The Journal of Family Practice

Not long ago, the grandmother of my son’s friend died of COVID-19 infection. She was elderly and unvaccinated. Her grandson had no regrets over her unvaccinated status. “Why would she inject poison into her body?” he said, and then expressed a strong opinion that she had died because the hospital physicians refused to give her ivermectin and hydroxychloroquine. My son, wisely, did not push the issue.

Soon thereafter, my personal family physician emailed a newsletter to his patients (me included) with 3 important messages: (1) COVID vaccines were available in the office; (2) He was not going to prescribe hydroxychloroquine, no matter how adamantly it was requested; and (3) He warned against threatening him or his staff with lawsuits or violence over refusal to prescribe any unproven medication.

Mistakes will be made; corrections will be issued. This is the scientific process in action.

How, as a country, have we come to this? A sizeable portion of the public trusts the advice of quacks, hacks, and political opportunists over that of the nation’s most expert scientists and physicians. The National Institutes of Health maintains a website with up-to-date recommendations on the use of treatments for COVID-19. They assess the existing evidence and make recommendations for or against a wide array of interventions. (They recommend against the use of both ivermectin and hydroxychloroquine.) The Centers for Disease Control and Prevention publishes extensively about the current knowledge on the safety and efficacy of vaccines. Neither agency is part of a “deep state” or conspiracy. They are comprised of some of the nation’s leading scientists, including physicians, trying to protect the public from disease and foster good health.

Sadly, some physicians have been a source of inaccurate vaccine information; some even prescribe ineffective treatments despite the evidence. These physicians are either letting their politics override their good sense or are improperly assessing the scientific literature, or both. Medical licensing agencies, and specialty certification boards, need to find ways to prevent this—ways that can survive judicial scrutiny and allow for legitimate scientific debate.

I have been tempted to just accept the current situation as the inevitable outcome of social media–fueled tribalism. But when we know that the COVID death rate among the unvaccinated is 9 times that of people who have received a booster dose,¹ I can’t sit idly and watch the Internet pundits prevail. Instead, I continue to advise and teach my students to have confidence in trustworthy authorities and websites. Mistakes will be made; corrections will be issued. However, this is not evidence of malintent or incompetence, but rather, the scientific process in action.

I tell my students that one of the biggest challenges facing them and society is to figure out how to stop, or at least minimize the effects of, incorrect information, misleading statements, and outright lies in a society that values free speech. Physicians—young and old alike—must remain committed to communicating factual information to a not-always-receptive audience. And I wish my young colleagues luck; I hope that their passion for family medicine and their insights into social media may be just the combination that’s needed to redirect the public’s trust back to where it belongs during a health care crisis.

Not long ago, the grandmother of my son’s friend died of COVID-19 infection. She was elderly and unvaccinated. Her grandson had no regrets over her unvaccinated status. “Why would she inject poison into her body?” he said, and then expressed a strong opinion that she had died because the hospital physicians refused to give her ivermectin and hydroxychloroquine. My son, wisely, did not push the issue.

Soon thereafter, my personal family physician emailed a newsletter to his patients (me included) with 3 important messages: (1) COVID vaccines were available in the office; (2) He was not going to prescribe hydroxychloroquine, no matter how adamantly it was requested; and (3) He warned against threatening him or his staff with lawsuits or violence over refusal to prescribe any unproven medication.

Mistakes will be made; corrections will be issued. This is the scientific process in action.

How, as a country, have we come to this? A sizeable portion of the public trusts the advice of quacks, hacks, and political opportunists over that of the nation’s most expert scientists and physicians. The National Institutes of Health maintains a website with up-to-date recommendations on the use of treatments for COVID-19. They assess the existing evidence and make recommendations for or against a wide array of interventions. (They recommend against the use of both ivermectin and hydroxychloroquine.) The Centers for Disease Control and Prevention publishes extensively about the current knowledge on the safety and efficacy of vaccines. Neither agency is part of a “deep state” or conspiracy. They are comprised of some of the nation’s leading scientists, including physicians, trying to protect the public from disease and foster good health.

Sadly, some physicians have been a source of inaccurate vaccine information; some even prescribe ineffective treatments despite the evidence. These physicians are either letting their politics override their good sense or are improperly assessing the scientific literature, or both. Medical licensing agencies, and specialty certification boards, need to find ways to prevent this—ways that can survive judicial scrutiny and allow for legitimate scientific debate.

I have been tempted to just accept the current situation as the inevitable outcome of social media–fueled tribalism. But when we know that the COVID death rate among the unvaccinated is 9 times that of people who have received a booster dose,¹ I can’t sit idly and watch the Internet pundits prevail. Instead, I continue to advise and teach my students to have confidence in trustworthy authorities and websites. Mistakes will be made; corrections will be issued. However, this is not evidence of malintent or incompetence, but rather, the scientific process in action.

