Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.¹ As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include biological therapies, immunotherapy, bronchial thermoplasty, and anti-inflammatory agents. This review will focus on the newer therapeutic options and provide guidance on when to seek expert pulmonary consultation (TABLE 1). But before we begin, it’s important to briefly review the pathophysiology of asthma and several key diagnostic considerations.

The pathophysiology of asthma provides key targets for therapy

There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology²:

Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.^2-4

In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.^5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.^8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).

It is important to determine whether patients with asthma-COPD overlap syndrome are asthma predominant or COPD predominant, because appropriate first-line treatment will differ.

Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.¹⁰ Longstanding inflammation can lead to structural changes and reduced airflow reversibility.

Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.^11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.^12,13

What we’ve learned about asthma can inform treatment decisions

Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV₁ > 12% or FVC > 200 mL from baseline).² If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.

Continue to: Additional diagnostic considerations...

Additional diagnostic considerations may impact the treatment plan for patients with asthma:

Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.¹⁴

Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.^2,5,15

Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.^16-18

Getting a handle on an ever-expanding asthma Tx arsenal

The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.

Continue to: Over the past decade...

Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.

Inhaled medications

This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting muscarinic agonists (LAMA).

ICS is the first choice for long-term control of persistent asthma.² Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.^19-22

LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death²³—a concern that has not been demonstrated with the combination of ICS-LABA.

LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received an FDA black box warning.

LABAs cause smooth muscle relaxation in the lungs.²⁴ There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).

Continue to: Once-daily fluticasone furoate/vilanterol...

Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV₁.²⁵ In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.²⁶

Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV₁ improved with olodeaterol when compared to placebo.²⁷

Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.²⁸ However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.²⁹

The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.¹⁵

Ideal candidates for biological therapy are patients who have exhausted other forms of severe asthma treatment.

Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M₁ and M₃.³⁰ Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.¹³ The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.

Continue to: Glycopyrronium bromide...

Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.³¹

Biological therapies

In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.

Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.³²

All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 3^15,33-47 summarizes all approved biologicals for the management of severe asthma.

Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).³⁴ Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).^33,34

Continue to: Its efficacy and safety...

Mepolizumab has shown a trend of greater benefit in patients with a very high eosinophil count.

Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.^35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.¹⁵

Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.

Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).³⁷

Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.^37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.^39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.³⁸

GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.

Continue to: Reslizumab (Cinqair)...

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-­generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

Continue to: Both treatment groups...

Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV₁ for up to 5 years.⁵¹

The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.⁵²

In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.

Immunotherapy

Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).

Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.

Continue to: SCIT

SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.⁵³

SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.

The potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis.

A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.⁵⁴ A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.⁵⁵

In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.⁵⁶ Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.

Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.¹⁵

Continue to: Azithromycin

Azithromycin

Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.

The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.⁵⁷ While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.

The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.⁵⁸

Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy

The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.⁵⁹

The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.

Continue to: A new era

 

 

A new era

We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.

It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.

CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; mrali@northwell.edu

Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.¹ As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include biological therapies, immunotherapy, bronchial thermoplasty, and anti-inflammatory agents. This review will focus on the newer therapeutic options and provide guidance on when to seek expert pulmonary consultation (TABLE 1). But before we begin, it’s important to briefly review the pathophysiology of asthma and several key diagnostic considerations.

The pathophysiology of asthma provides key targets for therapy

There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology²:

Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.^2-4

In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.^5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.^8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).

It is important to determine whether patients with asthma-COPD overlap syndrome are asthma predominant or COPD predominant, because appropriate first-line treatment will differ.

Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.¹⁰ Longstanding inflammation can lead to structural changes and reduced airflow reversibility.

Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.^11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.^12,13

What we’ve learned about asthma can inform treatment decisions

Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV₁ > 12% or FVC > 200 mL from baseline).² If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.

Continue to: Additional diagnostic considerations...

Additional diagnostic considerations may impact the treatment plan for patients with asthma:

Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.¹⁴

Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.^2,5,15

Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.^16-18

Getting a handle on an ever-expanding asthma Tx arsenal

The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.

Continue to: Over the past decade...

Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.

Inhaled medications

This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting muscarinic agonists (LAMA).

ICS is the first choice for long-term control of persistent asthma.² Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.^19-22

LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death²³—a concern that has not been demonstrated with the combination of ICS-LABA.

LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received an FDA black box warning.

LABAs cause smooth muscle relaxation in the lungs.²⁴ There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).

Continue to: Once-daily fluticasone furoate/vilanterol...

Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV₁.²⁵ In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.²⁶

Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV₁ improved with olodeaterol when compared to placebo.²⁷

Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.²⁸ However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.²⁹

The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.¹⁵

Ideal candidates for biological therapy are patients who have exhausted other forms of severe asthma treatment.

Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M₁ and M₃.³⁰ Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.¹³ The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.

Continue to: Glycopyrronium bromide...

Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.³¹

Biological therapies

In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.

Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.³²

All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 3^15,33-47 summarizes all approved biologicals for the management of severe asthma.

Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).³⁴ Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).^33,34

Continue to: Its efficacy and safety...

Mepolizumab has shown a trend of greater benefit in patients with a very high eosinophil count.

Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.^35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.¹⁵

Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.

Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).³⁷

Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.^37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.^39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.³⁸

GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.

Continue to: Reslizumab (Cinqair)...

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-­generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

Continue to: Both treatment groups...

Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV₁ for up to 5 years.⁵¹

The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.⁵²

In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.

Immunotherapy

Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).

Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.

Continue to: SCIT

SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.⁵³

SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.

The potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis.

A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.⁵⁴ A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.⁵⁵

In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.⁵⁶ Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.

Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.¹⁵

Continue to: Azithromycin

Azithromycin

Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.

The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.⁵⁷ While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.

The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.⁵⁸

Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy

The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.⁵⁹

The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.

Continue to: A new era

 

 

A new era

We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.

It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.

CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; mrali@northwell.edu

Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.¹ As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include biological therapies, immunotherapy, bronchial thermoplasty, and anti-inflammatory agents. This review will focus on the newer therapeutic options and provide guidance on when to seek expert pulmonary consultation (TABLE 1). But before we begin, it’s important to briefly review the pathophysiology of asthma and several key diagnostic considerations.

The pathophysiology of asthma provides key targets for therapy

There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology²:

Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.^2-4

In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.^5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.^8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).

It is important to determine whether patients with asthma-COPD overlap syndrome are asthma predominant or COPD predominant, because appropriate first-line treatment will differ.

Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.¹⁰ Longstanding inflammation can lead to structural changes and reduced airflow reversibility.

Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.^11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.^12,13

What we’ve learned about asthma can inform treatment decisions

Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV₁ > 12% or FVC > 200 mL from baseline).² If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.

Continue to: Additional diagnostic considerations...

Additional diagnostic considerations may impact the treatment plan for patients with asthma:

Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.¹⁴

Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.^2,5,15

Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.^16-18

Getting a handle on an ever-expanding asthma Tx arsenal

The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.

Continue to: Over the past decade...

Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.

Inhaled medications

This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting muscarinic agonists (LAMA).

ICS is the first choice for long-term control of persistent asthma.² Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.^19-22

LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death²³—a concern that has not been demonstrated with the combination of ICS-LABA.

LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received an FDA black box warning.

LABAs cause smooth muscle relaxation in the lungs.²⁴ There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).

Continue to: Once-daily fluticasone furoate/vilanterol...

Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV₁.²⁵ In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.²⁶

Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV₁ improved with olodeaterol when compared to placebo.²⁷

Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.²⁸ However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.²⁹

The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.¹⁵

Ideal candidates for biological therapy are patients who have exhausted other forms of severe asthma treatment.

Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M₁ and M₃.³⁰ Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.¹³ The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.

Continue to: Glycopyrronium bromide...

Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.³¹

Biological therapies

In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.

Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.³²

All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 3^15,33-47 summarizes all approved biologicals for the management of severe asthma.

Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).³⁴ Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).^33,34

Continue to: Its efficacy and safety...

Mepolizumab has shown a trend of greater benefit in patients with a very high eosinophil count.

Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.^35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.¹⁵

Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.

Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).³⁷

Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.^37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.^39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.³⁸

GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.

Continue to: Reslizumab (Cinqair)...

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-­generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

Continue to: Both treatment groups...

Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV₁ for up to 5 years.⁵¹

The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.⁵²

In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.

Immunotherapy

Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).

Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.

Continue to: SCIT

SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.⁵³

SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.

The potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis.

A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.⁵⁴ A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.⁵⁵

In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.⁵⁶ Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.

Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.¹⁵

Continue to: Azithromycin

Azithromycin

Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.

The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.⁵⁷ While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.

The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.⁵⁸

Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy

The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.⁵⁹

The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.

Continue to: A new era

 

 

A new era

We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.

It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.

CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; mrali@northwell.edu

Cervical pannus is a disease that could easily develop in an active-duty soldier or veteran. The disease has been associated with trauma and rheumatoid arthritis, or can be idiopathic. For years, cervical pannus has been closely tied to rheumatoid arthritis; however, a study published in 2019 showed that only 28% of patients with cervical pannus had an associated diagnosis of rheumatoid arthritis.¹ In the same study, 18% of patients had undergone some type of prior cervical spine surgery as the next most common cause. The condition also can occur years after an injury.

Background

In the US, 42,000 veterans are living with spinal cord disease, and thousands of these veterans have surgery every year.² Service men and women and veterans are at risk for cervical pannus as they age especially if they have a history of rheumatoid arthritis, cervical spine surgery, trauma, and numerous other causes. It is critical for health care providers who treat this population to understand cervical pannus, how to recognize it, and how to identify patients at risk. A cervical pannus can be life threatening if not detected and treated properly.

There is no clear definition for cervical pannus. Some researchers think of it as the chronically inflamed synovial membrane in patients with rheumatoid arthritis (RA); others consider it as a specialized synovial membrane derived from vascular soft tissue structures at or near the bone synovial membrane.³ The pathogenesis for developing a pannus is not well understood, and little is known when a pannus begins or its initial location. A pannus formation can occur in any synovial joint in the body, such as wrists, metacarpophalangeal joint, proximal interphalangeal joint, and cervical joints.

A cervical pannus can cause serious complications. It can lead to a cervical subluxation in up to 4% of patients with RA, or it also can occur spontaneously in some patients without RA especially those with trauma or cancer.⁴

There are 2 suggested mechanisms by which the synovial membrane proliferates. It was originally believed that T cells from the chronic inflamed joint lead to the pannus formation by initiating an autoimmune reaction through the production of different cytokines against arthritogenic agents.^3-5 These cytokines increase inflammation by recruiting neutrophils and activating various kinds of macrophages that might lead to increased osteoclast activity.⁶ Osteoclastic activity can damage bone and allow the synovium to penetrate the bone, forming the pannus.

