population. Whether the diaphragm or the pharyngeal muscles are predominantly affected may have something to do with the type of apnea a patient experiences; however, studies have shown that even in bulbar ALS, CSA is most common. It should be noted, that this is not Cheyne-Stokes CSA, but rather lack of chest wall and abdominal movement due to weakness. (David WS, et al. J Neurol Sci. 1997;152[suppl 1]:S29-35).

In myasthenia gravis (MG), about 40% to 60% of patients have SDB, and about 30% develop overt respiratory weakness, generally late in the course of their disease. Many of these patients report excessive daytime sleepiness, often attributed to myasthenic fatigue requiring treatment with corticosteroids. It is important to evaluate for sleep apnea, given that if diagnosed and treated, their generalized fatigue may improve and the need for steroids may be reduced or eliminated altogether. It is also important to note that the respiratory and sleep issues MG patients face may not correlate with the severity of their overall disease, such that patients well-controlled on medications from a generalized weakness standpoint may still require home noninvasive ventilation (NIV) for chronic respiratory failure due to weakness of the respiratory system muscles.

Duchenne muscular dystrophy (DMD), an X-linked disease associated with dysfunction of dystrophin synthesis, is often diagnosed in early childhood and gradually progresses over years. Their initial sleep and respiratory symptoms can be subtle and may start with increased nighttime awakenings and daytime somnolence. Generally, these patients will develop OSA in the first decade of life and progress to hypoventilation in their second decade and beyond. These patients are especially important to recognize, as studies have shown appropriate NIV therapy may significantly prolong their life (Finder JD, et al; American Thoracic Society. Am J Respir Crit Care Med. 2004(Aug 15);170[4]:456-465).

In addition to the well-known motor neuron and neuromuscular diseases mentioned above, neuropathic diseases can lead to sleep disturbances, as well. In Charcot-Marie-Tooth (CMT), pharyngeal and laryngeal neuropathy, as well as hypoglossal nerve dysfunction, lead to OSA. Similar to ALS and MG, there is a significant amount of CSA and hypoventilation, likely related to phrenic neuropathy. In contrast to MG, in CMT, the severity of neuropathic disease does correlate to the severity of sleep apnea.
 

Testing

Testing can range from overnight oximetry to polysomnogram (PSG) with CO₂ monitoring. Generally, all patients with a rapidly progressive neuromuscular disease should get pulmonary function testing (PFT) (upright and supine) to evaluate forced vital capacity (FVC) every 3 to 6 months to monitor for respiratory failure. Laboratory studies that can be helpful in assessing for SDB are the PaCO₂ (> 45 mm Hg) measured on an arterial blood gas and serum bicarbonate levels (>27 mmol/L or a base excess >4 mmol/L). Patients can qualify for NIV with an overnight SaO₂ less than or equal to 88% for greater than or equal to 5 minutes in a 2-hour recording period, PaCO₂ greater than or equal to 45 mm Hg, forced vital capacity (FVC) < 50% of predicted, or maximal inspiratory pressure (MIP) <60 cm H₂O. For ALS specifically, sniff nasal pressure < 40 cm H₂O and orthopnea are additional criteria that can be used. It is worth noting that a PSG is not required for NIV qualification in neuromuscular respiratory insufficiency. However, PSG is beneficial in patients with preserved PFTs but suspected of having early nocturnal respiratory impairment.
 

Therapy

NIV is the mainstay of therapy for SDB in patients with NMD and has been associated with a slower decline in FVC and improved survival in some cases, as demonstrated in studies of patients with DMD or ALS. Generally, a bi-level PAP mode is preferred; the expiratory positive airway pressure prevents micro-atelectasis and improves V/Q matching and the inspiratory positive airway pressure reduces inspiratory muscle load and optimizes ventilation. As weakness progresses, patients may have difficulty creating enough negative force to initiate a spontaneous breath, thus a mode with a set respiratory rate is preferred that can be implemented in bi-level PAP or more advanced modes such as volume-assured pressure support (VAPS) modality. For patients who are unable to tolerate NIV, particularly those with severe bulbar disease and difficult to manage respiratory secretions, tracheostomy with mechanical ventilation may ultimately be needed. This decision should be made as part of a multidisciplinary shared decision-making conversation with the patient, their family, and their team of providers.
 

Summary

Sleep is a particularly vulnerable state for patients with NMD, and in many patients, disturbances in sleep may be the first clue to their ultimate diagnosis. It is important that sleep medicine and pulmonary specialists understand the pathophysiology and management of NMD as they can play a vital role in the interdisciplinary care of these patients.
 

Dr. Greer is a Sleep Medicine Fellow, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine; Dr. Collop is Professor of Medicine and Neurology, Director, Emory Sleep Center; Emory University, Atlanta, Georgia.

The coronavirus disease 2019 (COVID-19) pandemic has changed the way we deliver healthcare for the foreseeable future. Not only have we had to rapidly learn how to evaluate, diagnose, and treat this new disease, we have also had to shift how we screen, triage, and care for other patients for both their safety and ours. As the virus is primarily spread via respiratory droplets, aerosol-generating procedures (AGP), such as bronchoscopy and tracheostomy, are high-risk for viral transmission. We have therefore had to reassess the risk/benefit ratio of performing these procedures – what is the risk to the patient by procedure postponement vs the risk to the health-care personnel (HCP) involved by moving ahead with the procedure? And, if proceeding, how should we protect ourselves? How do we screen patients to help us stratify risk? In order to answer these questions, we generally divide patients into three categories: the asymptomatic outpatient, the symptomatic patient, and the critically ill patient.

The asymptomatic outpatient

Early in the pandemic as cases began to spike in the US, many hospitals decided to postpone all elective procedures and surgeries. Guidelines quickly emerged stratifying bronchoscopic procedures into emergent, urgent, acute, subacute, and truly elective with recommendations on the subsequent timing of those procedures (Pritchett MA, et al. J Thorac Dis. 2020 May;12[5]:1781-1798). As we have obtained further data and our infrastructure has been bolstered, many physicians have begun performing more routine procedures. Preprocedural screening, both with symptom questionnaires and nasopharyngeal swabs, has been enacted as a measure to prevent inadvertent exposure to infected patients. While there are limited data regarding the reliability of this measure, emerging data have shown good concordance between nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) swabs and bronchoalveolar lavage (BAL) samples in low-risk patients (Oberg, et al. Personal communication, Sept 2020). Emergency procedures, such as foreign body aspiration, critical airway obstruction, and massive hemoptysis, were generally performed without delay throughout the pandemic. More recently, emphasis has been placed on prioritizing procedures for acute clinical diagnoses, such as biopsies for concerning lung nodules or masses in potentially early-stage patients, in those where staging is needed and in those where disease progression is suspected. Subacute procedures, such as inspection bronchoscopy for cough, minor hemoptysis, or airway stent surveillance, have generally been reintroduced while elective procedures, such as bronchial thermoplasty and bronchoscopic lung volume reduction, are considered elective, and their frequency and timing is determined mostly by the number of new cases of COVID-19 in the local community.