I tell my students that one of the biggest challenges facing them and society is to figure out how to stop, or at least minimize the effects of, incorrect information, misleading statements, and outright lies in a society that values free speech. Physicians—young and old alike—must remain committed to communicating factual information to a not-always-receptive audience. And I wish my young colleagues luck; I hope that their passion for family medicine and their insights into social media may be just the combination that’s needed to redirect the public’s trust back to where it belongs during a health care crisis.

Not long ago, the grandmother of my son’s friend died of COVID-19 infection. She was elderly and unvaccinated. Her grandson had no regrets over her unvaccinated status. “Why would she inject poison into her body?” he said, and then expressed a strong opinion that she had died because the hospital physicians refused to give her ivermectin and hydroxychloroquine. My son, wisely, did not push the issue.

Soon thereafter, my personal family physician emailed a newsletter to his patients (me included) with 3 important messages: (1) COVID vaccines were available in the office; (2) He was not going to prescribe hydroxychloroquine, no matter how adamantly it was requested; and (3) He warned against threatening him or his staff with lawsuits or violence over refusal to prescribe any unproven medication.

Mistakes will be made; corrections will be issued. This is the scientific process in action.

How, as a country, have we come to this? A sizeable portion of the public trusts the advice of quacks, hacks, and political opportunists over that of the nation’s most expert scientists and physicians. The National Institutes of Health maintains a website with up-to-date recommendations on the use of treatments for COVID-19. They assess the existing evidence and make recommendations for or against a wide array of interventions. (They recommend against the use of both ivermectin and hydroxychloroquine.) The Centers for Disease Control and Prevention publishes extensively about the current knowledge on the safety and efficacy of vaccines. Neither agency is part of a “deep state” or conspiracy. They are comprised of some of the nation’s leading scientists, including physicians, trying to protect the public from disease and foster good health.

Sadly, some physicians have been a source of inaccurate vaccine information; some even prescribe ineffective treatments despite the evidence. These physicians are either letting their politics override their good sense or are improperly assessing the scientific literature, or both. Medical licensing agencies, and specialty certification boards, need to find ways to prevent this—ways that can survive judicial scrutiny and allow for legitimate scientific debate.

I have been tempted to just accept the current situation as the inevitable outcome of social media–fueled tribalism. But when we know that the COVID death rate among the unvaccinated is 9 times that of people who have received a booster dose,¹ I can’t sit idly and watch the Internet pundits prevail. Instead, I continue to advise and teach my students to have confidence in trustworthy authorities and websites. Mistakes will be made; corrections will be issued. However, this is not evidence of malintent or incompetence, but rather, the scientific process in action.

I tell my students that one of the biggest challenges facing them and society is to figure out how to stop, or at least minimize the effects of, incorrect information, misleading statements, and outright lies in a society that values free speech. Physicians—young and old alike—must remain committed to communicating factual information to a not-always-receptive audience. And I wish my young colleagues luck; I hope that their passion for family medicine and their insights into social media may be just the combination that’s needed to redirect the public’s trust back to where it belongs during a health care crisis.

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

• Choose the right delivery device and drug while considering patient factors.
• Provide patient education through allied health professionals.
• Reduce environmental exposures.
• Rethink the use of inhaled corticosteroids (ICS).
• Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.² Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-­agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–­approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

• In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
• In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
• In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
• A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

• For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
• Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
• For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; [email protected]

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

• Choose the right delivery device and drug while considering patient factors.
• Provide patient education through allied health professionals.
• Reduce environmental exposures.
• Rethink the use of inhaled corticosteroids (ICS).
• Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.² Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-­agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–­approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

• In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
• In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
• In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
• A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

• For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
• Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
• For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; [email protected]

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

• Choose the right delivery device and drug while considering patient factors.
• Provide patient education through allied health professionals.
• Reduce environmental exposures.
• Rethink the use of inhaled corticosteroids (ICS).
• Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.² Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-­agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–­approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

• In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
• In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
• In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
• A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

• For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
• Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
• For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; [email protected]

A punch biopsy of the lesion was performed and the results were consistent with a dermatofibroma, which is a benign growth.

Dermatofibromas may manifest as a pink papule on fair-skinned individuals or a darker brown papule in patients of color. Clinically, the texture can be helpful to discern an etiology—dermatofibromas may dimple when pinched laterally, while melanocytic nevi or melanomas tend to be somewhat softer on palpation. Cutaneous sarcoma, while exceedingly rare, may be firmer and chaotic, and varied with multiple colors and topographical changes.

The dermoscopic pattern of a dermatofibroma includes central scar-like areas, a peripheral pigment network, occasional shiny white lines, and confluent circular brown macules. Other less frequent dermoscopic structures may also be seen. A prospective study of the dermoscopic morphology of 412 dermatofibromas found 10 distinct dermoscopic patterns, but also noted that 25% of the dermatofibromas exhibited an atypical pattern.¹ Atypical pigment, multiple scar-like areas, and dotted vessels can occur in a dermatofibroma, as well as in a Spitz nevus, and melanoma. Thus, such findings should prompt a biopsy.