Another proposed mechanism is that the synovial cells hyperpolarize and hypertrophy automatically without T-cell help by expressing oncogenes and their proteins.³ In either case, angiogenesis follows this proliferation and increases the influx of inflammatory cells into the joints, which can lead to more destruction.⁷ This increase in blood supply to the synovial membrane is important in the growth of the pannus and can have a damaging effect to cartilage, bone, and joints.^4,7

Cervical pannus can progress in patients with prolonged use of corticosteroids.⁸ Because a pannus can put pressure on any segment of the cervical spine and the cranio-cervical junction leading to cervical instability, patients with this condition may present with a variety of clinical symptoms.⁹ The most frequently reported clinical features include neck pain, easy fatigability, difficulty walking, abnormal gait, increased clumsiness, and numbness and tingling in the arms. Patients also may complain of neck stiffness and decreased neck motion.¹⁰Cervical pannus is most frequently seen in patients with RA. However, patients without a RA diagnosis and incidental atlantoaxial pannus on cervical spine magnetic resonance imaging (MRI) are unlikely to have previously undiagnosed RA.¹¹

Case Presentation

A 70-year-old white woman presented to the neurology clinic at Gretna Medical Center in Virginia in December 2016 with constant headache and imbalance that started in September 2016. She characterized the pain as predominately pressure (6 on a 10-point pain scale) with occasional shooting pains. The pain started at the left occipital lobe and radiated toward the left temporal lobe and left eye. The patient also stated that it was very difficult to lay her head down on a pillow to sleep and that she had to use a recliner in order to sleep over the past 3 months. She reported that the headache felt slightly worse if she had a lot of repetitive head and neck movements during the day. There was no photophobia, phonophobia, nausea, vomiting, facial paresthesias, lacrimation, nasal congestion, confusion, or impaired speech.

The patient’s lack of balance, which resulted in an unsteady gait, had started 1 month before and had increased significantly in the past 2 to 3 weeks. She stated that the unsteady gait was associated with numbness in her right upper and lower extremities, although more intense in the right lower extremity. Aside from the headaches, paresthesia, and unsteady gait, the patient reported no other major symptoms. She did not smoke tobacco or drink alcohol. Her family history revealed that her brothers had heart disease.

The patient’s vital signs at physical examination included heart rate, 83 beats per minute; blood pressure, 159/75 mm hg; temporal temperature, 97.9 °F; and respiratory rate, 20 breaths per minute. The patient’s gait was unsteady, needing stabilization by holding on to her husband’s arm, slightly favoring right lower extremity. Finger-to-nose test, rapid alternating movements, heel-knee-shin testing were all normal. The Romberg sign was positive. The patient could rise on toes and heels with slight balance disturbance. Deep tendon reflexes and reflexes in the upper and lower extremities was symmetric 2+ bilaterally. Musculoskeletal examination revealed strength and tone in all major muscle groups and demonstrated symmetrical movements with no fasciculation noted. A rheumatologic evaluation showed no abnormalities, including inspection of hands, feet, major joints, and other range of motion, besides her neck. The rest of the physical, cognitive, and neurologic examination findings were otherwise unremarkable. A routine rheumatologic laboratory evaluation was negative.

A head computed tomography ordered before coming to the clinic showed normal results. An MRI of the head was obtained to evaluate for ischemic cause or structural abnormality (Figures 1 and 2). Given the patient’s presentation and the pattern seen on the MRI results, it was determined that large pannus posterior to the dens, severely narrowing the spinal canal, was most likely the diagnosis. A second opinion confirmed the diagnosis, and a second MRI revealed stabilization with no signs of enhancement.

The patient was advised to meet with a neurosurgeon to remove the pannus. The patient agreed on occiput to C2 posterior instrument arthrodesis as well as decompression. A plain film radiograph showed C2-occipital repair after surgery (Figure 3). The patient recovered in the neurosurgical intensive care unit, and the rest of the recovery was uncomplicated. She showed some improvement in her headaches and unsteady gait. A postoperative pathologic evaluation of tissue was not available. She was referred to a rheumatologist to rule out an autoimmune disease as the cause for this pannus, but no autoimmune disease was found.

Discussion

Cervical pannus is relatively uncommon in those without RA. However, there are multiple reasons that a patient could develop a cervical pannus. Cervical pannus in RA and cervical pannus without RA may mimic each other clinically, but medical management is distinctly different. Consequently, a rheumatology consult is necessary to ensure that there is no undiagnosed autoimmune disorder. Our patient did not have RA, and a neurosurgery intervention was needed to manage her headaches and unsteady gait. Although we could not isolate a cause of this patient’s cervical pannus development, we believed that nonintervention would adversely affect this patient.

The course of pannus progression can be fatal especially if left untreated.¹² MRI can detect a pannus and may be helpful for planning surgery.¹³ Surgical resection has been the treatment of choice for patients with neurologic symptoms.¹⁴ However, some cases have reported resolution of pannus associated with RA and other forms of chronic atlantoaxial instability only after posterior stabilization.¹⁴In order to manage pannus, cervical spine examination for the diagnosis of cervical involvement is encouraged to prevent morbidity and mortality.¹³ There are new data that demonstrated the potential of using retinoid X receptor agonists, such as bexarotene, as a treatment against the development and progression of pannus.¹⁴

Conclusions

We present a patient with cervical pannus disease without RA whose diagnosis was based on the pathognomonic pattern seen on MRI. She showed a clinically significant recovery with an occiput to C2 posterior instrument arthrodesis as well as decompression. She showed marked improvements in her headaches and unsteady gait. This case report highlights the importance of realizing cervical pannus as a disease found in patients without RA. It serves as an alert to clinicians for timely detection, diagnosis, and initiation of treatment to prevent mortality and long-term neurologic sequelae of cervical pannus.

Although further studies of early diagnosis and treatment for cervical pannus are warranted, we propose that including pannus in a differential diagnosis for patients with no RA could be lifesaving.

Cervical pannus is a disease that could easily develop in an active-duty soldier or veteran. The disease has been associated with trauma and rheumatoid arthritis, or can be idiopathic. For years, cervical pannus has been closely tied to rheumatoid arthritis; however, a study published in 2019 showed that only 28% of patients with cervical pannus had an associated diagnosis of rheumatoid arthritis.¹ In the same study, 18% of patients had undergone some type of prior cervical spine surgery as the next most common cause. The condition also can occur years after an injury.

Background

In the US, 42,000 veterans are living with spinal cord disease, and thousands of these veterans have surgery every year.² Service men and women and veterans are at risk for cervical pannus as they age especially if they have a history of rheumatoid arthritis, cervical spine surgery, trauma, and numerous other causes. It is critical for health care providers who treat this population to understand cervical pannus, how to recognize it, and how to identify patients at risk. A cervical pannus can be life threatening if not detected and treated properly.

There is no clear definition for cervical pannus. Some researchers think of it as the chronically inflamed synovial membrane in patients with rheumatoid arthritis (RA); others consider it as a specialized synovial membrane derived from vascular soft tissue structures at or near the bone synovial membrane.³ The pathogenesis for developing a pannus is not well understood, and little is known when a pannus begins or its initial location. A pannus formation can occur in any synovial joint in the body, such as wrists, metacarpophalangeal joint, proximal interphalangeal joint, and cervical joints.

A cervical pannus can cause serious complications. It can lead to a cervical subluxation in up to 4% of patients with RA, or it also can occur spontaneously in some patients without RA especially those with trauma or cancer.⁴

There are 2 suggested mechanisms by which the synovial membrane proliferates. It was originally believed that T cells from the chronic inflamed joint lead to the pannus formation by initiating an autoimmune reaction through the production of different cytokines against arthritogenic agents.^3-5 These cytokines increase inflammation by recruiting neutrophils and activating various kinds of macrophages that might lead to increased osteoclast activity.⁶ Osteoclastic activity can damage bone and allow the synovium to penetrate the bone, forming the pannus.

Another proposed mechanism is that the synovial cells hyperpolarize and hypertrophy automatically without T-cell help by expressing oncogenes and their proteins.³ In either case, angiogenesis follows this proliferation and increases the influx of inflammatory cells into the joints, which can lead to more destruction.⁷ This increase in blood supply to the synovial membrane is important in the growth of the pannus and can have a damaging effect to cartilage, bone, and joints.^4,7

Cervical pannus can progress in patients with prolonged use of corticosteroids.⁸ Because a pannus can put pressure on any segment of the cervical spine and the cranio-cervical junction leading to cervical instability, patients with this condition may present with a variety of clinical symptoms.⁹ The most frequently reported clinical features include neck pain, easy fatigability, difficulty walking, abnormal gait, increased clumsiness, and numbness and tingling in the arms. Patients also may complain of neck stiffness and decreased neck motion.¹⁰Cervical pannus is most frequently seen in patients with RA. However, patients without a RA diagnosis and incidental atlantoaxial pannus on cervical spine magnetic resonance imaging (MRI) are unlikely to have previously undiagnosed RA.¹¹

Case Presentation

A 70-year-old white woman presented to the neurology clinic at Gretna Medical Center in Virginia in December 2016 with constant headache and imbalance that started in September 2016. She characterized the pain as predominately pressure (6 on a 10-point pain scale) with occasional shooting pains. The pain started at the left occipital lobe and radiated toward the left temporal lobe and left eye. The patient also stated that it was very difficult to lay her head down on a pillow to sleep and that she had to use a recliner in order to sleep over the past 3 months. She reported that the headache felt slightly worse if she had a lot of repetitive head and neck movements during the day. There was no photophobia, phonophobia, nausea, vomiting, facial paresthesias, lacrimation, nasal congestion, confusion, or impaired speech.

The patient’s lack of balance, which resulted in an unsteady gait, had started 1 month before and had increased significantly in the past 2 to 3 weeks. She stated that the unsteady gait was associated with numbness in her right upper and lower extremities, although more intense in the right lower extremity. Aside from the headaches, paresthesia, and unsteady gait, the patient reported no other major symptoms. She did not smoke tobacco or drink alcohol. Her family history revealed that her brothers had heart disease.

The patient’s vital signs at physical examination included heart rate, 83 beats per minute; blood pressure, 159/75 mm hg; temporal temperature, 97.9 °F; and respiratory rate, 20 breaths per minute. The patient’s gait was unsteady, needing stabilization by holding on to her husband’s arm, slightly favoring right lower extremity. Finger-to-nose test, rapid alternating movements, heel-knee-shin testing were all normal. The Romberg sign was positive. The patient could rise on toes and heels with slight balance disturbance. Deep tendon reflexes and reflexes in the upper and lower extremities was symmetric 2+ bilaterally. Musculoskeletal examination revealed strength and tone in all major muscle groups and demonstrated symmetrical movements with no fasciculation noted. A rheumatologic evaluation showed no abnormalities, including inspection of hands, feet, major joints, and other range of motion, besides her neck. The rest of the physical, cognitive, and neurologic examination findings were otherwise unremarkable. A routine rheumatologic laboratory evaluation was negative.

A head computed tomography ordered before coming to the clinic showed normal results. An MRI of the head was obtained to evaluate for ischemic cause or structural abnormality (Figures 1 and 2). Given the patient’s presentation and the pattern seen on the MRI results, it was determined that large pannus posterior to the dens, severely narrowing the spinal canal, was most likely the diagnosis. A second opinion confirmed the diagnosis, and a second MRI revealed stabilization with no signs of enhancement.

The patient was advised to meet with a neurosurgeon to remove the pannus. The patient agreed on occiput to C2 posterior instrument arthrodesis as well as decompression. A plain film radiograph showed C2-occipital repair after surgery (Figure 3). The patient recovered in the neurosurgical intensive care unit, and the rest of the recovery was uncomplicated. She showed some improvement in her headaches and unsteady gait. A postoperative pathologic evaluation of tissue was not available. She was referred to a rheumatologist to rule out an autoimmune disease as the cause for this pannus, but no autoimmune disease was found.