For all procedures, general modifications have been made. High-efficiency particulate air (HEPA) filters should be placed on all ventilatory circuits. When equivalent, flexible bronchoscopy is preferred over rigid bronchoscopy due to the closed circuit. Enhanced personal protective equipment (PPE) for all procedures is recommended – this typically includes a gown, gloves, hair bonnet, N-95 mask, and a face shield. Strict adherence to the Centers for Disease Control and Prevention (CDC) guidelines for postprocedure cleaning and sterilization is strongly recommended. In some cases, single-use bronchoscopes are being preferentially used, though no strong recommendations exist for this.
 

The symptomatic COVID-19 patient

In patients who have been diagnosed with SARS-CoV-2, we generally recommend postponing all procedures other than for life-threatening indications. For outpatients, we generally wait for two negative nasopharyngeal swabs prior to performing any nonemergent procedure. In inpatients, similar recommendations exist. Potential inpatient indications for bronchoscopy include diagnostic evaluation for alternate or coinfections, and therapeutic aspiration of clinically significant secretions. These should be carefully considered and performed only if deemed absolutely necessary. If bronchoscopy is needed in a patient with suspected or confirmed COVID-19, at a minimum, gown, gloves, head cover, face shield, and an N-95 mask should be worn. A powered air purifying respirator (PAPR) can be used and may provide increased protection. Proper donning and doffing techniques should be reviewed prior to any procedure. Personnel involved in the case should be limited to the minimum required. The procedure should be performed by experienced operators and limited in length. Removal and reinsertion of the bronchoscope should be minimized.

The critically ill COVID-19 patient

While the majority of patients infected with SARS-CoV-2 will have only mild symptoms, we know that a subset of patients will develop respiratory failure. Of those, a small but significant number will require prolonged mechanical ventilation during their clinical course. Thus, the consideration for tracheostomy comes into play.

Multiple issues arise when discussing tracheostomy placement in the COVID-19 world. Should it be done at all? If yes, what is the best technique and who should do it? When and where should it be done? Importantly – how do we care for patients once it is in place to facilitate recovery and, hopefully, decannulation?

Tracheostomy tubes are used in the ICU for patients who require prolonged mechanical ventilation for many reasons – patient comfort, decreased need for sedation, and to facilitate transfer out of the ICU to less acute care areas. These reasons are just as important in patients afflicted with respiratory failure from COVID-19, if not more so. As the patient volumes surge, health-care systems can quickly become overwhelmed. The ability to safely move patients out of the ICU frees up those resources for others who are more acutely ill.

The optimal technique for tracheostomy placement largely depends on the technological and human capital of each institution. Emphasis should be placed on procedural experience, efficiency, safety, and minimizing risk to HCP. While mortality rates do not differ between the surgical and percutaneous techniques, the percutaneous approach has been shown to require less procedural time (Iftikhar IH, et al. Lung. 2019[Jun];197[3]:267-275), an important infection control advantage in COVID-19 patients. Additionally, percutaneous tracheostomies are typically performed at the bedside, which offers the immediate benefit of minimizing patient transfer. This decreases exposure to multiple HCP, as well as contamination of other health-care areas. If performing a bronchoscopic-guided percutaneous tracheostomy, apnea should be maintained from insertion of the guiding catheter to tracheostomy insertion in order to minimize aerosolization. A novel technique involving placing the bronchoscope beside the endotracheal tube instead of through it has also been described (Angel L, et al. Ann Thorac Surg. 2020[Sep];110[3]:1006–1011).

Timing of tracheostomy placement in COVID-19 patients has varied widely. Initially, concern for the safety of HCP performing these procedures led to recommendations of waiting at least 21 days of intubation or until COVID-19 testing became negative. However, more recently, multiple recommendations have been made for tracheostomy placement after day 10 of intubation (McGrath, et al. Lancet Respir Med. 2020[Jul];8[7]:717-725).

Finally, once a tracheostomy tube has been placed, the care does not stop there. As patients are transitioned to rehabilitation centers or skilled nursing facilities and are assessed for weaning, downsizing, and decannulation, care should be taken to avoid virus aerosolization during key high-risk steps. Modifications such as performing spontaneous breathing trials using pressure support (a closed circuit) rather than tracheostomy mask, bypassing speaking valve trials in favor of direct tracheostomy capping, and avoiding routine tracheostomy downsizing are examples of simple steps that can be taken to facilitate patient progress while minimizing HCP risk (Divo, et al. Respir Care. 2020[Aug]5;respcare.08157).
 

What’s ahead?

As we move forward, we will continue to balance caring for patients effectively and efficiently while minimizing risk to ourselves and others. Ultimately until a vaccine exists, we will have to focus on prevention of infection and spread; therefore, the core principles of hand hygiene, mask wearing, and social distancing have never been more important. We encourage continued study, scrutiny, and collaboration in order to optimize procedural techniques as more information becomes available.
 

Dr. Oberg is with the Section of Interventional Pulmonology, David Geffen School of Medicine at UCLA; Dr. Beattie is with the Section of Interventional Pulmonology, Memorial Sloan Kettering Cancer Center, New York; and Dr. Folch is with the Section of Interventional Pulmonology, Massachusetts General Hospital, Harvard Medical School.

The coronavirus disease 2019 (COVID-19) pandemic has changed the way we deliver healthcare for the foreseeable future. Not only have we had to rapidly learn how to evaluate, diagnose, and treat this new disease, we have also had to shift how we screen, triage, and care for other patients for both their safety and ours. As the virus is primarily spread via respiratory droplets, aerosol-generating procedures (AGP), such as bronchoscopy and tracheostomy, are high-risk for viral transmission. We have therefore had to reassess the risk/benefit ratio of performing these procedures – what is the risk to the patient by procedure postponement vs the risk to the health-care personnel (HCP) involved by moving ahead with the procedure? And, if proceeding, how should we protect ourselves? How do we screen patients to help us stratify risk? In order to answer these questions, we generally divide patients into three categories: the asymptomatic outpatient, the symptomatic patient, and the critically ill patient.