Dermatofibromas are safe to observe, but they can be surgically excised if they cause pain or cosmetic concerns.

This patient was reassured to know that the lesion would not require surgical intervention and was unlikely to enlarge or change significantly over time.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

A punch biopsy of the lesion was performed and the results were consistent with a dermatofibroma, which is a benign growth.

Dermatofibromas may manifest as a pink papule on fair-skinned individuals or a darker brown papule in patients of color. Clinically, the texture can be helpful to discern an etiology—dermatofibromas may dimple when pinched laterally, while melanocytic nevi or melanomas tend to be somewhat softer on palpation. Cutaneous sarcoma, while exceedingly rare, may be firmer and chaotic, and varied with multiple colors and topographical changes.

The dermoscopic pattern of a dermatofibroma includes central scar-like areas, a peripheral pigment network, occasional shiny white lines, and confluent circular brown macules. Other less frequent dermoscopic structures may also be seen. A prospective study of the dermoscopic morphology of 412 dermatofibromas found 10 distinct dermoscopic patterns, but also noted that 25% of the dermatofibromas exhibited an atypical pattern.¹ Atypical pigment, multiple scar-like areas, and dotted vessels can occur in a dermatofibroma, as well as in a Spitz nevus, and melanoma. Thus, such findings should prompt a biopsy.

Dermatofibromas are safe to observe, but they can be surgically excised if they cause pain or cosmetic concerns.

This patient was reassured to know that the lesion would not require surgical intervention and was unlikely to enlarge or change significantly over time.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

A punch biopsy of the lesion was performed and the results were consistent with a dermatofibroma, which is a benign growth.

Dermatofibromas may manifest as a pink papule on fair-skinned individuals or a darker brown papule in patients of color. Clinically, the texture can be helpful to discern an etiology—dermatofibromas may dimple when pinched laterally, while melanocytic nevi or melanomas tend to be somewhat softer on palpation. Cutaneous sarcoma, while exceedingly rare, may be firmer and chaotic, and varied with multiple colors and topographical changes.

The dermoscopic pattern of a dermatofibroma includes central scar-like areas, a peripheral pigment network, occasional shiny white lines, and confluent circular brown macules. Other less frequent dermoscopic structures may also be seen. A prospective study of the dermoscopic morphology of 412 dermatofibromas found 10 distinct dermoscopic patterns, but also noted that 25% of the dermatofibromas exhibited an atypical pattern.¹ Atypical pigment, multiple scar-like areas, and dotted vessels can occur in a dermatofibroma, as well as in a Spitz nevus, and melanoma. Thus, such findings should prompt a biopsy.

Dermatofibromas are safe to observe, but they can be surgically excised if they cause pain or cosmetic concerns.

This patient was reassured to know that the lesion would not require surgical intervention and was unlikely to enlarge or change significantly over time.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

In recent weeks, the COVID-19 vaccine arsenal has grown more robust. Here’s what you need to know:

Variant-specific boosters. On September 1, the Advisory Committee on Immunization Practices (ACIP) adopted a recommendation for a booster of either a new bivalent Pfizer-BioNTech COVID-19 vaccine (for individuals ages 12 years and older) or bivalent Moderna COVID-19 vaccine (for individuals ages 18 years and older) at least 2 months after receipt of a primary series or prior monovalent booster dose. Both bivalent vaccines were recently approved by the Food and Drug Administration (FDA) under an Emergency Use Authorization (EUA) and offer protection against one of the more common circulating strains of SARS-COV-2 (BA.1) while boosting immunity to the original strain. Both options are approved only as booster shots, not as an original COVID vaccine series.¹

Novavax vaccine. This summer, the FDA issued an EUA for the Novavax COVID-19 vaccine in adults and a later EUA for adolescents (ages 12 to 17 years).² Novavax is the fourth vaccine available to combat COVID-19 infection. This newest addition to the COVID armamentarium consists of coronavirus protein subunits, produced using recombinant technology, and a matrix adjuvant. The primary series consists of 2 doses administered at least 3 weeks apart.^3,4

A few caveats: The Novavax vaccine comes in 10-dose vials, which should be kept refrigerated until use. Once the first dose is used, the vial should be discarded after 6 hours. This may present some scheduling and logistical issues. Also, the Novavax vaccine is not currently approved for use in children younger than 12 years, or as a booster to other vaccines.^3,4

The effectiveness and safety of the Novavax vaccine appears to be comparable to that of the other vaccines approved to date, although measuring vaccine effectiveness is a tricky business given the rapid mutation of the virus and changing dominant strains.^3,4 The Novavax vaccine’s efficacy against currently circulating Omicron variants of the virus (eg, BA.2.12.1, BA.4, BA.5) remains to be determined.