Discussion

Cervical pannus is relatively uncommon in those without RA. However, there are multiple reasons that a patient could develop a cervical pannus. Cervical pannus in RA and cervical pannus without RA may mimic each other clinically, but medical management is distinctly different. Consequently, a rheumatology consult is necessary to ensure that there is no undiagnosed autoimmune disorder. Our patient did not have RA, and a neurosurgery intervention was needed to manage her headaches and unsteady gait. Although we could not isolate a cause of this patient’s cervical pannus development, we believed that nonintervention would adversely affect this patient.

The course of pannus progression can be fatal especially if left untreated.¹² MRI can detect a pannus and may be helpful for planning surgery.¹³ Surgical resection has been the treatment of choice for patients with neurologic symptoms.¹⁴ However, some cases have reported resolution of pannus associated with RA and other forms of chronic atlantoaxial instability only after posterior stabilization.¹⁴In order to manage pannus, cervical spine examination for the diagnosis of cervical involvement is encouraged to prevent morbidity and mortality.¹³ There are new data that demonstrated the potential of using retinoid X receptor agonists, such as bexarotene, as a treatment against the development and progression of pannus.¹⁴

Conclusions

We present a patient with cervical pannus disease without RA whose diagnosis was based on the pathognomonic pattern seen on MRI. She showed a clinically significant recovery with an occiput to C2 posterior instrument arthrodesis as well as decompression. She showed marked improvements in her headaches and unsteady gait. This case report highlights the importance of realizing cervical pannus as a disease found in patients without RA. It serves as an alert to clinicians for timely detection, diagnosis, and initiation of treatment to prevent mortality and long-term neurologic sequelae of cervical pannus.

Although further studies of early diagnosis and treatment for cervical pannus are warranted, we propose that including pannus in a differential diagnosis for patients with no RA could be lifesaving.

Cervical pannus is a disease that could easily develop in an active-duty soldier or veteran. The disease has been associated with trauma and rheumatoid arthritis, or can be idiopathic. For years, cervical pannus has been closely tied to rheumatoid arthritis; however, a study published in 2019 showed that only 28% of patients with cervical pannus had an associated diagnosis of rheumatoid arthritis.¹ In the same study, 18% of patients had undergone some type of prior cervical spine surgery as the next most common cause. The condition also can occur years after an injury.

Background

In the US, 42,000 veterans are living with spinal cord disease, and thousands of these veterans have surgery every year.² Service men and women and veterans are at risk for cervical pannus as they age especially if they have a history of rheumatoid arthritis, cervical spine surgery, trauma, and numerous other causes. It is critical for health care providers who treat this population to understand cervical pannus, how to recognize it, and how to identify patients at risk. A cervical pannus can be life threatening if not detected and treated properly.

There is no clear definition for cervical pannus. Some researchers think of it as the chronically inflamed synovial membrane in patients with rheumatoid arthritis (RA); others consider it as a specialized synovial membrane derived from vascular soft tissue structures at or near the bone synovial membrane.³ The pathogenesis for developing a pannus is not well understood, and little is known when a pannus begins or its initial location. A pannus formation can occur in any synovial joint in the body, such as wrists, metacarpophalangeal joint, proximal interphalangeal joint, and cervical joints.

A cervical pannus can cause serious complications. It can lead to a cervical subluxation in up to 4% of patients with RA, or it also can occur spontaneously in some patients without RA especially those with trauma or cancer.⁴

There are 2 suggested mechanisms by which the synovial membrane proliferates. It was originally believed that T cells from the chronic inflamed joint lead to the pannus formation by initiating an autoimmune reaction through the production of different cytokines against arthritogenic agents.^3-5 These cytokines increase inflammation by recruiting neutrophils and activating various kinds of macrophages that might lead to increased osteoclast activity.⁶ Osteoclastic activity can damage bone and allow the synovium to penetrate the bone, forming the pannus.

Another proposed mechanism is that the synovial cells hyperpolarize and hypertrophy automatically without T-cell help by expressing oncogenes and their proteins.³ In either case, angiogenesis follows this proliferation and increases the influx of inflammatory cells into the joints, which can lead to more destruction.⁷ This increase in blood supply to the synovial membrane is important in the growth of the pannus and can have a damaging effect to cartilage, bone, and joints.^4,7

Cervical pannus can progress in patients with prolonged use of corticosteroids.⁸ Because a pannus can put pressure on any segment of the cervical spine and the cranio-cervical junction leading to cervical instability, patients with this condition may present with a variety of clinical symptoms.⁹ The most frequently reported clinical features include neck pain, easy fatigability, difficulty walking, abnormal gait, increased clumsiness, and numbness and tingling in the arms. Patients also may complain of neck stiffness and decreased neck motion.¹⁰Cervical pannus is most frequently seen in patients with RA. However, patients without a RA diagnosis and incidental atlantoaxial pannus on cervical spine magnetic resonance imaging (MRI) are unlikely to have previously undiagnosed RA.¹¹

Case Presentation

A 70-year-old white woman presented to the neurology clinic at Gretna Medical Center in Virginia in December 2016 with constant headache and imbalance that started in September 2016. She characterized the pain as predominately pressure (6 on a 10-point pain scale) with occasional shooting pains. The pain started at the left occipital lobe and radiated toward the left temporal lobe and left eye. The patient also stated that it was very difficult to lay her head down on a pillow to sleep and that she had to use a recliner in order to sleep over the past 3 months. She reported that the headache felt slightly worse if she had a lot of repetitive head and neck movements during the day. There was no photophobia, phonophobia, nausea, vomiting, facial paresthesias, lacrimation, nasal congestion, confusion, or impaired speech.

The patient’s lack of balance, which resulted in an unsteady gait, had started 1 month before and had increased significantly in the past 2 to 3 weeks. She stated that the unsteady gait was associated with numbness in her right upper and lower extremities, although more intense in the right lower extremity. Aside from the headaches, paresthesia, and unsteady gait, the patient reported no other major symptoms. She did not smoke tobacco or drink alcohol. Her family history revealed that her brothers had heart disease.

The patient’s vital signs at physical examination included heart rate, 83 beats per minute; blood pressure, 159/75 mm hg; temporal temperature, 97.9 °F; and respiratory rate, 20 breaths per minute. The patient’s gait was unsteady, needing stabilization by holding on to her husband’s arm, slightly favoring right lower extremity. Finger-to-nose test, rapid alternating movements, heel-knee-shin testing were all normal. The Romberg sign was positive. The patient could rise on toes and heels with slight balance disturbance. Deep tendon reflexes and reflexes in the upper and lower extremities was symmetric 2+ bilaterally. Musculoskeletal examination revealed strength and tone in all major muscle groups and demonstrated symmetrical movements with no fasciculation noted. A rheumatologic evaluation showed no abnormalities, including inspection of hands, feet, major joints, and other range of motion, besides her neck. The rest of the physical, cognitive, and neurologic examination findings were otherwise unremarkable. A routine rheumatologic laboratory evaluation was negative.

A head computed tomography ordered before coming to the clinic showed normal results. An MRI of the head was obtained to evaluate for ischemic cause or structural abnormality (Figures 1 and 2). Given the patient’s presentation and the pattern seen on the MRI results, it was determined that large pannus posterior to the dens, severely narrowing the spinal canal, was most likely the diagnosis. A second opinion confirmed the diagnosis, and a second MRI revealed stabilization with no signs of enhancement.

The patient was advised to meet with a neurosurgeon to remove the pannus. The patient agreed on occiput to C2 posterior instrument arthrodesis as well as decompression. A plain film radiograph showed C2-occipital repair after surgery (Figure 3). The patient recovered in the neurosurgical intensive care unit, and the rest of the recovery was uncomplicated. She showed some improvement in her headaches and unsteady gait. A postoperative pathologic evaluation of tissue was not available. She was referred to a rheumatologist to rule out an autoimmune disease as the cause for this pannus, but no autoimmune disease was found.

Discussion

Cervical pannus is relatively uncommon in those without RA. However, there are multiple reasons that a patient could develop a cervical pannus. Cervical pannus in RA and cervical pannus without RA may mimic each other clinically, but medical management is distinctly different. Consequently, a rheumatology consult is necessary to ensure that there is no undiagnosed autoimmune disorder. Our patient did not have RA, and a neurosurgery intervention was needed to manage her headaches and unsteady gait. Although we could not isolate a cause of this patient’s cervical pannus development, we believed that nonintervention would adversely affect this patient.

The course of pannus progression can be fatal especially if left untreated.¹² MRI can detect a pannus and may be helpful for planning surgery.¹³ Surgical resection has been the treatment of choice for patients with neurologic symptoms.¹⁴ However, some cases have reported resolution of pannus associated with RA and other forms of chronic atlantoaxial instability only after posterior stabilization.¹⁴In order to manage pannus, cervical spine examination for the diagnosis of cervical involvement is encouraged to prevent morbidity and mortality.¹³ There are new data that demonstrated the potential of using retinoid X receptor agonists, such as bexarotene, as a treatment against the development and progression of pannus.¹⁴

Conclusions

We present a patient with cervical pannus disease without RA whose diagnosis was based on the pathognomonic pattern seen on MRI. She showed a clinically significant recovery with an occiput to C2 posterior instrument arthrodesis as well as decompression. She showed marked improvements in her headaches and unsteady gait. This case report highlights the importance of realizing cervical pannus as a disease found in patients without RA. It serves as an alert to clinicians for timely detection, diagnosis, and initiation of treatment to prevent mortality and long-term neurologic sequelae of cervical pannus.

Although further studies of early diagnosis and treatment for cervical pannus are warranted, we propose that including pannus in a differential diagnosis for patients with no RA could be lifesaving.

Bronchogenic cyst is a rare foregut malformation that typically presents during the second decade of life that arises due to aberrant development from the tracheobronchial tree.¹ Mediastinal bronchogenic cyst is the most common primary cystic lesion of the mediastinum, and bronchogenic cysts of the mediastinum represent 18% of all primary mediastinal malformations.² Patients with mediastinal bronchogenic cysts may present with symptoms of cough, dyspnea, or wheezing if there is encroachment on surrounding structures.

Rarely, bronchogenic cysts can become infected. Definitive treatment of bronchogenic cysts is surgical excision; however, endobronchial ultrasound (EBUS)-guided drainage also can be employed. EBUS-guided drainage may be used when the cyst cannot be distinguished from solid mass on computed tomography (CT) images, to relieve symptomatic compression of surrounding structures, or to provide a histologic or microbial diagnosis in cases where surgical excision is not immediately available. We present the first-ever described case of bronchogenic cyst infected with Actinomyces, diagnosed by EBUS-guided drainage as well as a review of the literature regarding infected bronchogenic cysts and management of cysts affecting mediastinal structures.

Case Presentation

A 57-year-old African American male presented with a 4-day history of continuous, sharp, substernal chest pain accompanied by dyspnea. Additionally, the patient reported progressive dysphagia to solids. The posteroanterior view of a chest X-ray showed a widened mediastinum with splaying of the carina. A contrast-enhanced CT of the chest showed a large, middle mediastinal mass of heterogenous density measuring 7.3. × 7.0 × 6.0 cm with compression of the right pulmonary artery, left atria, superior vena cava and esophagus (Figure 1).