The asymptomatic outpatient

Early in the pandemic as cases began to spike in the US, many hospitals decided to postpone all elective procedures and surgeries. Guidelines quickly emerged stratifying bronchoscopic procedures into emergent, urgent, acute, subacute, and truly elective with recommendations on the subsequent timing of those procedures (Pritchett MA, et al. J Thorac Dis. 2020 May;12[5]:1781-1798). As we have obtained further data and our infrastructure has been bolstered, many physicians have begun performing more routine procedures. Preprocedural screening, both with symptom questionnaires and nasopharyngeal swabs, has been enacted as a measure to prevent inadvertent exposure to infected patients. While there are limited data regarding the reliability of this measure, emerging data have shown good concordance between nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) swabs and bronchoalveolar lavage (BAL) samples in low-risk patients (Oberg, et al. Personal communication, Sept 2020). Emergency procedures, such as foreign body aspiration, critical airway obstruction, and massive hemoptysis, were generally performed without delay throughout the pandemic. More recently, emphasis has been placed on prioritizing procedures for acute clinical diagnoses, such as biopsies for concerning lung nodules or masses in potentially early-stage patients, in those where staging is needed and in those where disease progression is suspected. Subacute procedures, such as inspection bronchoscopy for cough, minor hemoptysis, or airway stent surveillance, have generally been reintroduced while elective procedures, such as bronchial thermoplasty and bronchoscopic lung volume reduction, are considered elective, and their frequency and timing is determined mostly by the number of new cases of COVID-19 in the local community.

For all procedures, general modifications have been made. High-efficiency particulate air (HEPA) filters should be placed on all ventilatory circuits. When equivalent, flexible bronchoscopy is preferred over rigid bronchoscopy due to the closed circuit. Enhanced personal protective equipment (PPE) for all procedures is recommended – this typically includes a gown, gloves, hair bonnet, N-95 mask, and a face shield. Strict adherence to the Centers for Disease Control and Prevention (CDC) guidelines for postprocedure cleaning and sterilization is strongly recommended. In some cases, single-use bronchoscopes are being preferentially used, though no strong recommendations exist for this.
 

The symptomatic COVID-19 patient

In patients who have been diagnosed with SARS-CoV-2, we generally recommend postponing all procedures other than for life-threatening indications. For outpatients, we generally wait for two negative nasopharyngeal swabs prior to performing any nonemergent procedure. In inpatients, similar recommendations exist. Potential inpatient indications for bronchoscopy include diagnostic evaluation for alternate or coinfections, and therapeutic aspiration of clinically significant secretions. These should be carefully considered and performed only if deemed absolutely necessary. If bronchoscopy is needed in a patient with suspected or confirmed COVID-19, at a minimum, gown, gloves, head cover, face shield, and an N-95 mask should be worn. A powered air purifying respirator (PAPR) can be used and may provide increased protection. Proper donning and doffing techniques should be reviewed prior to any procedure. Personnel involved in the case should be limited to the minimum required. The procedure should be performed by experienced operators and limited in length. Removal and reinsertion of the bronchoscope should be minimized.

The critically ill COVID-19 patient

While the majority of patients infected with SARS-CoV-2 will have only mild symptoms, we know that a subset of patients will develop respiratory failure. Of those, a small but significant number will require prolonged mechanical ventilation during their clinical course. Thus, the consideration for tracheostomy comes into play.

Multiple issues arise when discussing tracheostomy placement in the COVID-19 world. Should it be done at all? If yes, what is the best technique and who should do it? When and where should it be done? Importantly – how do we care for patients once it is in place to facilitate recovery and, hopefully, decannulation?

Tracheostomy tubes are used in the ICU for patients who require prolonged mechanical ventilation for many reasons – patient comfort, decreased need for sedation, and to facilitate transfer out of the ICU to less acute care areas. These reasons are just as important in patients afflicted with respiratory failure from COVID-19, if not more so. As the patient volumes surge, health-care systems can quickly become overwhelmed. The ability to safely move patients out of the ICU frees up those resources for others who are more acutely ill.

The optimal technique for tracheostomy placement largely depends on the technological and human capital of each institution. Emphasis should be placed on procedural experience, efficiency, safety, and minimizing risk to HCP. While mortality rates do not differ between the surgical and percutaneous techniques, the percutaneous approach has been shown to require less procedural time (Iftikhar IH, et al. Lung. 2019[Jun];197[3]:267-275), an important infection control advantage in COVID-19 patients. Additionally, percutaneous tracheostomies are typically performed at the bedside, which offers the immediate benefit of minimizing patient transfer. This decreases exposure to multiple HCP, as well as contamination of other health-care areas. If performing a bronchoscopic-guided percutaneous tracheostomy, apnea should be maintained from insertion of the guiding catheter to tracheostomy insertion in order to minimize aerosolization. A novel technique involving placing the bronchoscope beside the endotracheal tube instead of through it has also been described (Angel L, et al. Ann Thorac Surg. 2020[Sep];110[3]:1006–1011).

Timing of tracheostomy placement in COVID-19 patients has varied widely. Initially, concern for the safety of HCP performing these procedures led to recommendations of waiting at least 21 days of intubation or until COVID-19 testing became negative. However, more recently, multiple recommendations have been made for tracheostomy placement after day 10 of intubation (McGrath, et al. Lancet Respir Med. 2020[Jul];8[7]:717-725).

Finally, once a tracheostomy tube has been placed, the care does not stop there. As patients are transitioned to rehabilitation centers or skilled nursing facilities and are assessed for weaning, downsizing, and decannulation, care should be taken to avoid virus aerosolization during key high-risk steps. Modifications such as performing spontaneous breathing trials using pressure support (a closed circuit) rather than tracheostomy mask, bypassing speaking valve trials in favor of direct tracheostomy capping, and avoiding routine tracheostomy downsizing are examples of simple steps that can be taken to facilitate patient progress while minimizing HCP risk (Divo, et al. Respir Care. 2020[Aug]5;respcare.08157).
 

What’s ahead?

As we move forward, we will continue to balance caring for patients effectively and efficiently while minimizing risk to ourselves and others. Ultimately until a vaccine exists, we will have to focus on prevention of infection and spread; therefore, the core principles of hand hygiene, mask wearing, and social distancing have never been more important. We encourage continued study, scrutiny, and collaboration in order to optimize procedural techniques as more information becomes available.
 

Dr. Oberg is with the Section of Interventional Pulmonology, David Geffen School of Medicine at UCLA; Dr. Beattie is with the Section of Interventional Pulmonology, Memorial Sloan Kettering Cancer Center, New York; and Dr. Folch is with the Section of Interventional Pulmonology, Massachusetts General Hospital, Harvard Medical School.