As far as safety, preliminary studies indicate that Novavax may be associated with rare cases of myocarditis.^3,4 Myocarditis can result from the COVID infection itself at an overall rate of 1 to 2 per 1000, which is 16 times the rate in adults without COVID.⁵

Could it provide reassurance to the hesitant? The Novavax COVID vaccine was developed using a vaccine platform and production process similar to that of other commonly administered vaccines, such as hepatitis B vaccine and human papillomavirus vaccine. This may make it an appealing option for patients who have shown hesitancy toward new vaccine technologies.

And, of course, there are the Pfizer and Moderna vaccines. Currently, there are 2 vaccines approved under the normal licensing process for adults, both of which are mRNA-based vaccines: Pfizer/BioNTech (Comirnaty) for those ages 12 years and older and Moderna (Spikevax) for those ages 18 and older. A third COVID vaccine option is manufactured by Johnson & Johnson (Janssen) and uses an adenovirus platform. The FDA revised its EUA in May to limit its use.⁶ The Johnson & Johnson vaccine has been associated with rare but serious reactions called thrombosis with thrombocytopenia. ACIP recommends all other vaccines in preference to the Johnson & Johnson vaccine.

For more on COVID vaccination for patients of all ages, see: www.cdc.gov/vaccines/covid-19/downloads/COVID-19-immunization-schedule-ages-6months-older.pdf

In recent weeks, the COVID-19 vaccine arsenal has grown more robust. Here’s what you need to know:

Variant-specific boosters. On September 1, the Advisory Committee on Immunization Practices (ACIP) adopted a recommendation for a booster of either a new bivalent Pfizer-BioNTech COVID-19 vaccine (for individuals ages 12 years and older) or bivalent Moderna COVID-19 vaccine (for individuals ages 18 years and older) at least 2 months after receipt of a primary series or prior monovalent booster dose. Both bivalent vaccines were recently approved by the Food and Drug Administration (FDA) under an Emergency Use Authorization (EUA) and offer protection against one of the more common circulating strains of SARS-COV-2 (BA.1) while boosting immunity to the original strain. Both options are approved only as booster shots, not as an original COVID vaccine series.¹

Novavax vaccine. This summer, the FDA issued an EUA for the Novavax COVID-19 vaccine in adults and a later EUA for adolescents (ages 12 to 17 years).² Novavax is the fourth vaccine available to combat COVID-19 infection. This newest addition to the COVID armamentarium consists of coronavirus protein subunits, produced using recombinant technology, and a matrix adjuvant. The primary series consists of 2 doses administered at least 3 weeks apart.^3,4

A few caveats: The Novavax vaccine comes in 10-dose vials, which should be kept refrigerated until use. Once the first dose is used, the vial should be discarded after 6 hours. This may present some scheduling and logistical issues. Also, the Novavax vaccine is not currently approved for use in children younger than 12 years, or as a booster to other vaccines.^3,4

The effectiveness and safety of the Novavax vaccine appears to be comparable to that of the other vaccines approved to date, although measuring vaccine effectiveness is a tricky business given the rapid mutation of the virus and changing dominant strains.^3,4 The Novavax vaccine’s efficacy against currently circulating Omicron variants of the virus (eg, BA.2.12.1, BA.4, BA.5) remains to be determined.

As far as safety, preliminary studies indicate that Novavax may be associated with rare cases of myocarditis.^3,4 Myocarditis can result from the COVID infection itself at an overall rate of 1 to 2 per 1000, which is 16 times the rate in adults without COVID.⁵

Could it provide reassurance to the hesitant? The Novavax COVID vaccine was developed using a vaccine platform and production process similar to that of other commonly administered vaccines, such as hepatitis B vaccine and human papillomavirus vaccine. This may make it an appealing option for patients who have shown hesitancy toward new vaccine technologies.

And, of course, there are the Pfizer and Moderna vaccines. Currently, there are 2 vaccines approved under the normal licensing process for adults, both of which are mRNA-based vaccines: Pfizer/BioNTech (Comirnaty) for those ages 12 years and older and Moderna (Spikevax) for those ages 18 and older. A third COVID vaccine option is manufactured by Johnson & Johnson (Janssen) and uses an adenovirus platform. The FDA revised its EUA in May to limit its use.⁶ The Johnson & Johnson vaccine has been associated with rare but serious reactions called thrombosis with thrombocytopenia. ACIP recommends all other vaccines in preference to the Johnson & Johnson vaccine.