The mass demonstrated neither clear fluid-fluid level nor rounded structure with a distinct wall and uniform attenuation consistent with pure cystic structure and, in fact, was concerning for malignant process, such as lymphoma. Due to the malignancy concern and the findings of significant compression of surrounding mediastinal structures, the decision was made to proceed with bronchoscopy and EBUS-guided transbronchial needle aspiration (EBUS-TBNA) to assist in diagnosis and potentially provide symptomatic relief.

Under general anesthesia a P160 Olympus bronchoscope was advanced into the tracheobronchial tree; bronchoscopy with airway inspection revealed splayed carina with obtuse angle but was otherwise unremarkable. Next, an EBUS P160 fiber optic Olympus bronchoscope was advanced; ultrasound demonstrated a cystic structure. The EBUS-TBNA of cystic structure yielded 20 mL of brown, purulent fluid with decompression bringing pulmonary artery in ultrasound field (Figure 2). Rapid on-site cytology was performed with no preliminary findings of malignancy. The fluid was then sent for cytology and microbiologic evaluation.

The patient was placed on amoxicillin/clavulanate 875 mg to 125 mg twice daily for 4 weeks based on antibiotic susceptibility testing to prevent progression to mediastinitis related to Actinomyces infection. The duration of therapy was extrapolated from treatment regimens described in case series of cervicofacial and abdominal Actinomyces infections.³ Thoracic surgery evaluation for definitive excision of cyst was recommended after the patient completed his course of antibiotics.

The patient underwent dental evaluation to identify the source of Actinomyces infection but there appeared to be no odontogenic source. The patient also had extensive skin survey with no findings of overt source of Actinomyces and CT abdomen/pelvis also identified no abscess that could be a potential source. He subsequently underwent thoracoscopic resection with pathology demonstrating a fibrous cyst wall lined with ciliated columnar epithelium consistent with diagnosis of bronchogenic cyst (Figure 5).

Discussion

Bronchogenic cysts can present at birth or later in life; patients may be asymptomatic for decades prior to discovery.⁴ Cysts located in the mediastinum can cause compression of the trachea and esophagus and cause cough, dyspnea, chest pain, and dysphagia.⁵ More life-threatening complications include infection, tracheal compression, malignant transformation, superior vena cava syndrome, or spontaneous rupture into the airway.^6,7

Infection can occasionally occur, and various bacterial etiologies have been described. Hernandez-Solis and colleagues describe 12 cases of superinfected bronchogenic cysts with Staphylococcus aureus and Pseudomonas aeroginosa, the most commonly described organisms.⁸ Casal and colleagues describe a case of α-hemolytic Streptococci treated with amoxicillin.⁹ Liman and colleagues describe 2 cases of bronchogenic cyst infected with Mycobacterium and cite an additional case report by Lin and colleagues similarly infected by Mycobacterium.^10,11 Only 1 case was identified to have direct bronchial communication as a potential source of introduction of infection into bronchogenic cyst. In other cases, potential sources of infection were not identified, though it was postulated that direct ventilation could be a potential source of inoculation.

Surgical resection of mediastinal bronchogenic cysts has traditionally been considered the definitive treatment of choice.^12,13 However, bronchogenic cysts may sometimes be difficult to differentiate from soft tissue tumors by chest CT, especially in cases of cysts with nonserous fluid. In particular, cysts that are infected are likely to have increased density and high attenuation on imaging; therefore, surgical excision may be delayed until diagnosis is made.¹⁴ Due to low complication rates, EBUS is increasingly used in the diagnosis and therapeutic management of bronchogenic cysts as an alternative to surgery, particularly for those who are symptomatic.^15,16 Ultrasound guidance can allow for complete aspiration of the cyst, causing complete collapse of the cystic space and can facilitate adhesion between the mucosal surfaces lining the cavity and reduce recurrence.¹⁷ Nonetheless, bronchogenic cysts that are found to be infected, recur, or have a malignant component should be resected for definitive treatment.¹⁸

The mass discovered on our patient’s imaging appeared to have heterogenous attenuation consistent with malignancy rather than homogenous attenuation surrounded by a clearly demarcated wall consistent with a cystic structure; therefore, EBUS-TBNA was initially pursued and yielded an expedited diagnosis of the first-ever described bronchogenic cyst with Actinomyces superinfection as well as dramatic symptomatic relief of compression of surrounding mediastinal structures, particularly of the right pulmonary artery. As this is a congenital malformation, the patient was likely asymptomatic until the cyst became infected, after which he likely experience cyst growth with subsequent encroachment of surrounding mediastinal structures. Additionally, identification of pathogen by TBNA allowed for treatment before surgical excision, possibly avoiding accidental spread of pathogen intraoperatively.

Conclusions

Our case adds to the literature on the use of EBUS-TBNA as a diagnostic and therapeutic modality for bronchogenic cyst. While cases of mediastinitis and pleural effusion following EBUS-guided aspiration of bronchogenic cysts have been reported, complications are extremely rare.¹⁹ EBUS is increasingly favored as a means of immediate diagnosis and treatment in cases where CT imaging may not overtly suggest cystic structure and in patients experiencing compression of critical mediastinal structures.

Bronchogenic cyst is a rare foregut malformation that typically presents during the second decade of life that arises due to aberrant development from the tracheobronchial tree.¹ Mediastinal bronchogenic cyst is the most common primary cystic lesion of the mediastinum, and bronchogenic cysts of the mediastinum represent 18% of all primary mediastinal malformations.² Patients with mediastinal bronchogenic cysts may present with symptoms of cough, dyspnea, or wheezing if there is encroachment on surrounding structures.

Rarely, bronchogenic cysts can become infected. Definitive treatment of bronchogenic cysts is surgical excision; however, endobronchial ultrasound (EBUS)-guided drainage also can be employed. EBUS-guided drainage may be used when the cyst cannot be distinguished from solid mass on computed tomography (CT) images, to relieve symptomatic compression of surrounding structures, or to provide a histologic or microbial diagnosis in cases where surgical excision is not immediately available. We present the first-ever described case of bronchogenic cyst infected with Actinomyces, diagnosed by EBUS-guided drainage as well as a review of the literature regarding infected bronchogenic cysts and management of cysts affecting mediastinal structures.

Case Presentation

A 57-year-old African American male presented with a 4-day history of continuous, sharp, substernal chest pain accompanied by dyspnea. Additionally, the patient reported progressive dysphagia to solids. The posteroanterior view of a chest X-ray showed a widened mediastinum with splaying of the carina. A contrast-enhanced CT of the chest showed a large, middle mediastinal mass of heterogenous density measuring 7.3. × 7.0 × 6.0 cm with compression of the right pulmonary artery, left atria, superior vena cava and esophagus (Figure 1).

The mass demonstrated neither clear fluid-fluid level nor rounded structure with a distinct wall and uniform attenuation consistent with pure cystic structure and, in fact, was concerning for malignant process, such as lymphoma. Due to the malignancy concern and the findings of significant compression of surrounding mediastinal structures, the decision was made to proceed with bronchoscopy and EBUS-guided transbronchial needle aspiration (EBUS-TBNA) to assist in diagnosis and potentially provide symptomatic relief.

Under general anesthesia a P160 Olympus bronchoscope was advanced into the tracheobronchial tree; bronchoscopy with airway inspection revealed splayed carina with obtuse angle but was otherwise unremarkable. Next, an EBUS P160 fiber optic Olympus bronchoscope was advanced; ultrasound demonstrated a cystic structure. The EBUS-TBNA of cystic structure yielded 20 mL of brown, purulent fluid with decompression bringing pulmonary artery in ultrasound field (Figure 2). Rapid on-site cytology was performed with no preliminary findings of malignancy. The fluid was then sent for cytology and microbiologic evaluation.

The patient was placed on amoxicillin/clavulanate 875 mg to 125 mg twice daily for 4 weeks based on antibiotic susceptibility testing to prevent progression to mediastinitis related to Actinomyces infection. The duration of therapy was extrapolated from treatment regimens described in case series of cervicofacial and abdominal Actinomyces infections.³ Thoracic surgery evaluation for definitive excision of cyst was recommended after the patient completed his course of antibiotics.

The patient underwent dental evaluation to identify the source of Actinomyces infection but there appeared to be no odontogenic source. The patient also had extensive skin survey with no findings of overt source of Actinomyces and CT abdomen/pelvis also identified no abscess that could be a potential source. He subsequently underwent thoracoscopic resection with pathology demonstrating a fibrous cyst wall lined with ciliated columnar epithelium consistent with diagnosis of bronchogenic cyst (Figure 5).

Discussion

Bronchogenic cysts can present at birth or later in life; patients may be asymptomatic for decades prior to discovery.⁴ Cysts located in the mediastinum can cause compression of the trachea and esophagus and cause cough, dyspnea, chest pain, and dysphagia.⁵ More life-threatening complications include infection, tracheal compression, malignant transformation, superior vena cava syndrome, or spontaneous rupture into the airway.^6,7

Infection can occasionally occur, and various bacterial etiologies have been described. Hernandez-Solis and colleagues describe 12 cases of superinfected bronchogenic cysts with Staphylococcus aureus and Pseudomonas aeroginosa, the most commonly described organisms.⁸ Casal and colleagues describe a case of α-hemolytic Streptococci treated with amoxicillin.⁹ Liman and colleagues describe 2 cases of bronchogenic cyst infected with Mycobacterium and cite an additional case report by Lin and colleagues similarly infected by Mycobacterium.^10,11 Only 1 case was identified to have direct bronchial communication as a potential source of introduction of infection into bronchogenic cyst. In other cases, potential sources of infection were not identified, though it was postulated that direct ventilation could be a potential source of inoculation.

Surgical resection of mediastinal bronchogenic cysts has traditionally been considered the definitive treatment of choice.^12,13 However, bronchogenic cysts may sometimes be difficult to differentiate from soft tissue tumors by chest CT, especially in cases of cysts with nonserous fluid. In particular, cysts that are infected are likely to have increased density and high attenuation on imaging; therefore, surgical excision may be delayed until diagnosis is made.¹⁴ Due to low complication rates, EBUS is increasingly used in the diagnosis and therapeutic management of bronchogenic cysts as an alternative to surgery, particularly for those who are symptomatic.^15,16 Ultrasound guidance can allow for complete aspiration of the cyst, causing complete collapse of the cystic space and can facilitate adhesion between the mucosal surfaces lining the cavity and reduce recurrence.¹⁷ Nonetheless, bronchogenic cysts that are found to be infected, recur, or have a malignant component should be resected for definitive treatment.¹⁸

The mass discovered on our patient’s imaging appeared to have heterogenous attenuation consistent with malignancy rather than homogenous attenuation surrounded by a clearly demarcated wall consistent with a cystic structure; therefore, EBUS-TBNA was initially pursued and yielded an expedited diagnosis of the first-ever described bronchogenic cyst with Actinomyces superinfection as well as dramatic symptomatic relief of compression of surrounding mediastinal structures, particularly of the right pulmonary artery. As this is a congenital malformation, the patient was likely asymptomatic until the cyst became infected, after which he likely experience cyst growth with subsequent encroachment of surrounding mediastinal structures. Additionally, identification of pathogen by TBNA allowed for treatment before surgical excision, possibly avoiding accidental spread of pathogen intraoperatively.