The coronavirus disease 2019 (COVID-19) pandemic has changed the way we deliver healthcare for the foreseeable future. Not only have we had to rapidly learn how to evaluate, diagnose, and treat this new disease, we have also had to shift how we screen, triage, and care for other patients for both their safety and ours. As the virus is primarily spread via respiratory droplets, aerosol-generating procedures (AGP), such as bronchoscopy and tracheostomy, are high-risk for viral transmission. We have therefore had to reassess the risk/benefit ratio of performing these procedures – what is the risk to the patient by procedure postponement vs the risk to the health-care personnel (HCP) involved by moving ahead with the procedure? And, if proceeding, how should we protect ourselves? How do we screen patients to help us stratify risk? In order to answer these questions, we generally divide patients into three categories: the asymptomatic outpatient, the symptomatic patient, and the critically ill patient.

The asymptomatic outpatient

Early in the pandemic as cases began to spike in the US, many hospitals decided to postpone all elective procedures and surgeries. Guidelines quickly emerged stratifying bronchoscopic procedures into emergent, urgent, acute, subacute, and truly elective with recommendations on the subsequent timing of those procedures (Pritchett MA, et al. J Thorac Dis. 2020 May;12[5]:1781-1798). As we have obtained further data and our infrastructure has been bolstered, many physicians have begun performing more routine procedures. Preprocedural screening, both with symptom questionnaires and nasopharyngeal swabs, has been enacted as a measure to prevent inadvertent exposure to infected patients. While there are limited data regarding the reliability of this measure, emerging data have shown good concordance between nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) swabs and bronchoalveolar lavage (BAL) samples in low-risk patients (Oberg, et al. Personal communication, Sept 2020). Emergency procedures, such as foreign body aspiration, critical airway obstruction, and massive hemoptysis, were generally performed without delay throughout the pandemic. More recently, emphasis has been placed on prioritizing procedures for acute clinical diagnoses, such as biopsies for concerning lung nodules or masses in potentially early-stage patients, in those where staging is needed and in those where disease progression is suspected. Subacute procedures, such as inspection bronchoscopy for cough, minor hemoptysis, or airway stent surveillance, have generally been reintroduced while elective procedures, such as bronchial thermoplasty and bronchoscopic lung volume reduction, are considered elective, and their frequency and timing is determined mostly by the number of new cases of COVID-19 in the local community.

For all procedures, general modifications have been made. High-efficiency particulate air (HEPA) filters should be placed on all ventilatory circuits. When equivalent, flexible bronchoscopy is preferred over rigid bronchoscopy due to the closed circuit. Enhanced personal protective equipment (PPE) for all procedures is recommended – this typically includes a gown, gloves, hair bonnet, N-95 mask, and a face shield. Strict adherence to the Centers for Disease Control and Prevention (CDC) guidelines for postprocedure cleaning and sterilization is strongly recommended. In some cases, single-use bronchoscopes are being preferentially used, though no strong recommendations exist for this.
 

The symptomatic COVID-19 patient

In patients who have been diagnosed with SARS-CoV-2, we generally recommend postponing all procedures other than for life-threatening indications. For outpatients, we generally wait for two negative nasopharyngeal swabs prior to performing any nonemergent procedure. In inpatients, similar recommendations exist. Potential inpatient indications for bronchoscopy include diagnostic evaluation for alternate or coinfections, and therapeutic aspiration of clinically significant secretions. These should be carefully considered and performed only if deemed absolutely necessary. If bronchoscopy is needed in a patient with suspected or confirmed COVID-19, at a minimum, gown, gloves, head cover, face shield, and an N-95 mask should be worn. A powered air purifying respirator (PAPR) can be used and may provide increased protection. Proper donning and doffing techniques should be reviewed prior to any procedure. Personnel involved in the case should be limited to the minimum required. The procedure should be performed by experienced operators and limited in length. Removal and reinsertion of the bronchoscope should be minimized.

The critically ill COVID-19 patient

While the majority of patients infected with SARS-CoV-2 will have only mild symptoms, we know that a subset of patients will develop respiratory failure. Of those, a small but significant number will require prolonged mechanical ventilation during their clinical course. Thus, the consideration for tracheostomy comes into play.

Multiple issues arise when discussing tracheostomy placement in the COVID-19 world. Should it be done at all? If yes, what is the best technique and who should do it? When and where should it be done? Importantly – how do we care for patients once it is in place to facilitate recovery and, hopefully, decannulation?

Tracheostomy tubes are used in the ICU for patients who require prolonged mechanical ventilation for many reasons – patient comfort, decreased need for sedation, and to facilitate transfer out of the ICU to less acute care areas. These reasons are just as important in patients afflicted with respiratory failure from COVID-19, if not more so. As the patient volumes surge, health-care systems can quickly become overwhelmed. The ability to safely move patients out of the ICU frees up those resources for others who are more acutely ill.

The optimal technique for tracheostomy placement largely depends on the technological and human capital of each institution. Emphasis should be placed on procedural experience, efficiency, safety, and minimizing risk to HCP. While mortality rates do not differ between the surgical and percutaneous techniques, the percutaneous approach has been shown to require less procedural time (Iftikhar IH, et al. Lung. 2019[Jun];197[3]:267-275), an important infection control advantage in COVID-19 patients. Additionally, percutaneous tracheostomies are typically performed at the bedside, which offers the immediate benefit of minimizing patient transfer. This decreases exposure to multiple HCP, as well as contamination of other health-care areas. If performing a bronchoscopic-guided percutaneous tracheostomy, apnea should be maintained from insertion of the guiding catheter to tracheostomy insertion in order to minimize aerosolization. A novel technique involving placing the bronchoscope beside the endotracheal tube instead of through it has also been described (Angel L, et al. Ann Thorac Surg. 2020[Sep];110[3]:1006–1011).

Timing of tracheostomy placement in COVID-19 patients has varied widely. Initially, concern for the safety of HCP performing these procedures led to recommendations of waiting at least 21 days of intubation or until COVID-19 testing became negative. However, more recently, multiple recommendations have been made for tracheostomy placement after day 10 of intubation (McGrath, et al. Lancet Respir Med. 2020[Jul];8[7]:717-725).

Finally, once a tracheostomy tube has been placed, the care does not stop there. As patients are transitioned to rehabilitation centers or skilled nursing facilities and are assessed for weaning, downsizing, and decannulation, care should be taken to avoid virus aerosolization during key high-risk steps. Modifications such as performing spontaneous breathing trials using pressure support (a closed circuit) rather than tracheostomy mask, bypassing speaking valve trials in favor of direct tracheostomy capping, and avoiding routine tracheostomy downsizing are examples of simple steps that can be taken to facilitate patient progress while minimizing HCP risk (Divo, et al. Respir Care. 2020[Aug]5;respcare.08157).
 

What’s ahead?