For more on COVID vaccination for patients of all ages, see: www.cdc.gov/vaccines/covid-19/downloads/COVID-19-immunization-schedule-ages-6months-older.pdf

In recent weeks, the COVID-19 vaccine arsenal has grown more robust. Here’s what you need to know:

Variant-specific boosters. On September 1, the Advisory Committee on Immunization Practices (ACIP) adopted a recommendation for a booster of either a new bivalent Pfizer-BioNTech COVID-19 vaccine (for individuals ages 12 years and older) or bivalent Moderna COVID-19 vaccine (for individuals ages 18 years and older) at least 2 months after receipt of a primary series or prior monovalent booster dose. Both bivalent vaccines were recently approved by the Food and Drug Administration (FDA) under an Emergency Use Authorization (EUA) and offer protection against one of the more common circulating strains of SARS-COV-2 (BA.1) while boosting immunity to the original strain. Both options are approved only as booster shots, not as an original COVID vaccine series.¹

Novavax vaccine. This summer, the FDA issued an EUA for the Novavax COVID-19 vaccine in adults and a later EUA for adolescents (ages 12 to 17 years).² Novavax is the fourth vaccine available to combat COVID-19 infection. This newest addition to the COVID armamentarium consists of coronavirus protein subunits, produced using recombinant technology, and a matrix adjuvant. The primary series consists of 2 doses administered at least 3 weeks apart.^3,4

A few caveats: The Novavax vaccine comes in 10-dose vials, which should be kept refrigerated until use. Once the first dose is used, the vial should be discarded after 6 hours. This may present some scheduling and logistical issues. Also, the Novavax vaccine is not currently approved for use in children younger than 12 years, or as a booster to other vaccines.^3,4

The effectiveness and safety of the Novavax vaccine appears to be comparable to that of the other vaccines approved to date, although measuring vaccine effectiveness is a tricky business given the rapid mutation of the virus and changing dominant strains.^3,4 The Novavax vaccine’s efficacy against currently circulating Omicron variants of the virus (eg, BA.2.12.1, BA.4, BA.5) remains to be determined.

As far as safety, preliminary studies indicate that Novavax may be associated with rare cases of myocarditis.^3,4 Myocarditis can result from the COVID infection itself at an overall rate of 1 to 2 per 1000, which is 16 times the rate in adults without COVID.⁵

Could it provide reassurance to the hesitant? The Novavax COVID vaccine was developed using a vaccine platform and production process similar to that of other commonly administered vaccines, such as hepatitis B vaccine and human papillomavirus vaccine. This may make it an appealing option for patients who have shown hesitancy toward new vaccine technologies.

And, of course, there are the Pfizer and Moderna vaccines. Currently, there are 2 vaccines approved under the normal licensing process for adults, both of which are mRNA-based vaccines: Pfizer/BioNTech (Comirnaty) for those ages 12 years and older and Moderna (Spikevax) for those ages 18 and older. A third COVID vaccine option is manufactured by Johnson & Johnson (Janssen) and uses an adenovirus platform. The FDA revised its EUA in May to limit its use.⁶ The Johnson & Johnson vaccine has been associated with rare but serious reactions called thrombosis with thrombocytopenia. ACIP recommends all other vaccines in preference to the Johnson & Johnson vaccine.

For more on COVID vaccination for patients of all ages, see: www.cdc.gov/vaccines/covid-19/downloads/COVID-19-immunization-schedule-ages-6months-older.pdf

Punch biopsies for standard pathology and direct immunofluorescence were performed and ruled out vesiculobullous disease. Further conversation with the patient revealed that this was a phototoxic drug eruption that resulted from a medication mix-up. The patient had intended to treat an eczema flare with a topical steroid but had inadvertently applied 5-fluorouracil (5-FU), which he had left over from a previous bout of actinic keratosis. While selective to precancerous cells with rapid DNA replication, 5-FU can trigger a significant photodermatitis when applied to heavily sun-exposed skin.

Phototoxic skin reactions can be an adverse result of multiple systemic and topical therapies. Common systemic examples include amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, isotretinoin, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib, and voriconazole.¹ Topical examples include retinoids, levulinic acid, and 5-FU. Treatment requires that the patient stop the offending medication and use photoprotection. The patient followed this protocol and his erosions resolved over the course of a few weeks.

This case demonstrates that topical therapies, like systemic medications, can have chemical names that are confusing to patients. Further complicating matters can be the practice of folding metal tubes of cream over their life of use, thus obscuring the label.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME. 

Punch biopsies for standard pathology and direct immunofluorescence were performed and ruled out vesiculobullous disease. Further conversation with the patient revealed that this was a phototoxic drug eruption that resulted from a medication mix-up. The patient had intended to treat an eczema flare with a topical steroid but had inadvertently applied 5-fluorouracil (5-FU), which he had left over from a previous bout of actinic keratosis. While selective to precancerous cells with rapid DNA replication, 5-FU can trigger a significant photodermatitis when applied to heavily sun-exposed skin.

Phototoxic skin reactions can be an adverse result of multiple systemic and topical therapies. Common systemic examples include amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, isotretinoin, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib, and voriconazole.¹ Topical examples include retinoids, levulinic acid, and 5-FU. Treatment requires that the patient stop the offending medication and use photoprotection. The patient followed this protocol and his erosions resolved over the course of a few weeks.

This case demonstrates that topical therapies, like systemic medications, can have chemical names that are confusing to patients. Further complicating matters can be the practice of folding metal tubes of cream over their life of use, thus obscuring the label.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME. 