Conclusions

Our case adds to the literature on the use of EBUS-TBNA as a diagnostic and therapeutic modality for bronchogenic cyst. While cases of mediastinitis and pleural effusion following EBUS-guided aspiration of bronchogenic cysts have been reported, complications are extremely rare.¹⁹ EBUS is increasingly favored as a means of immediate diagnosis and treatment in cases where CT imaging may not overtly suggest cystic structure and in patients experiencing compression of critical mediastinal structures.

Bronchogenic cyst is a rare foregut malformation that typically presents during the second decade of life that arises due to aberrant development from the tracheobronchial tree.¹ Mediastinal bronchogenic cyst is the most common primary cystic lesion of the mediastinum, and bronchogenic cysts of the mediastinum represent 18% of all primary mediastinal malformations.² Patients with mediastinal bronchogenic cysts may present with symptoms of cough, dyspnea, or wheezing if there is encroachment on surrounding structures.

Rarely, bronchogenic cysts can become infected. Definitive treatment of bronchogenic cysts is surgical excision; however, endobronchial ultrasound (EBUS)-guided drainage also can be employed. EBUS-guided drainage may be used when the cyst cannot be distinguished from solid mass on computed tomography (CT) images, to relieve symptomatic compression of surrounding structures, or to provide a histologic or microbial diagnosis in cases where surgical excision is not immediately available. We present the first-ever described case of bronchogenic cyst infected with Actinomyces, diagnosed by EBUS-guided drainage as well as a review of the literature regarding infected bronchogenic cysts and management of cysts affecting mediastinal structures.

Case Presentation

A 57-year-old African American male presented with a 4-day history of continuous, sharp, substernal chest pain accompanied by dyspnea. Additionally, the patient reported progressive dysphagia to solids. The posteroanterior view of a chest X-ray showed a widened mediastinum with splaying of the carina. A contrast-enhanced CT of the chest showed a large, middle mediastinal mass of heterogenous density measuring 7.3. × 7.0 × 6.0 cm with compression of the right pulmonary artery, left atria, superior vena cava and esophagus (Figure 1).

The mass demonstrated neither clear fluid-fluid level nor rounded structure with a distinct wall and uniform attenuation consistent with pure cystic structure and, in fact, was concerning for malignant process, such as lymphoma. Due to the malignancy concern and the findings of significant compression of surrounding mediastinal structures, the decision was made to proceed with bronchoscopy and EBUS-guided transbronchial needle aspiration (EBUS-TBNA) to assist in diagnosis and potentially provide symptomatic relief.

Under general anesthesia a P160 Olympus bronchoscope was advanced into the tracheobronchial tree; bronchoscopy with airway inspection revealed splayed carina with obtuse angle but was otherwise unremarkable. Next, an EBUS P160 fiber optic Olympus bronchoscope was advanced; ultrasound demonstrated a cystic structure. The EBUS-TBNA of cystic structure yielded 20 mL of brown, purulent fluid with decompression bringing pulmonary artery in ultrasound field (Figure 2). Rapid on-site cytology was performed with no preliminary findings of malignancy. The fluid was then sent for cytology and microbiologic evaluation.

The patient was placed on amoxicillin/clavulanate 875 mg to 125 mg twice daily for 4 weeks based on antibiotic susceptibility testing to prevent progression to mediastinitis related to Actinomyces infection. The duration of therapy was extrapolated from treatment regimens described in case series of cervicofacial and abdominal Actinomyces infections.³ Thoracic surgery evaluation for definitive excision of cyst was recommended after the patient completed his course of antibiotics.

The patient underwent dental evaluation to identify the source of Actinomyces infection but there appeared to be no odontogenic source. The patient also had extensive skin survey with no findings of overt source of Actinomyces and CT abdomen/pelvis also identified no abscess that could be a potential source. He subsequently underwent thoracoscopic resection with pathology demonstrating a fibrous cyst wall lined with ciliated columnar epithelium consistent with diagnosis of bronchogenic cyst (Figure 5).

Discussion

Bronchogenic cysts can present at birth or later in life; patients may be asymptomatic for decades prior to discovery.⁴ Cysts located in the mediastinum can cause compression of the trachea and esophagus and cause cough, dyspnea, chest pain, and dysphagia.⁵ More life-threatening complications include infection, tracheal compression, malignant transformation, superior vena cava syndrome, or spontaneous rupture into the airway.^6,7

Infection can occasionally occur, and various bacterial etiologies have been described. Hernandez-Solis and colleagues describe 12 cases of superinfected bronchogenic cysts with Staphylococcus aureus and Pseudomonas aeroginosa, the most commonly described organisms.⁸ Casal and colleagues describe a case of α-hemolytic Streptococci treated with amoxicillin.⁹ Liman and colleagues describe 2 cases of bronchogenic cyst infected with Mycobacterium and cite an additional case report by Lin and colleagues similarly infected by Mycobacterium.^10,11 Only 1 case was identified to have direct bronchial communication as a potential source of introduction of infection into bronchogenic cyst. In other cases, potential sources of infection were not identified, though it was postulated that direct ventilation could be a potential source of inoculation.

Surgical resection of mediastinal bronchogenic cysts has traditionally been considered the definitive treatment of choice.^12,13 However, bronchogenic cysts may sometimes be difficult to differentiate from soft tissue tumors by chest CT, especially in cases of cysts with nonserous fluid. In particular, cysts that are infected are likely to have increased density and high attenuation on imaging; therefore, surgical excision may be delayed until diagnosis is made.¹⁴ Due to low complication rates, EBUS is increasingly used in the diagnosis and therapeutic management of bronchogenic cysts as an alternative to surgery, particularly for those who are symptomatic.^15,16 Ultrasound guidance can allow for complete aspiration of the cyst, causing complete collapse of the cystic space and can facilitate adhesion between the mucosal surfaces lining the cavity and reduce recurrence.¹⁷ Nonetheless, bronchogenic cysts that are found to be infected, recur, or have a malignant component should be resected for definitive treatment.¹⁸

The mass discovered on our patient’s imaging appeared to have heterogenous attenuation consistent with malignancy rather than homogenous attenuation surrounded by a clearly demarcated wall consistent with a cystic structure; therefore, EBUS-TBNA was initially pursued and yielded an expedited diagnosis of the first-ever described bronchogenic cyst with Actinomyces superinfection as well as dramatic symptomatic relief of compression of surrounding mediastinal structures, particularly of the right pulmonary artery. As this is a congenital malformation, the patient was likely asymptomatic until the cyst became infected, after which he likely experience cyst growth with subsequent encroachment of surrounding mediastinal structures. Additionally, identification of pathogen by TBNA allowed for treatment before surgical excision, possibly avoiding accidental spread of pathogen intraoperatively.

Conclusions

Our case adds to the literature on the use of EBUS-TBNA as a diagnostic and therapeutic modality for bronchogenic cyst. While cases of mediastinitis and pleural effusion following EBUS-guided aspiration of bronchogenic cysts have been reported, complications are extremely rare.¹⁹ EBUS is increasingly favored as a means of immediate diagnosis and treatment in cases where CT imaging may not overtly suggest cystic structure and in patients experiencing compression of critical mediastinal structures.

“Whenever possible, we will develop innovative, low-cost, and small-footprint approaches to achieve our security objectives.” ¹

Team member and participant observations can deliver valuable insight into the effectiveness of an activity or project. Certainly, documentation of such qualitative assessment through survey questions or narratives can reveal important information for future action. This qualitative aspect was a significant consideration in the formation of an embedded health engagement team (EHET) intended to improve foreign assistance and health outcomes for global humanitarian and security cooperation activities.

Since health activities are centered on human interaction and relationships, some observation or qualitative assessment must be included to truly determine short-term local buy-in and long-term outcomes. The following observations include the direct narrative perspectives of team members from a multidisciplinary primary care EHET that add experiential depth to prior assessment of the pilot test of such teams during Continuing Promise 2011, a 9-country series of health engagement activities employed from the USNS Comfort.² The embedded team consisted of US Air Force (USAF), US Navy (USN), and nongovernmental organization (NGO) personnel working directly in a primary care clinic of the Costa Rican public health system.

This is small sample of a few team members who responded to a simple, open-ended prompt to record their impression of the EHET concept and experiences. Documenting this information should highlight the importance of seeking similar qualitative mission data for future health engagements. Standardized questionnaires have been used to evaluate health activities and have provided valuable analysis and recommendations that have advanced US Department of Defense (DoD) global health engagement.³ Captured narrative observation from the EHET pilot study is a complementary qualitative method that supports the concept of small, well prepared, culturally competent, EHETs tailored to work within a partner system rather than outside of it will achieve greater mutual benefit, including the application of better, more equitable health and health system principles.⁴ In this embedded manner, health care professionals may readily contribute to host nation health sector plans and goals while achieving military objectives, political goals, and mutual strategic interests through both military-military and military-civilian applications.

Observations and Reflections

Family Physician (Maj, Second Physician, USAF)

“Overall, the experience I had with the embedded team was truly rewarding. I hope this becomes a tool used to augment humanitarian missions. There is no way to truly understand a systems strengths and weakness except by being embedded in the clinic or hospital. For 3 days I worked alongside a bilingual physician at a local family practice clinic. The clinic did full spectrum family practice, including prenatal care. The doctor saw between 25 and 35 patients each day plus covered urgent care during lunch. Paper charting was used although the clinic is looking into electronic records. The clinic was very efficient. All team members were very aware of their roles and did their jobs with a smile and worked well together.

“Most patient encounters took between 10 and 15 minutes although the patient might stay around for IV therapy, intramuscular pain medications, or other treatments that were carried out by the nursing staff. There was a small procedure room and procedures would be performed on the same day they were identified. The nursing staff would set up everything, and in between patients the provider would complete the procedure. On the first day I mostly shadowed, but in the afternoon, I was asked to consult on some of the more complicated patients with diabetes mellitus or hypertension. On the second day I shadowed a health care provider who did not speak English and through an interpreter he asked for my input. In the afternoon the nursing staff asked me to discuss the treatment of abscesses. I discussed techniques of incision and drainage and importance of packing and proper wound care, worked with one of their wound care nurses on packing of several wounds, and consulted on a patient with a venous stasis ulcer.

“We identified an educational opportunity for the nursing staff. On the third day I brought a US certified wound care specialist and I gave a Microsoft PowerPoint presentation on venous stasis ulcers and proper wound care. The nursing staff and clinic were very receptive and asked if we would develop a patient-based educational presentation. The wound care specialist spent the afternoon giving hands-on demonstrations in the wound care clinic, and I taught technique for excisional biopsy of skin tags and moles to physicians. One of the host physicians arranged for more consultations on more of the clinic’s complicated patients, which included a staff member and a relative.”

Medical Technician (MSgt, E-7, Independent Duty Medical Technician, USAF)

“The first day I was assigned to work with the ‘auxiliaries,’ nurses working in the urgent care area at the clinic. Their urgent care area had limited equipment and supplies and included equipment such as mercury thermometers, a few stethoscopes and 1 blood pressure cuff. Their duties consisted of screening patients, starting IVs, giving injections and breathing treatments. They also had a minor surgery room where the nurses helped.