As we move forward, we will continue to balance caring for patients effectively and efficiently while minimizing risk to ourselves and others. Ultimately until a vaccine exists, we will have to focus on prevention of infection and spread; therefore, the core principles of hand hygiene, mask wearing, and social distancing have never been more important. We encourage continued study, scrutiny, and collaboration in order to optimize procedural techniques as more information becomes available.
 

Dr. Oberg is with the Section of Interventional Pulmonology, David Geffen School of Medicine at UCLA; Dr. Beattie is with the Section of Interventional Pulmonology, Memorial Sloan Kettering Cancer Center, New York; and Dr. Folch is with the Section of Interventional Pulmonology, Massachusetts General Hospital, Harvard Medical School.

The hypersomnias are an etiologically diverse group of disorders of wakefulness and sleep, characterized principally by excessive daytime sleepiness (EDS), often despite sufficient or even long total sleep durations. Hypersomnolence may be severely disabling and isolating for patients, is associated with decreased quality of life and economic disadvantage, and, in some cases, may pose a personal and public health danger through drowsy driving. Though historically, management of these patients has been principally supportive and aimed at reducing daytime functional impairment, new and evolving treatments are quickly changing management paradigms in this population. This brief review highlights some of the newest pharmacotherapeutic advances in this dynamic field.

Hypersomnolence is a common presenting concern primary care and sleep clinics, with an estimated prevalence of EDS in the general adult population of as high as 6%.¹ The initial diagnosis of hypersomnia is, broadly, a clinical one, with careful consideration to the patient’s report of daytime sleepiness and functional impairment, sleep/wake cycle, and any medical comorbidities. The primary hypersomnias include narcolepsy type 1 (narcolepsy with cataplexy, NT1) and narcolepsy type 2 (without cataplexy, NT2), Kleine-Levin Syndrome (KLS), and idiopathic hypersomnia. Secondary hypersomnia disorders are more commonly encountered in clinical practice and include hypersomnia attributable to another medical condition (including psychiatric and neurologic disorders), hypersomnia related to medication effects, and EDS related to behaviorally insufficient sleep. Distinguishing primary and secondary etiologies, when possible, is important as treatment pathways may vary considerably between hypersomnias.

Generally, overnight in-lab polysomnography is warranted to exclude untreated or sub-optimally treated sleep-disordered breathing or movement disorders which may undermine sleep quality. In the absence of any such findings, this is usually followed by daytime multiple sleep latency testing (MSLT). The MSLT is comprised of four to five scheduled daytime naps in the sleep lab and is designed to quantify a patient’s propensity to sleep during the day and to identify architectural sleep abnormalities which indicate narcolepsy. Specifically, narcolepsy is identified by MSLT when a patient exhibits a sleep onset latency of ≤ 8 minutes and at least two sleep-onset REM periods (SOREMPs), or, one SOREMP on MSLT with a second noted on the preceding night’s PSG. Actigraphy or sleep logs may be helpful in quantifying a patient’s total sleep time in their home environment. Adjunctive laboratory tests for narcolepsy including HLA typing and CSF hypocretin testing may sometimes be indicated.

General hypersomnia management usually consists of the use of wakefulness promoting agents, such as stimulants (eg, dexmethylphenidate) and dopamine-modulating agents (eg, modafinil, armodafinil), and adjunctive supportive strategies, including planned daytime naps and elimination of modifiable secondary causes. In those patients with hypersomnolence associated with depression or anxiety, the use of antidepressants, including SSRI, SNRI, and DNRIs, is often effective, and these medications can also improve cataplexy symptoms in narcoleptics. KLS may respond to treatment with lithium, shortening the duration of the striking hypersomnolent episodes characteristic of this rare syndrome, and there is some indication that ketamine may also be a helpful adjunctive in some cases. In treatment-refractory cases of hypersomnolence associated with GABA-A receptor potentiation, drugs such as flumazenil and clarithromycin appear to improve subjective measures of hypersomnolence.^2,3 In patients with narcolepsy, sodium oxybate (available as Xyrem and, more recently, as a generic medication) has proven to be clinically very useful, reducing EDS and the frequency and severity of cataplexy and sleep disturbance associated with this condition. In July 2020, the FDA approved a new, low-sodium formulation of sodium oxybate (Xywav) for patients 7 years of age and older with a diagnosis of narcolepsy, a helpful option in those patients with cardiovascular and renal disease.

Despite this broadening armamentarium, in many cases daytime sleepiness and functional impairment is refractory to typical pharmacotherapy. In this context, we would like to highlight two newer pharmacotherapeutic options, solriamfetol and pitolisant.


 

Solriamfetol

Solriamfetol (Sunosi) is a Schedule IV FDA-approved medication indicated for treatment of EDS in adults with narcolepsy or obstructive sleep apnea. The precise mechanism of action is unknown, but this medication is believed to inhibit both dopamine and norepinerphrine reuptake in the brain, similar to the widely-prescribed NDRI buproprion. In a 12-week RCT study on its effects on narcolepsy in adults, solriamfetol improved important measures of wakefulness and sleepiness, without associated polysomnographic evidence of significant sleep disruption.⁴ In another 12-week RCT study of solriamfetol in adult patients with EDS related to OSA, there was a dose-dependent improvement in measures of wakefulness.⁵ Some notable side-effects seen with this medication include anxiety and elevated mood, as well as increases in blood pressure. A subsequent study of this medication found that it was efficacious at maintenance of improvements at 6 months.⁶ Given the theorized mechanism of action as an NDRI, future observation and studies could provide insights on its effect on depression, as well.

Pitolisant

Histaminergic neurons within the CNS play an important role in the promotion of wakefulness. Pitolisant (Wakix) is an interesting wakefulness-promoting agent for adult patients with narcolepsy. It acts as an inverse agonist and antagonist of histamine H3 receptors, resulting in a reduction of the usual feedback inhibition effected through the H3 receptor, thereby enhancing CNS release of histamine and other neurotransmitters. This medication was approved by the FDA in August 2019 and is currently indicated for adult patients with narcolepsy. The HARMONY I trial comparing pitolisant with both placebo and modafinil in adults with narcolepsy and EDS demonstrated improvement in measures of sleepiness and maintenance of wakefulness over placebo, and noninferiority to modafinil.⁷ In addition, pitolisant had a favorable side-effect profile compared with modafinil. Subsequent studies have reaffirmed the safety profile of pitolisant, including its minimal abuse potential. In one recent placebo-controlled trial of the use of pitolisant in a population of 268 adults with positive airway pressure (PAP) non-adherence, pitolisant was found to improve measures of EDS and related patient-reported measurements in patients with OSA who were CPAP nonadherent.⁸ Though generally well-tolerated by patients, in initial clinical trials pitolisant was associated with increased headache, insomnia, and nausea relative to placebo, among other less commonly reported adverse effects. Pitolisant is QT interval-prolonging, so caution must be taken when using this medication in combination other medications which may induce QT interval prolongation, including SSRIs.