Punch biopsies for standard pathology and direct immunofluorescence were performed and ruled out vesiculobullous disease. Further conversation with the patient revealed that this was a phototoxic drug eruption that resulted from a medication mix-up. The patient had intended to treat an eczema flare with a topical steroid but had inadvertently applied 5-fluorouracil (5-FU), which he had left over from a previous bout of actinic keratosis. While selective to precancerous cells with rapid DNA replication, 5-FU can trigger a significant photodermatitis when applied to heavily sun-exposed skin.

Phototoxic skin reactions can be an adverse result of multiple systemic and topical therapies. Common systemic examples include amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, isotretinoin, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib, and voriconazole.¹ Topical examples include retinoids, levulinic acid, and 5-FU. Treatment requires that the patient stop the offending medication and use photoprotection. The patient followed this protocol and his erosions resolved over the course of a few weeks.

This case demonstrates that topical therapies, like systemic medications, can have chemical names that are confusing to patients. Further complicating matters can be the practice of folding metal tubes of cream over their life of use, thus obscuring the label.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME. 

We are deeply saddened by the recent death of our friend and colleague, John Hickner. Although we are grieving, we consider ourselves fortunate to have had John in our lives and to be able to share a few of his many accomplishments and attributes. Anyone who knew John knew that he had many gifts. But above all, John was kind, generous, and thoughtful. Val, John’s wife of 48 years, and their family were at the center of John’s world. Everything John did was a reflection of his love for his family.

John was a small-town family physician, and this guided virtually all of his professional endeavors. He was a member of the faculty for the Michigan State University Department of Family Medicine in Escanaba, in Michigan’s Upper Peninsula. While in the Upper Peninsula, he helped establish 2 practice-based research networks: the statewide Michigan Research Network (MiRNet) and the regional Upper Peninsula Research Network (UPRNet). If you ever had the chance to attend the UPRNet meetings, you would have observed the entire practice staff included in planning research activities, sharing, and troubleshooting common practice hiccups. At the end of those meetings, John would conclude by reading a children’s story such as Goodnight Moon or play a song on his guitar and then give a final thoughtful message.

In 1999, John worked with the American Academy of Family Physicians to create the National Research Network, now composed of more than 870 practices and nearly 2400 members. His own interests in respiratory infections, stemming from his experiences with his own children, led to work with the North American Respiratory Infection Study Group and with the Centers for Disease Control and Prevention.

John’s interests in practice-based research paralleled his interests in evidence-based medicine, largely as a way to translate research into daily practice. This focus on evidence guided much of his work as Editor-in-Chief for The Journal of Family Practice, a title he held for a decade. He also worked with state Academies of Family Physicians for more than a decade to create a new conference series centered on short, practical clinical topics and based completely on summaries of recent research. Any listener of the Primary Care Update podcasts could hear his thoughtful questioning of current research and his wise approach to its integration into practice.

John was more than a thoughtful and kind clinician, an outstanding educator, and a gifted researcher; he was a natural leader. John had the capacity to understand the systems in which he worked and was able to skillfully guide teams to improve those systems. He served as the Chair of Family Medicine at the Cleveland Clinic and then at the University of Illinois Chicago (UIC), and mentored many faculty, residents, and students during his time at those institutions.

After retiring from UIC, John and Val moved back to Escanaba. At his retirement dinner, his children (Michael, Laura, Zach, Anna, and Olivia) gifted him a beautiful maple acoustic guitar with which he then serenaded the attendees. John was an avid tennis player and often would tell us he would have to skip meeting us for dinner while away at a conference because he had found a tennis opponent! Most of all, he loved to set out on his 35-foot sailboat on Big Bay de Noc or on Green Bay. We have fond memories of the days spent sailing with John and hope that he has found fair winds and following seas.

Henry C. Barry, MD, MS
Mark Ebell, MD, MS
Kate Rowland, MD, MS, FAAFP

We are deeply saddened by the recent death of our friend and colleague, John Hickner. Although we are grieving, we consider ourselves fortunate to have had John in our lives and to be able to share a few of his many accomplishments and attributes. Anyone who knew John knew that he had many gifts. But above all, John was kind, generous, and thoughtful. Val, John’s wife of 48 years, and their family were at the center of John’s world. Everything John did was a reflection of his love for his family.

John was a small-town family physician, and this guided virtually all of his professional endeavors. He was a member of the faculty for the Michigan State University Department of Family Medicine in Escanaba, in Michigan’s Upper Peninsula. While in the Upper Peninsula, he helped establish 2 practice-based research networks: the statewide Michigan Research Network (MiRNet) and the regional Upper Peninsula Research Network (UPRNet). If you ever had the chance to attend the UPRNet meetings, you would have observed the entire practice staff included in planning research activities, sharing, and troubleshooting common practice hiccups. At the end of those meetings, John would conclude by reading a children’s story such as Goodnight Moon or play a song on his guitar and then give a final thoughtful message.