“During the observation of the placement of an IV catheter, I noticed that they were using a port and attaching a needle to the IV tubing and leaving the needle attached to the patient. I asked them about their procedure and incidents with needlesticks since they had to be pretty accurate in getting the needle through the port. The nurse stated there were a significant number of cases of needlesticks. The following day, we brought 18-g, 20-g, and 23-g IV catheters, saline locks, syringes, and our team’s junior physician and I instructed the nurses how to set up an IV without using the needle port.

“The third day at the clinic, I assisted in checking in patients (blood pressure, weight, interviews). I also helped run the immunizations clinic, assisting in giving both pediatric and adult immunizations. Since there was only 1 nurse on shift that day, we multitasked and also gave injections prescribed by the providers, such as medroxyprogesterone and dexamethasone. By far, this was the most rewarding part of the mission. I really felt as though we were part of the team and believe we truly made a difference.”

Administrator (LTC, Medical Service Corps, USN)

“I learned many items from our visit to Clinica Dr. Francisco Quintanas Area de Salud 4 Chacarita. I reviewed the business plan contained in two 1.5-inch hardbound books. Their business plan outlined the population served, projections for upcoming year, and contracts. Area 4 served 21,344 people (11,197 men and 10,147 women). The business plan reviewed historical encounter information (ie, average patient is seen 2.6 times annually, 203,285 laboratory tests were performed in 2010, no radiology capabilities) and contained metrics for key programs for upcoming year (eg, vaccinations, women wellness) that seemed similar to US Healthcare Effectiveness Data and Information Set (HEDIS) measures.

“Our partners discussed financing of the health care they provide, including money flows to and from the government, the work center, and the employees. The business plan contains contract information and costs for maintenance, utilities, personnel, and other issues that would be typical for US-based operations as well. Housekeeping, some of the secretaries, and security staff are not employees—they are contracted personnel. Money is shifted to meet unexpected needs (ie, in 2009/2010–H1N1 influenza was unanticipated). Money was taken from other programs to meet the need.

“Within the Area 4 clinics there are 94 personnel, including 15 physicians. They have a document that is similar to our Activity Manning Document, which outlines personnel billet code, name, and specialty. The Asistentes Técnicos de Atención Primaria are the personnel who conduct home visits and are a unique capability—we do not have an exact equivalent in most US health care systems. Pregnant workers are released from work 1 month prior to the due date and are expected to return to work 3 months postdelivery.”

Medical Logistics (Capt, Medical Service Corps, USAF)

“Costa Rica is still growing in aspects of national health care but has a reliable system in place it seems. Similar to many of the countries visited, it has great capacity for building, but is challenged to increase its infrastructure. In 2011, part of this was due to a recent economic decline in the nation and its health care sector. They have interaction both with other regional clinics managed under the same national health system construct (Caja Costarricense del Seguro Social) as well as with private practices and specialty services. The clinics are open only daytime business hours. Only the regional hospital is open 24/7 for emergent care.

“Supplies are distributed to the regional clinics primarily from San José (the capital and largest city), but also there are some smaller warehousing of clinical materials located around the region. One of these warehouses was in Puntarenas where our clinic was located. To get better information for future supply chain management support we would need to speak with the central distribution/suppliers of all nationalized clinic-run entities. What our partners did teach is that at a higher, national level the clinics are standardized with what they will carry and need to keep on-hand depending upon the clinic classification (ie, level 1, 2, or 3).

“Equipment is purchased similar to the DoD method: Requests are submitted toward the end of the year, the administration prioritizes the lists, and then buys what they feel is most beneficial to the clinic with the resources available. Our hosts stated that before the end of the year, it is very difficult to prioritize needs other than some of the items that they ‘always need’ because they are unlikely to receive items very low on their list. The hosts stated that they would be very interested in having a chance to receive any excess US military equipment from their priority lists if there was a mechanism to do so. In future EHET missions, advance coordination would need to occur to see if (locally compatible) equipment needs could be met through the Defense Reutilization and Marketing Office (DRMO). Alternatively, an embedded team focused on Biomedical Equipment repair could work alongside partners such as at this clinic to develop a sustainable preventive maintenance and equipment testing program. Advance coordination on equipment status would foster improvement for resourceful partner clinics such as Chacarita, with targeted involvement from US military biomedical equipment technicians.”

Discussion

These 4 firsthand accounts from a multidisciplinary, primary-care focused, EHET offers multiple preliminary evidence of the value of this small-scale embedded approach. The accounts are responses to an open-ended prompt for personal impressions and key thoughts as part of an EHET. Three of the advantages gleaned from these accounts are greater personal satisfaction, detailed insight into local operations and health systems, and deeper empathy and respect for common challenges despite health system differences compared with the US military health system.

These advantages are critical to afford the US military personnel the ability to more effectively execute engagement goals, such as meeting health needs in humanitarian assistance, advancing interoperable capacity for security cooperation, or achieving targeted training to enhance US medical operational skills. The greater personal satisfaction was evident in the team member responses that, despite mission stops in 7 prior countries, “This by far was the most rewarding part of the Continuing Promise 2011 mission” and “I hope this becomes a tool used to augment humanitarian missions.”

The descriptions by both the administrator and the logistician on the intimate details that the hosts shared with them is a testament to the rapid trust engendered by the embedded approach. There was a trust to share information as a result of acknowledged local strengths and legitimate interest in local challenges. Peer appreciation was evident; although they did not speak the same literal language, they spoke the same professional language, which was apparent even through the use of an interpreter.

A third advantage, evident from these written exchanges is a regular acknowledgement that health system issues, pursued processes, and desired outcomes are similar between different systems. There may be significant differences in actual resources and infrastructure, but some of the bureaucracy is similar. This last insight is essential to grasp in order to seek capacity building and interoperable solutions toward common goals; empathy is needed to encourage local ownership and sustainability while respecting local challenges and different problem-solving approaches and processes.

Conclusions 

The EHET concept afforded deep insight by team members into ways to partner with their hosts to target better health outcomes and meaningful partnership for potential long-term geopolitical impact. Long duration embedded teams, or recurrent insertion, in a single location will achieve greater long-term benefits because of greater health system and cultural understanding. EHETs, once accepted and refined from prototype to standard employment tool, should prove to be a more effective tool in building partnerships, building capacity, and increased security cooperation by using US military resources to support legitimate health needs either in a military-military or military-civilian setting.⁵ These firsthand accounts provide preliminary evidence that embedded teams may be a critical and needed tool to “ensure that military health engagement is appropriate, constructive, effective, and coordinated with other actors.”⁶

Acknowledgments

Additional original EHET team members included LCDR Jeanne Jimenez, RN; CDR Francine Worthington, Health Administrator; Maj Tony McClung, RN; Mrs. Romero, RN of LDS Charities, and the staff of the Chacarita clinics in Costa Rica.

“Whenever possible, we will develop innovative, low-cost, and small-footprint approaches to achieve our security objectives.” ¹

Team member and participant observations can deliver valuable insight into the effectiveness of an activity or project. Certainly, documentation of such qualitative assessment through survey questions or narratives can reveal important information for future action. This qualitative aspect was a significant consideration in the formation of an embedded health engagement team (EHET) intended to improve foreign assistance and health outcomes for global humanitarian and security cooperation activities.

Since health activities are centered on human interaction and relationships, some observation or qualitative assessment must be included to truly determine short-term local buy-in and long-term outcomes. The following observations include the direct narrative perspectives of team members from a multidisciplinary primary care EHET that add experiential depth to prior assessment of the pilot test of such teams during Continuing Promise 2011, a 9-country series of health engagement activities employed from the USNS Comfort.² The embedded team consisted of US Air Force (USAF), US Navy (USN), and nongovernmental organization (NGO) personnel working directly in a primary care clinic of the Costa Rican public health system.

This is small sample of a few team members who responded to a simple, open-ended prompt to record their impression of the EHET concept and experiences. Documenting this information should highlight the importance of seeking similar qualitative mission data for future health engagements. Standardized questionnaires have been used to evaluate health activities and have provided valuable analysis and recommendations that have advanced US Department of Defense (DoD) global health engagement.³ Captured narrative observation from the EHET pilot study is a complementary qualitative method that supports the concept of small, well prepared, culturally competent, EHETs tailored to work within a partner system rather than outside of it will achieve greater mutual benefit, including the application of better, more equitable health and health system principles.⁴ In this embedded manner, health care professionals may readily contribute to host nation health sector plans and goals while achieving military objectives, political goals, and mutual strategic interests through both military-military and military-civilian applications.

Observations and Reflections

Family Physician (Maj, Second Physician, USAF)

“Overall, the experience I had with the embedded team was truly rewarding. I hope this becomes a tool used to augment humanitarian missions. There is no way to truly understand a systems strengths and weakness except by being embedded in the clinic or hospital. For 3 days I worked alongside a bilingual physician at a local family practice clinic. The clinic did full spectrum family practice, including prenatal care. The doctor saw between 25 and 35 patients each day plus covered urgent care during lunch. Paper charting was used although the clinic is looking into electronic records. The clinic was very efficient. All team members were very aware of their roles and did their jobs with a smile and worked well together.

“Most patient encounters took between 10 and 15 minutes although the patient might stay around for IV therapy, intramuscular pain medications, or other treatments that were carried out by the nursing staff. There was a small procedure room and procedures would be performed on the same day they were identified. The nursing staff would set up everything, and in between patients the provider would complete the procedure. On the first day I mostly shadowed, but in the afternoon, I was asked to consult on some of the more complicated patients with diabetes mellitus or hypertension. On the second day I shadowed a health care provider who did not speak English and through an interpreter he asked for my input. In the afternoon the nursing staff asked me to discuss the treatment of abscesses. I discussed techniques of incision and drainage and importance of packing and proper wound care, worked with one of their wound care nurses on packing of several wounds, and consulted on a patient with a venous stasis ulcer.

“We identified an educational opportunity for the nursing staff. On the third day I brought a US certified wound care specialist and I gave a Microsoft PowerPoint presentation on venous stasis ulcers and proper wound care. The nursing staff and clinic were very receptive and asked if we would develop a patient-based educational presentation. The wound care specialist spent the afternoon giving hands-on demonstrations in the wound care clinic, and I taught technique for excisional biopsy of skin tags and moles to physicians. One of the host physicians arranged for more consultations on more of the clinic’s complicated patients, which included a staff member and a relative.”

Medical Technician (MSgt, E-7, Independent Duty Medical Technician, USAF)

“The first day I was assigned to work with the ‘auxiliaries,’ nurses working in the urgent care area at the clinic. Their urgent care area had limited equipment and supplies and included equipment such as mercury thermometers, a few stethoscopes and 1 blood pressure cuff. Their duties consisted of screening patients, starting IVs, giving injections and breathing treatments. They also had a minor surgery room where the nurses helped.

“During the observation of the placement of an IV catheter, I noticed that they were using a port and attaching a needle to the IV tubing and leaving the needle attached to the patient. I asked them about their procedure and incidents with needlesticks since they had to be pretty accurate in getting the needle through the port. The nurse stated there were a significant number of cases of needlesticks. The following day, we brought 18-g, 20-g, and 23-g IV catheters, saline locks, syringes, and our team’s junior physician and I instructed the nurses how to set up an IV without using the needle port.