Future directions

Greater awareness of the hypersomnias and their management has led to improved outcomes and access to care for these patients, yet these disorders remain burdensome and the treatments imperfect. Looking forward, novel pharmacotherapies that target underlying mechanisms rather than symptom palliation will allow for more precise treatments. Ongoing investigations of hypocretin receptor agonists seek to target one critical central mediator of wakefulness. Recent studies have highlighted the association of dysautonomia with hypersomnia, offering interesting insight into possible future targets to improve the function and quality of life of these patients.⁹ Similarly, understanding of the interplay between psychiatric disorders and primary and secondary hypersomnias may offer new therapeutic pathways.

As treatment plans targeting hypersomnia become more comprehensive and holistic, with an increased emphasis on self-care, sleep hygiene, and mental health awareness, in addition to mechanism-specific treatments, we hope they will ultimately provide improved symptom and burden relief for our patients.
 

Dr. Shih Yee-Marie Tan Gipson is a psychiatrist and Dr. Kevin Gipson is a sleep medicine specialist, both with Massachusetts General Hospital, Boston.

References

¹ Dauvilliers, et al. Hypersomnia. Dialogues Clin Neurosci. 2005;7(4):347-356.

² Trotti, et al. Clarithromycin in gamma-aminobutyric acid-related hypersomnolence: A randomized, crossover trial. Ann Neurol. 2015;78(3):454-465. doi: 10.1002/ana.24459.

³ Trotti, et al. Flumazenil for the treatment of refractory hypersomnolence: Clinical experience with 153 patients. J Clin Sleep Med. 2016;12(10):1389-1394. doi: 10.5664/jcsm.6196.

⁴ Thorpy, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019; 85(3):359-370. doi: 10.1002/ana.25423.

⁵ Schweitzer, et al. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3): A randomized controlled trial. Am J Respir Crit Care Med. 2019;199(11):1421-1431. doi: 10.1164/rccm.201806-1100OC.

⁶ Malhotra, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. Sleep. 2020; 43(2): doi: 10.1093/sleep/zsz220.

⁷ Dauvilliers, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. doi: 10.1016/S1474-4422(13)70225-4.

⁸ Dauvilliers, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: A randomized trial. Am J Respir Crit Care Med. 2020. doi: 10.1164/rccm.201907-1284OC.

⁹ Miglis, et al. Frequency and severity of autonomic symptoms in idiopathic hypersomnia. J Clin Sleep Med. 2020; 16(5):749-756. doi: 10.5664/jcsm.8344.
 

The hypersomnias are an etiologically diverse group of disorders of wakefulness and sleep, characterized principally by excessive daytime sleepiness (EDS), often despite sufficient or even long total sleep durations. Hypersomnolence may be severely disabling and isolating for patients, is associated with decreased quality of life and economic disadvantage, and, in some cases, may pose a personal and public health danger through drowsy driving. Though historically, management of these patients has been principally supportive and aimed at reducing daytime functional impairment, new and evolving treatments are quickly changing management paradigms in this population. This brief review highlights some of the newest pharmacotherapeutic advances in this dynamic field.

Hypersomnolence is a common presenting concern primary care and sleep clinics, with an estimated prevalence of EDS in the general adult population of as high as 6%.¹ The initial diagnosis of hypersomnia is, broadly, a clinical one, with careful consideration to the patient’s report of daytime sleepiness and functional impairment, sleep/wake cycle, and any medical comorbidities. The primary hypersomnias include narcolepsy type 1 (narcolepsy with cataplexy, NT1) and narcolepsy type 2 (without cataplexy, NT2), Kleine-Levin Syndrome (KLS), and idiopathic hypersomnia. Secondary hypersomnia disorders are more commonly encountered in clinical practice and include hypersomnia attributable to another medical condition (including psychiatric and neurologic disorders), hypersomnia related to medication effects, and EDS related to behaviorally insufficient sleep. Distinguishing primary and secondary etiologies, when possible, is important as treatment pathways may vary considerably between hypersomnias.

Generally, overnight in-lab polysomnography is warranted to exclude untreated or sub-optimally treated sleep-disordered breathing or movement disorders which may undermine sleep quality. In the absence of any such findings, this is usually followed by daytime multiple sleep latency testing (MSLT). The MSLT is comprised of four to five scheduled daytime naps in the sleep lab and is designed to quantify a patient’s propensity to sleep during the day and to identify architectural sleep abnormalities which indicate narcolepsy. Specifically, narcolepsy is identified by MSLT when a patient exhibits a sleep onset latency of ≤ 8 minutes and at least two sleep-onset REM periods (SOREMPs), or, one SOREMP on MSLT with a second noted on the preceding night’s PSG. Actigraphy or sleep logs may be helpful in quantifying a patient’s total sleep time in their home environment. Adjunctive laboratory tests for narcolepsy including HLA typing and CSF hypocretin testing may sometimes be indicated.

General hypersomnia management usually consists of the use of wakefulness promoting agents, such as stimulants (eg, dexmethylphenidate) and dopamine-modulating agents (eg, modafinil, armodafinil), and adjunctive supportive strategies, including planned daytime naps and elimination of modifiable secondary causes. In those patients with hypersomnolence associated with depression or anxiety, the use of antidepressants, including SSRI, SNRI, and DNRIs, is often effective, and these medications can also improve cataplexy symptoms in narcoleptics. KLS may respond to treatment with lithium, shortening the duration of the striking hypersomnolent episodes characteristic of this rare syndrome, and there is some indication that ketamine may also be a helpful adjunctive in some cases. In treatment-refractory cases of hypersomnolence associated with GABA-A receptor potentiation, drugs such as flumazenil and clarithromycin appear to improve subjective measures of hypersomnolence.^2,3 In patients with narcolepsy, sodium oxybate (available as Xyrem and, more recently, as a generic medication) has proven to be clinically very useful, reducing EDS and the frequency and severity of cataplexy and sleep disturbance associated with this condition. In July 2020, the FDA approved a new, low-sodium formulation of sodium oxybate (Xywav) for patients 7 years of age and older with a diagnosis of narcolepsy, a helpful option in those patients with cardiovascular and renal disease.

Despite this broadening armamentarium, in many cases daytime sleepiness and functional impairment is refractory to typical pharmacotherapy. In this context, we would like to highlight two newer pharmacotherapeutic options, solriamfetol and pitolisant.