In 1999, John worked with the American Academy of Family Physicians to create the National Research Network, now composed of more than 870 practices and nearly 2400 members. His own interests in respiratory infections, stemming from his experiences with his own children, led to work with the North American Respiratory Infection Study Group and with the Centers for Disease Control and Prevention.

John’s interests in practice-based research paralleled his interests in evidence-based medicine, largely as a way to translate research into daily practice. This focus on evidence guided much of his work as Editor-in-Chief for The Journal of Family Practice, a title he held for a decade. He also worked with state Academies of Family Physicians for more than a decade to create a new conference series centered on short, practical clinical topics and based completely on summaries of recent research. Any listener of the Primary Care Update podcasts could hear his thoughtful questioning of current research and his wise approach to its integration into practice.

John was more than a thoughtful and kind clinician, an outstanding educator, and a gifted researcher; he was a natural leader. John had the capacity to understand the systems in which he worked and was able to skillfully guide teams to improve those systems. He served as the Chair of Family Medicine at the Cleveland Clinic and then at the University of Illinois Chicago (UIC), and mentored many faculty, residents, and students during his time at those institutions.

After retiring from UIC, John and Val moved back to Escanaba. At his retirement dinner, his children (Michael, Laura, Zach, Anna, and Olivia) gifted him a beautiful maple acoustic guitar with which he then serenaded the attendees. John was an avid tennis player and often would tell us he would have to skip meeting us for dinner while away at a conference because he had found a tennis opponent! Most of all, he loved to set out on his 35-foot sailboat on Big Bay de Noc or on Green Bay. We have fond memories of the days spent sailing with John and hope that he has found fair winds and following seas.

Henry C. Barry, MD, MS
Mark Ebell, MD, MS
Kate Rowland, MD, MS, FAAFP

We are deeply saddened by the recent death of our friend and colleague, John Hickner. Although we are grieving, we consider ourselves fortunate to have had John in our lives and to be able to share a few of his many accomplishments and attributes. Anyone who knew John knew that he had many gifts. But above all, John was kind, generous, and thoughtful. Val, John’s wife of 48 years, and their family were at the center of John’s world. Everything John did was a reflection of his love for his family.

John was a small-town family physician, and this guided virtually all of his professional endeavors. He was a member of the faculty for the Michigan State University Department of Family Medicine in Escanaba, in Michigan’s Upper Peninsula. While in the Upper Peninsula, he helped establish 2 practice-based research networks: the statewide Michigan Research Network (MiRNet) and the regional Upper Peninsula Research Network (UPRNet). If you ever had the chance to attend the UPRNet meetings, you would have observed the entire practice staff included in planning research activities, sharing, and troubleshooting common practice hiccups. At the end of those meetings, John would conclude by reading a children’s story such as Goodnight Moon or play a song on his guitar and then give a final thoughtful message.

In 1999, John worked with the American Academy of Family Physicians to create the National Research Network, now composed of more than 870 practices and nearly 2400 members. His own interests in respiratory infections, stemming from his experiences with his own children, led to work with the North American Respiratory Infection Study Group and with the Centers for Disease Control and Prevention.

John’s interests in practice-based research paralleled his interests in evidence-based medicine, largely as a way to translate research into daily practice. This focus on evidence guided much of his work as Editor-in-Chief for The Journal of Family Practice, a title he held for a decade. He also worked with state Academies of Family Physicians for more than a decade to create a new conference series centered on short, practical clinical topics and based completely on summaries of recent research. Any listener of the Primary Care Update podcasts could hear his thoughtful questioning of current research and his wise approach to its integration into practice.

John was more than a thoughtful and kind clinician, an outstanding educator, and a gifted researcher; he was a natural leader. John had the capacity to understand the systems in which he worked and was able to skillfully guide teams to improve those systems. He served as the Chair of Family Medicine at the Cleveland Clinic and then at the University of Illinois Chicago (UIC), and mentored many faculty, residents, and students during his time at those institutions.

After retiring from UIC, John and Val moved back to Escanaba. At his retirement dinner, his children (Michael, Laura, Zach, Anna, and Olivia) gifted him a beautiful maple acoustic guitar with which he then serenaded the attendees. John was an avid tennis player and often would tell us he would have to skip meeting us for dinner while away at a conference because he had found a tennis opponent! Most of all, he loved to set out on his 35-foot sailboat on Big Bay de Noc or on Green Bay. We have fond memories of the days spent sailing with John and hope that he has found fair winds and following seas.

Henry C. Barry, MD, MS
Mark Ebell, MD, MS
Kate Rowland, MD, MS, FAAFP

The patient’s initial injury was probably a subungual hematoma, which can take 12 to 18 months to resolve (the time it takes for a new toenail to grow). However, the precipitating trauma likely created an opportunity for fungal elements to invade the nail plate, resulting in the current complaint of superficial onychomycosis.