“The third day at the clinic, I assisted in checking in patients (blood pressure, weight, interviews). I also helped run the immunizations clinic, assisting in giving both pediatric and adult immunizations. Since there was only 1 nurse on shift that day, we multitasked and also gave injections prescribed by the providers, such as medroxyprogesterone and dexamethasone. By far, this was the most rewarding part of the mission. I really felt as though we were part of the team and believe we truly made a difference.”

Administrator (LTC, Medical Service Corps, USN)

“I learned many items from our visit to Clinica Dr. Francisco Quintanas Area de Salud 4 Chacarita. I reviewed the business plan contained in two 1.5-inch hardbound books. Their business plan outlined the population served, projections for upcoming year, and contracts. Area 4 served 21,344 people (11,197 men and 10,147 women). The business plan reviewed historical encounter information (ie, average patient is seen 2.6 times annually, 203,285 laboratory tests were performed in 2010, no radiology capabilities) and contained metrics for key programs for upcoming year (eg, vaccinations, women wellness) that seemed similar to US Healthcare Effectiveness Data and Information Set (HEDIS) measures.

“Our partners discussed financing of the health care they provide, including money flows to and from the government, the work center, and the employees. The business plan contains contract information and costs for maintenance, utilities, personnel, and other issues that would be typical for US-based operations as well. Housekeeping, some of the secretaries, and security staff are not employees—they are contracted personnel. Money is shifted to meet unexpected needs (ie, in 2009/2010–H1N1 influenza was unanticipated). Money was taken from other programs to meet the need.

“Within the Area 4 clinics there are 94 personnel, including 15 physicians. They have a document that is similar to our Activity Manning Document, which outlines personnel billet code, name, and specialty. The Asistentes Técnicos de Atención Primaria are the personnel who conduct home visits and are a unique capability—we do not have an exact equivalent in most US health care systems. Pregnant workers are released from work 1 month prior to the due date and are expected to return to work 3 months postdelivery.”

Medical Logistics (Capt, Medical Service Corps, USAF)

“Costa Rica is still growing in aspects of national health care but has a reliable system in place it seems. Similar to many of the countries visited, it has great capacity for building, but is challenged to increase its infrastructure. In 2011, part of this was due to a recent economic decline in the nation and its health care sector. They have interaction both with other regional clinics managed under the same national health system construct (Caja Costarricense del Seguro Social) as well as with private practices and specialty services. The clinics are open only daytime business hours. Only the regional hospital is open 24/7 for emergent care.

“Supplies are distributed to the regional clinics primarily from San José (the capital and largest city), but also there are some smaller warehousing of clinical materials located around the region. One of these warehouses was in Puntarenas where our clinic was located. To get better information for future supply chain management support we would need to speak with the central distribution/suppliers of all nationalized clinic-run entities. What our partners did teach is that at a higher, national level the clinics are standardized with what they will carry and need to keep on-hand depending upon the clinic classification (ie, level 1, 2, or 3).

“Equipment is purchased similar to the DoD method: Requests are submitted toward the end of the year, the administration prioritizes the lists, and then buys what they feel is most beneficial to the clinic with the resources available. Our hosts stated that before the end of the year, it is very difficult to prioritize needs other than some of the items that they ‘always need’ because they are unlikely to receive items very low on their list. The hosts stated that they would be very interested in having a chance to receive any excess US military equipment from their priority lists if there was a mechanism to do so. In future EHET missions, advance coordination would need to occur to see if (locally compatible) equipment needs could be met through the Defense Reutilization and Marketing Office (DRMO). Alternatively, an embedded team focused on Biomedical Equipment repair could work alongside partners such as at this clinic to develop a sustainable preventive maintenance and equipment testing program. Advance coordination on equipment status would foster improvement for resourceful partner clinics such as Chacarita, with targeted involvement from US military biomedical equipment technicians.”

Discussion

These 4 firsthand accounts from a multidisciplinary, primary-care focused, EHET offers multiple preliminary evidence of the value of this small-scale embedded approach. The accounts are responses to an open-ended prompt for personal impressions and key thoughts as part of an EHET. Three of the advantages gleaned from these accounts are greater personal satisfaction, detailed insight into local operations and health systems, and deeper empathy and respect for common challenges despite health system differences compared with the US military health system.

These advantages are critical to afford the US military personnel the ability to more effectively execute engagement goals, such as meeting health needs in humanitarian assistance, advancing interoperable capacity for security cooperation, or achieving targeted training to enhance US medical operational skills. The greater personal satisfaction was evident in the team member responses that, despite mission stops in 7 prior countries, “This by far was the most rewarding part of the Continuing Promise 2011 mission” and “I hope this becomes a tool used to augment humanitarian missions.”

The descriptions by both the administrator and the logistician on the intimate details that the hosts shared with them is a testament to the rapid trust engendered by the embedded approach. There was a trust to share information as a result of acknowledged local strengths and legitimate interest in local challenges. Peer appreciation was evident; although they did not speak the same literal language, they spoke the same professional language, which was apparent even through the use of an interpreter.

A third advantage, evident from these written exchanges is a regular acknowledgement that health system issues, pursued processes, and desired outcomes are similar between different systems. There may be significant differences in actual resources and infrastructure, but some of the bureaucracy is similar. This last insight is essential to grasp in order to seek capacity building and interoperable solutions toward common goals; empathy is needed to encourage local ownership and sustainability while respecting local challenges and different problem-solving approaches and processes.

Conclusions 

The EHET concept afforded deep insight by team members into ways to partner with their hosts to target better health outcomes and meaningful partnership for potential long-term geopolitical impact. Long duration embedded teams, or recurrent insertion, in a single location will achieve greater long-term benefits because of greater health system and cultural understanding. EHETs, once accepted and refined from prototype to standard employment tool, should prove to be a more effective tool in building partnerships, building capacity, and increased security cooperation by using US military resources to support legitimate health needs either in a military-military or military-civilian setting.⁵ These firsthand accounts provide preliminary evidence that embedded teams may be a critical and needed tool to “ensure that military health engagement is appropriate, constructive, effective, and coordinated with other actors.”⁶

Acknowledgments

Additional original EHET team members included LCDR Jeanne Jimenez, RN; CDR Francine Worthington, Health Administrator; Maj Tony McClung, RN; Mrs. Romero, RN of LDS Charities, and the staff of the Chacarita clinics in Costa Rica.

“Whenever possible, we will develop innovative, low-cost, and small-footprint approaches to achieve our security objectives.” ¹

Team member and participant observations can deliver valuable insight into the effectiveness of an activity or project. Certainly, documentation of such qualitative assessment through survey questions or narratives can reveal important information for future action. This qualitative aspect was a significant consideration in the formation of an embedded health engagement team (EHET) intended to improve foreign assistance and health outcomes for global humanitarian and security cooperation activities.

Since health activities are centered on human interaction and relationships, some observation or qualitative assessment must be included to truly determine short-term local buy-in and long-term outcomes. The following observations include the direct narrative perspectives of team members from a multidisciplinary primary care EHET that add experiential depth to prior assessment of the pilot test of such teams during Continuing Promise 2011, a 9-country series of health engagement activities employed from the USNS Comfort.² The embedded team consisted of US Air Force (USAF), US Navy (USN), and nongovernmental organization (NGO) personnel working directly in a primary care clinic of the Costa Rican public health system.

This is small sample of a few team members who responded to a simple, open-ended prompt to record their impression of the EHET concept and experiences. Documenting this information should highlight the importance of seeking similar qualitative mission data for future health engagements. Standardized questionnaires have been used to evaluate health activities and have provided valuable analysis and recommendations that have advanced US Department of Defense (DoD) global health engagement.³ Captured narrative observation from the EHET pilot study is a complementary qualitative method that supports the concept of small, well prepared, culturally competent, EHETs tailored to work within a partner system rather than outside of it will achieve greater mutual benefit, including the application of better, more equitable health and health system principles.⁴ In this embedded manner, health care professionals may readily contribute to host nation health sector plans and goals while achieving military objectives, political goals, and mutual strategic interests through both military-military and military-civilian applications.

Observations and Reflections

Family Physician (Maj, Second Physician, USAF)

“Overall, the experience I had with the embedded team was truly rewarding. I hope this becomes a tool used to augment humanitarian missions. There is no way to truly understand a systems strengths and weakness except by being embedded in the clinic or hospital. For 3 days I worked alongside a bilingual physician at a local family practice clinic. The clinic did full spectrum family practice, including prenatal care. The doctor saw between 25 and 35 patients each day plus covered urgent care during lunch. Paper charting was used although the clinic is looking into electronic records. The clinic was very efficient. All team members were very aware of their roles and did their jobs with a smile and worked well together.

“Most patient encounters took between 10 and 15 minutes although the patient might stay around for IV therapy, intramuscular pain medications, or other treatments that were carried out by the nursing staff. There was a small procedure room and procedures would be performed on the same day they were identified. The nursing staff would set up everything, and in between patients the provider would complete the procedure. On the first day I mostly shadowed, but in the afternoon, I was asked to consult on some of the more complicated patients with diabetes mellitus or hypertension. On the second day I shadowed a health care provider who did not speak English and through an interpreter he asked for my input. In the afternoon the nursing staff asked me to discuss the treatment of abscesses. I discussed techniques of incision and drainage and importance of packing and proper wound care, worked with one of their wound care nurses on packing of several wounds, and consulted on a patient with a venous stasis ulcer.

“We identified an educational opportunity for the nursing staff. On the third day I brought a US certified wound care specialist and I gave a Microsoft PowerPoint presentation on venous stasis ulcers and proper wound care. The nursing staff and clinic were very receptive and asked if we would develop a patient-based educational presentation. The wound care specialist spent the afternoon giving hands-on demonstrations in the wound care clinic, and I taught technique for excisional biopsy of skin tags and moles to physicians. One of the host physicians arranged for more consultations on more of the clinic’s complicated patients, which included a staff member and a relative.”

Medical Technician (MSgt, E-7, Independent Duty Medical Technician, USAF)

“The first day I was assigned to work with the ‘auxiliaries,’ nurses working in the urgent care area at the clinic. Their urgent care area had limited equipment and supplies and included equipment such as mercury thermometers, a few stethoscopes and 1 blood pressure cuff. Their duties consisted of screening patients, starting IVs, giving injections and breathing treatments. They also had a minor surgery room where the nurses helped.

“During the observation of the placement of an IV catheter, I noticed that they were using a port and attaching a needle to the IV tubing and leaving the needle attached to the patient. I asked them about their procedure and incidents with needlesticks since they had to be pretty accurate in getting the needle through the port. The nurse stated there were a significant number of cases of needlesticks. The following day, we brought 18-g, 20-g, and 23-g IV catheters, saline locks, syringes, and our team’s junior physician and I instructed the nurses how to set up an IV without using the needle port.

“The third day at the clinic, I assisted in checking in patients (blood pressure, weight, interviews). I also helped run the immunizations clinic, assisting in giving both pediatric and adult immunizations. Since there was only 1 nurse on shift that day, we multitasked and also gave injections prescribed by the providers, such as medroxyprogesterone and dexamethasone. By far, this was the most rewarding part of the mission. I really felt as though we were part of the team and believe we truly made a difference.”