 

Solriamfetol

Solriamfetol (Sunosi) is a Schedule IV FDA-approved medication indicated for treatment of EDS in adults with narcolepsy or obstructive sleep apnea. The precise mechanism of action is unknown, but this medication is believed to inhibit both dopamine and norepinerphrine reuptake in the brain, similar to the widely-prescribed NDRI buproprion. In a 12-week RCT study on its effects on narcolepsy in adults, solriamfetol improved important measures of wakefulness and sleepiness, without associated polysomnographic evidence of significant sleep disruption.⁴ In another 12-week RCT study of solriamfetol in adult patients with EDS related to OSA, there was a dose-dependent improvement in measures of wakefulness.⁵ Some notable side-effects seen with this medication include anxiety and elevated mood, as well as increases in blood pressure. A subsequent study of this medication found that it was efficacious at maintenance of improvements at 6 months.⁶ Given the theorized mechanism of action as an NDRI, future observation and studies could provide insights on its effect on depression, as well.

Pitolisant

Histaminergic neurons within the CNS play an important role in the promotion of wakefulness. Pitolisant (Wakix) is an interesting wakefulness-promoting agent for adult patients with narcolepsy. It acts as an inverse agonist and antagonist of histamine H3 receptors, resulting in a reduction of the usual feedback inhibition effected through the H3 receptor, thereby enhancing CNS release of histamine and other neurotransmitters. This medication was approved by the FDA in August 2019 and is currently indicated for adult patients with narcolepsy. The HARMONY I trial comparing pitolisant with both placebo and modafinil in adults with narcolepsy and EDS demonstrated improvement in measures of sleepiness and maintenance of wakefulness over placebo, and noninferiority to modafinil.⁷ In addition, pitolisant had a favorable side-effect profile compared with modafinil. Subsequent studies have reaffirmed the safety profile of pitolisant, including its minimal abuse potential. In one recent placebo-controlled trial of the use of pitolisant in a population of 268 adults with positive airway pressure (PAP) non-adherence, pitolisant was found to improve measures of EDS and related patient-reported measurements in patients with OSA who were CPAP nonadherent.⁸ Though generally well-tolerated by patients, in initial clinical trials pitolisant was associated with increased headache, insomnia, and nausea relative to placebo, among other less commonly reported adverse effects. Pitolisant is QT interval-prolonging, so caution must be taken when using this medication in combination other medications which may induce QT interval prolongation, including SSRIs.

Future directions

Greater awareness of the hypersomnias and their management has led to improved outcomes and access to care for these patients, yet these disorders remain burdensome and the treatments imperfect. Looking forward, novel pharmacotherapies that target underlying mechanisms rather than symptom palliation will allow for more precise treatments. Ongoing investigations of hypocretin receptor agonists seek to target one critical central mediator of wakefulness. Recent studies have highlighted the association of dysautonomia with hypersomnia, offering interesting insight into possible future targets to improve the function and quality of life of these patients.⁹ Similarly, understanding of the interplay between psychiatric disorders and primary and secondary hypersomnias may offer new therapeutic pathways.

As treatment plans targeting hypersomnia become more comprehensive and holistic, with an increased emphasis on self-care, sleep hygiene, and mental health awareness, in addition to mechanism-specific treatments, we hope they will ultimately provide improved symptom and burden relief for our patients.
 

Dr. Shih Yee-Marie Tan Gipson is a psychiatrist and Dr. Kevin Gipson is a sleep medicine specialist, both with Massachusetts General Hospital, Boston.

References

¹ Dauvilliers, et al. Hypersomnia. Dialogues Clin Neurosci. 2005;7(4):347-356.

² Trotti, et al. Clarithromycin in gamma-aminobutyric acid-related hypersomnolence: A randomized, crossover trial. Ann Neurol. 2015;78(3):454-465. doi: 10.1002/ana.24459.

³ Trotti, et al. Flumazenil for the treatment of refractory hypersomnolence: Clinical experience with 153 patients. J Clin Sleep Med. 2016;12(10):1389-1394. doi: 10.5664/jcsm.6196.

⁴ Thorpy, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019; 85(3):359-370. doi: 10.1002/ana.25423.

⁵ Schweitzer, et al. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3): A randomized controlled trial. Am J Respir Crit Care Med. 2019;199(11):1421-1431. doi: 10.1164/rccm.201806-1100OC.

⁶ Malhotra, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. Sleep. 2020; 43(2): doi: 10.1093/sleep/zsz220.

⁷ Dauvilliers, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. doi: 10.1016/S1474-4422(13)70225-4.

⁸ Dauvilliers, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: A randomized trial. Am J Respir Crit Care Med. 2020. doi: 10.1164/rccm.201907-1284OC.

⁹ Miglis, et al. Frequency and severity of autonomic symptoms in idiopathic hypersomnia. J Clin Sleep Med. 2020; 16(5):749-756. doi: 10.5664/jcsm.8344.
 

The hypersomnias are an etiologically diverse group of disorders of wakefulness and sleep, characterized principally by excessive daytime sleepiness (EDS), often despite sufficient or even long total sleep durations. Hypersomnolence may be severely disabling and isolating for patients, is associated with decreased quality of life and economic disadvantage, and, in some cases, may pose a personal and public health danger through drowsy driving. Though historically, management of these patients has been principally supportive and aimed at reducing daytime functional impairment, new and evolving treatments are quickly changing management paradigms in this population. This brief review highlights some of the newest pharmacotherapeutic advances in this dynamic field.

Hypersomnolence is a common presenting concern primary care and sleep clinics, with an estimated prevalence of EDS in the general adult population of as high as 6%.¹ The initial diagnosis of hypersomnia is, broadly, a clinical one, with careful consideration to the patient’s report of daytime sleepiness and functional impairment, sleep/wake cycle, and any medical comorbidities. The primary hypersomnias include narcolepsy type 1 (narcolepsy with cataplexy, NT1) and narcolepsy type 2 (without cataplexy, NT2), Kleine-Levin Syndrome (KLS), and idiopathic hypersomnia. Secondary hypersomnia disorders are more commonly encountered in clinical practice and include hypersomnia attributable to another medical condition (including psychiatric and neurologic disorders), hypersomnia related to medication effects, and EDS related to behaviorally insufficient sleep. Distinguishing primary and secondary etiologies, when possible, is important as treatment pathways may vary considerably between hypersomnias.

Generally, overnight in-lab polysomnography is warranted to exclude untreated or sub-optimally treated sleep-disordered breathing or movement disorders which may undermine sleep quality. In the absence of any such findings, this is usually followed by daytime multiple sleep latency testing (MSLT). The MSLT is comprised of four to five scheduled daytime naps in the sleep lab and is designed to quantify a patient’s propensity to sleep during the day and to identify architectural sleep abnormalities which indicate narcolepsy. Specifically, narcolepsy is identified by MSLT when a patient exhibits a sleep onset latency of ≤ 8 minutes and at least two sleep-onset REM periods (SOREMPs), or, one SOREMP on MSLT with a second noted on the preceding night’s PSG. Actigraphy or sleep logs may be helpful in quantifying a patient’s total sleep time in their home environment. Adjunctive laboratory tests for narcolepsy including HLA typing and CSF hypocretin testing may sometimes be indicated.