Onychomycosis is a frequently seen condition with increasing prevalence in older patients. It has several clinical presentations: Superficial onychomycosis manifests with chalky white changes on the surface of the nail. Distal subungual onychomycosis develops at the distal aspect of the nail with thickening and subungual debris. Proximal subungual onychomycosis occurs in the proximal aspect of the nail.

Although often asymptomatic, onychomycosis can cause thickening of the nails and development of subsequent deformity or pincer nails (which painfully “pinch” the underlying skin). It is especially concerning in patients with diabetes or peripheral neuropathy, in whom the abnormal thickness and shape of the nails can lead to microtrauma at the proximal and lateral attachments of the nail. These patients have an increased risk of secondary infection, possible complications, and even, for some, amputation.

If the patient is asymptomatic, and does not have diabetes, neuropathy, or other risk factors, treatment is not required. For those who would benefit from treatment, it is usually safe and inexpensive with the current generation of oral antifungal medications.

Some recommend confirmatory testing before treatment intiation,¹ but the low adverse effect profile of terbinafine and its current cost below $10/month² make empiric treatment safe and cost effective in most cases.³ If needed, and with access to microscopy, a potassium hydroxide (KOH) prep can be performed on scrapings from the affected portions of the nail. If that is not available, scrapings or clippings can be sent to the lab for KOH and periodic acid-Schiff staining.

The US Food and Drug Administration previously recommended follow-up liver enzyme tests if terbinafine is used for more than 6 weeks. (Fingernails require only 6 weeks of treatment, but toenails grow more slowly and require 12 weeks of treatment.) However, research has demonstrated that hepatotoxicity risk is extremely low and transaminase elevations are rare.⁴ In the rare cases that liver dysfunction has occurred, patients developed symptoms of jaundice, malaise, dark urine, or pruritis.⁴

This patient was counseled regarding the fungal nature of onychomycosis and the general safety of a 90-day course of oral terbinafine 250 mg/d—provided he did not have underlying liver or kidney disease or leukopenia. He reported that he had not had any blood work performed in the past year but was due for his annual wellness evaluation, at which he would discuss his overall health with his primary care provider, obtain baseline blood testing, and determine whether to proceed with treatment. He was advised that if, after starting treatment, he developed any symptoms of jaundice, dark urine, or other difficulties, he should report them to his care team.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The patient’s initial injury was probably a subungual hematoma, which can take 12 to 18 months to resolve (the time it takes for a new toenail to grow). However, the precipitating trauma likely created an opportunity for fungal elements to invade the nail plate, resulting in the current complaint of superficial onychomycosis.

Onychomycosis is a frequently seen condition with increasing prevalence in older patients. It has several clinical presentations: Superficial onychomycosis manifests with chalky white changes on the surface of the nail. Distal subungual onychomycosis develops at the distal aspect of the nail with thickening and subungual debris. Proximal subungual onychomycosis occurs in the proximal aspect of the nail.

Although often asymptomatic, onychomycosis can cause thickening of the nails and development of subsequent deformity or pincer nails (which painfully “pinch” the underlying skin). It is especially concerning in patients with diabetes or peripheral neuropathy, in whom the abnormal thickness and shape of the nails can lead to microtrauma at the proximal and lateral attachments of the nail. These patients have an increased risk of secondary infection, possible complications, and even, for some, amputation.

If the patient is asymptomatic, and does not have diabetes, neuropathy, or other risk factors, treatment is not required. For those who would benefit from treatment, it is usually safe and inexpensive with the current generation of oral antifungal medications.

Some recommend confirmatory testing before treatment intiation,¹ but the low adverse effect profile of terbinafine and its current cost below $10/month² make empiric treatment safe and cost effective in most cases.³ If needed, and with access to microscopy, a potassium hydroxide (KOH) prep can be performed on scrapings from the affected portions of the nail. If that is not available, scrapings or clippings can be sent to the lab for KOH and periodic acid-Schiff staining.

The US Food and Drug Administration previously recommended follow-up liver enzyme tests if terbinafine is used for more than 6 weeks. (Fingernails require only 6 weeks of treatment, but toenails grow more slowly and require 12 weeks of treatment.) However, research has demonstrated that hepatotoxicity risk is extremely low and transaminase elevations are rare.⁴ In the rare cases that liver dysfunction has occurred, patients developed symptoms of jaundice, malaise, dark urine, or pruritis.⁴

This patient was counseled regarding the fungal nature of onychomycosis and the general safety of a 90-day course of oral terbinafine 250 mg/d—provided he did not have underlying liver or kidney disease or leukopenia. He reported that he had not had any blood work performed in the past year but was due for his annual wellness evaluation, at which he would discuss his overall health with his primary care provider, obtain baseline blood testing, and determine whether to proceed with treatment. He was advised that if, after starting treatment, he developed any symptoms of jaundice, dark urine, or other difficulties, he should report them to his care team.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.