General hypersomnia management usually consists of the use of wakefulness promoting agents, such as stimulants (eg, dexmethylphenidate) and dopamine-modulating agents (eg, modafinil, armodafinil), and adjunctive supportive strategies, including planned daytime naps and elimination of modifiable secondary causes. In those patients with hypersomnolence associated with depression or anxiety, the use of antidepressants, including SSRI, SNRI, and DNRIs, is often effective, and these medications can also improve cataplexy symptoms in narcoleptics. KLS may respond to treatment with lithium, shortening the duration of the striking hypersomnolent episodes characteristic of this rare syndrome, and there is some indication that ketamine may also be a helpful adjunctive in some cases. In treatment-refractory cases of hypersomnolence associated with GABA-A receptor potentiation, drugs such as flumazenil and clarithromycin appear to improve subjective measures of hypersomnolence.^2,3 In patients with narcolepsy, sodium oxybate (available as Xyrem and, more recently, as a generic medication) has proven to be clinically very useful, reducing EDS and the frequency and severity of cataplexy and sleep disturbance associated with this condition. In July 2020, the FDA approved a new, low-sodium formulation of sodium oxybate (Xywav) for patients 7 years of age and older with a diagnosis of narcolepsy, a helpful option in those patients with cardiovascular and renal disease.

Despite this broadening armamentarium, in many cases daytime sleepiness and functional impairment is refractory to typical pharmacotherapy. In this context, we would like to highlight two newer pharmacotherapeutic options, solriamfetol and pitolisant.


 

Solriamfetol

Solriamfetol (Sunosi) is a Schedule IV FDA-approved medication indicated for treatment of EDS in adults with narcolepsy or obstructive sleep apnea. The precise mechanism of action is unknown, but this medication is believed to inhibit both dopamine and norepinerphrine reuptake in the brain, similar to the widely-prescribed NDRI buproprion. In a 12-week RCT study on its effects on narcolepsy in adults, solriamfetol improved important measures of wakefulness and sleepiness, without associated polysomnographic evidence of significant sleep disruption.⁴ In another 12-week RCT study of solriamfetol in adult patients with EDS related to OSA, there was a dose-dependent improvement in measures of wakefulness.⁵ Some notable side-effects seen with this medication include anxiety and elevated mood, as well as increases in blood pressure. A subsequent study of this medication found that it was efficacious at maintenance of improvements at 6 months.⁶ Given the theorized mechanism of action as an NDRI, future observation and studies could provide insights on its effect on depression, as well.

Pitolisant

Histaminergic neurons within the CNS play an important role in the promotion of wakefulness. Pitolisant (Wakix) is an interesting wakefulness-promoting agent for adult patients with narcolepsy. It acts as an inverse agonist and antagonist of histamine H3 receptors, resulting in a reduction of the usual feedback inhibition effected through the H3 receptor, thereby enhancing CNS release of histamine and other neurotransmitters. This medication was approved by the FDA in August 2019 and is currently indicated for adult patients with narcolepsy. The HARMONY I trial comparing pitolisant with both placebo and modafinil in adults with narcolepsy and EDS demonstrated improvement in measures of sleepiness and maintenance of wakefulness over placebo, and noninferiority to modafinil.⁷ In addition, pitolisant had a favorable side-effect profile compared with modafinil. Subsequent studies have reaffirmed the safety profile of pitolisant, including its minimal abuse potential. In one recent placebo-controlled trial of the use of pitolisant in a population of 268 adults with positive airway pressure (PAP) non-adherence, pitolisant was found to improve measures of EDS and related patient-reported measurements in patients with OSA who were CPAP nonadherent.⁸ Though generally well-tolerated by patients, in initial clinical trials pitolisant was associated with increased headache, insomnia, and nausea relative to placebo, among other less commonly reported adverse effects. Pitolisant is QT interval-prolonging, so caution must be taken when using this medication in combination other medications which may induce QT interval prolongation, including SSRIs.

Future directions

Greater awareness of the hypersomnias and their management has led to improved outcomes and access to care for these patients, yet these disorders remain burdensome and the treatments imperfect. Looking forward, novel pharmacotherapies that target underlying mechanisms rather than symptom palliation will allow for more precise treatments. Ongoing investigations of hypocretin receptor agonists seek to target one critical central mediator of wakefulness. Recent studies have highlighted the association of dysautonomia with hypersomnia, offering interesting insight into possible future targets to improve the function and quality of life of these patients.⁹ Similarly, understanding of the interplay between psychiatric disorders and primary and secondary hypersomnias may offer new therapeutic pathways.

As treatment plans targeting hypersomnia become more comprehensive and holistic, with an increased emphasis on self-care, sleep hygiene, and mental health awareness, in addition to mechanism-specific treatments, we hope they will ultimately provide improved symptom and burden relief for our patients.
 

Dr. Shih Yee-Marie Tan Gipson is a psychiatrist and Dr. Kevin Gipson is a sleep medicine specialist, both with Massachusetts General Hospital, Boston.

References

¹ Dauvilliers, et al. Hypersomnia. Dialogues Clin Neurosci. 2005;7(4):347-356.

² Trotti, et al. Clarithromycin in gamma-aminobutyric acid-related hypersomnolence: A randomized, crossover trial. Ann Neurol. 2015;78(3):454-465. doi: 10.1002/ana.24459.

³ Trotti, et al. Flumazenil for the treatment of refractory hypersomnolence: Clinical experience with 153 patients. J Clin Sleep Med. 2016;12(10):1389-1394. doi: 10.5664/jcsm.6196.

⁴ Thorpy, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019; 85(3):359-370. doi: 10.1002/ana.25423.

⁵ Schweitzer, et al. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3): A randomized controlled trial. Am J Respir Crit Care Med. 2019;199(11):1421-1431. doi: 10.1164/rccm.201806-1100OC.

⁶ Malhotra, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. Sleep. 2020; 43(2): doi: 10.1093/sleep/zsz220.

⁷ Dauvilliers, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. doi: 10.1016/S1474-4422(13)70225-4.

⁸ Dauvilliers, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: A randomized trial. Am J Respir Crit Care Med. 2020. doi: 10.1164/rccm.201907-1284OC.

⁹ Miglis, et al. Frequency and severity of autonomic symptoms in idiopathic hypersomnia. J Clin Sleep Med. 2020; 16(5):749-756. doi: 10.5664/jcsm.8344.