Administrator (LTC, Medical Service Corps, USN)

“I learned many items from our visit to Clinica Dr. Francisco Quintanas Area de Salud 4 Chacarita. I reviewed the business plan contained in two 1.5-inch hardbound books. Their business plan outlined the population served, projections for upcoming year, and contracts. Area 4 served 21,344 people (11,197 men and 10,147 women). The business plan reviewed historical encounter information (ie, average patient is seen 2.6 times annually, 203,285 laboratory tests were performed in 2010, no radiology capabilities) and contained metrics for key programs for upcoming year (eg, vaccinations, women wellness) that seemed similar to US Healthcare Effectiveness Data and Information Set (HEDIS) measures.

“Our partners discussed financing of the health care they provide, including money flows to and from the government, the work center, and the employees. The business plan contains contract information and costs for maintenance, utilities, personnel, and other issues that would be typical for US-based operations as well. Housekeeping, some of the secretaries, and security staff are not employees—they are contracted personnel. Money is shifted to meet unexpected needs (ie, in 2009/2010–H1N1 influenza was unanticipated). Money was taken from other programs to meet the need.

“Within the Area 4 clinics there are 94 personnel, including 15 physicians. They have a document that is similar to our Activity Manning Document, which outlines personnel billet code, name, and specialty. The Asistentes Técnicos de Atención Primaria are the personnel who conduct home visits and are a unique capability—we do not have an exact equivalent in most US health care systems. Pregnant workers are released from work 1 month prior to the due date and are expected to return to work 3 months postdelivery.”

Medical Logistics (Capt, Medical Service Corps, USAF)

“Costa Rica is still growing in aspects of national health care but has a reliable system in place it seems. Similar to many of the countries visited, it has great capacity for building, but is challenged to increase its infrastructure. In 2011, part of this was due to a recent economic decline in the nation and its health care sector. They have interaction both with other regional clinics managed under the same national health system construct (Caja Costarricense del Seguro Social) as well as with private practices and specialty services. The clinics are open only daytime business hours. Only the regional hospital is open 24/7 for emergent care.

“Supplies are distributed to the regional clinics primarily from San José (the capital and largest city), but also there are some smaller warehousing of clinical materials located around the region. One of these warehouses was in Puntarenas where our clinic was located. To get better information for future supply chain management support we would need to speak with the central distribution/suppliers of all nationalized clinic-run entities. What our partners did teach is that at a higher, national level the clinics are standardized with what they will carry and need to keep on-hand depending upon the clinic classification (ie, level 1, 2, or 3).

“Equipment is purchased similar to the DoD method: Requests are submitted toward the end of the year, the administration prioritizes the lists, and then buys what they feel is most beneficial to the clinic with the resources available. Our hosts stated that before the end of the year, it is very difficult to prioritize needs other than some of the items that they ‘always need’ because they are unlikely to receive items very low on their list. The hosts stated that they would be very interested in having a chance to receive any excess US military equipment from their priority lists if there was a mechanism to do so. In future EHET missions, advance coordination would need to occur to see if (locally compatible) equipment needs could be met through the Defense Reutilization and Marketing Office (DRMO). Alternatively, an embedded team focused on Biomedical Equipment repair could work alongside partners such as at this clinic to develop a sustainable preventive maintenance and equipment testing program. Advance coordination on equipment status would foster improvement for resourceful partner clinics such as Chacarita, with targeted involvement from US military biomedical equipment technicians.”

Discussion

These 4 firsthand accounts from a multidisciplinary, primary-care focused, EHET offers multiple preliminary evidence of the value of this small-scale embedded approach. The accounts are responses to an open-ended prompt for personal impressions and key thoughts as part of an EHET. Three of the advantages gleaned from these accounts are greater personal satisfaction, detailed insight into local operations and health systems, and deeper empathy and respect for common challenges despite health system differences compared with the US military health system.

These advantages are critical to afford the US military personnel the ability to more effectively execute engagement goals, such as meeting health needs in humanitarian assistance, advancing interoperable capacity for security cooperation, or achieving targeted training to enhance US medical operational skills. The greater personal satisfaction was evident in the team member responses that, despite mission stops in 7 prior countries, “This by far was the most rewarding part of the Continuing Promise 2011 mission” and “I hope this becomes a tool used to augment humanitarian missions.”

The descriptions by both the administrator and the logistician on the intimate details that the hosts shared with them is a testament to the rapid trust engendered by the embedded approach. There was a trust to share information as a result of acknowledged local strengths and legitimate interest in local challenges. Peer appreciation was evident; although they did not speak the same literal language, they spoke the same professional language, which was apparent even through the use of an interpreter.

A third advantage, evident from these written exchanges is a regular acknowledgement that health system issues, pursued processes, and desired outcomes are similar between different systems. There may be significant differences in actual resources and infrastructure, but some of the bureaucracy is similar. This last insight is essential to grasp in order to seek capacity building and interoperable solutions toward common goals; empathy is needed to encourage local ownership and sustainability while respecting local challenges and different problem-solving approaches and processes.

Conclusions 

The EHET concept afforded deep insight by team members into ways to partner with their hosts to target better health outcomes and meaningful partnership for potential long-term geopolitical impact. Long duration embedded teams, or recurrent insertion, in a single location will achieve greater long-term benefits because of greater health system and cultural understanding. EHETs, once accepted and refined from prototype to standard employment tool, should prove to be a more effective tool in building partnerships, building capacity, and increased security cooperation by using US military resources to support legitimate health needs either in a military-military or military-civilian setting.⁵ These firsthand accounts provide preliminary evidence that embedded teams may be a critical and needed tool to “ensure that military health engagement is appropriate, constructive, effective, and coordinated with other actors.”⁶

Acknowledgments

Additional original EHET team members included LCDR Jeanne Jimenez, RN; CDR Francine Worthington, Health Administrator; Maj Tony McClung, RN; Mrs. Romero, RN of LDS Charities, and the staff of the Chacarita clinics in Costa Rica.

MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.

At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.

This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.

For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.

The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.

Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.

The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.

“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.

Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.

Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.

For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.

When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.

The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.

She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.

“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.

She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.

bjancin@mdedge.com

MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.

At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.

This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.

For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.

The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.

Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.

The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.

“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.

Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.

Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.

For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.

When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.

The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.

She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.

“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.

She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.

bjancin@mdedge.com

MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.

At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.

This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.

For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.

The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.

Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.

The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.

“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.

Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.

Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.

For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.

When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.

The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.

She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.

“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.

She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.

bjancin@mdedge.com

Since the beginning of the American Republic, servicemen have been captured and held as prisoners of war (POWs), including > 130,000 in World War II , > 7,100 in the Korean War, > 700 in the Vietnam War, and 37 in Operation Desert Storm and recent conflicts.^1,2 Also, > 80 servicewomen have been held during these conflicts.^1-3 Of those living former POWs (FPOWs), almost all are geriatric (aged > 65 years) with a significant portion aged ≥ 85 years.

The physical hardships and psychological stress endured by FPOWs have lifelong deleterious sequelae on health and social functioning.^3-5 The experiences of FPOWs are associated with higher prevalence of chronic diseases and diminished functional performance in later life as demonstrated by a survey of FPOWs from World War II.⁴ The survey assessed health and functional status in a random sample of 101 FPOWs and a group of 107 non-POW combatants from the same military operations. FPOWs reported a higher mean number of somatic symptoms than did non-POWs (7.2 vs 5.4, respectively; P = .002), a higher mean number of diagnosed health conditions (9.4 vs 7.7, respectively; P < .001), and used a greater mean number of medications (4.5 vs 3.4, respectively; P = .001). Among 15 broad categories of diagnoses, differences were found in gastrointestinal disorders (FPOWs 63% vs non-POWs 49%, P = .032), musculoskeletal disorders (FPOWs 76% vs non-POWs 60%, P = .001), and cognitive disorders (FPOWs 31% vs non-POWs 15%, P = .006). FPOWs had a significantly higher proportion of 7 extrapyramidal signs and 6 signs relating to ataxia. On the Instrumental Activities of Daily Living scale, FPOWs were more likely to be impaired than were non-POWs (33% vs 17%, respectively; P = .01). In addition, FPOWs have an increased risk of developing dementia, and this risk is doubled in FPOWs with posttraumatic stress disorder (PTSD) compared with non-FPOWs without PTSD.⁵

These data indicate that FPOW status is associated with increased risk of disability and loss of independence. Federal statutes established the presumption of a relationship between FPOW status and many comorbidities for VA disability determinations in recognition of such data and to overcome lack of medical records during POW confinement and to accord benefit of the doubt where medical science cannot conclusively link disease etiology to FPOW status, to FPOWs.

Service-Connected Conditions

The historical development of conditions with a presumption of service connection for adjudication of VA compensation/disability claims began in 1921 with the Act to Establish a Veterans’ Bureau and to Improve the Facilities.¹ The act simplified and streamlined the claims adjudication process by eliminating the need to obtain evidence on the part of the veteran. The presumption of service connection also facilitated increased accuracy and consistency in adjudications by requiring similar treatment for similar claims. This “presumptive” process relieved claimants and VA of the necessity of producing direct evidence when it was impractical to do so.

In 1970, the first presumptives specific to FPOWs were legislatively established and covered 17 diseases for a FPOW who had been confined for ≥ 30 days (Pub. L. 91-376). The 30-day confinement requirement was later relaxed, and additional presumptives were established that related to diseases that were more common among FPOWs than they were among non-FPOWs. These disorders included traumatic arthritis, stroke, heart disease, osteoporosis, peripheral neuropathy, cold injuries, as well as a variety of digestive and neuropsychiatric disorders. If a FPOW is diagnosed as having ≥ 1 of these conditions and it is judged to be ≥ 10% disabling, the condition is presumed to be a sequelae of the POW experience, and it is classified as a service-connected disability (Table).

FPOW Care And Benefits Teams

Several Veterans Health Administration (VHA) directives have been issued, including the recent VHA directive 1650, which requires that each VHA medical facility have a special Care and Benefits Team (CBT) that is charged with the evaluation and treatment of FPOWs to ensure that “FPOWs receive the highest quality care and benefit services.”⁶ CBTs must be composed of a clinician trained in internal medicine or family practice; a clinician who is certified through the VA Office of Disability and Medical Assessment to conduct General Medical Compensation and Pension evaluations; a FPOW advocate who typically is a VHA clinical social worker; and a Veterans Benefits Administration (VBA) FPOW coordinator appointed by the local VBA regional office. CBTs can be expanded to include other members as needed. The CBTs are tasked with facilitating interactions between FPOWs, the VHA, and the VBA.

CBTs face several challenges in meeting their responsibilities. For example, the POW experience often results in psychological trauma that foments denial and distrust; hence, thoughtful sensitivity to the sequelae of captivity when approaching FPOWs about personal issues, such as health care, is required. Establishing trusting relationships with FPOWs is necessary if their needs are to be effectively addressed.

While the VHA is mandated to provide priority treatment for FPOWs, including hospital, nursing home, dental, and outpatient treatment, a significant number of FPOWs do not avail themselves of benefits to which they are entitled. Often these FPOWs have not used VA programs and facilities because they are uninformed or confused about VA benefits for FPOWs. As a result, referrals of eligible FPOWs to appropriate programs can be overlooked. Maximizing the service-connected disability rating of FPOWs not only impacts the disability pensions received by these veterans, but also impacts their eligibility for VHA programs, including long-term care and Dependency and Indemnity Compensation, a monthly benefit paid to spouses, children, and/or surviving parents.

In 2013, the FPOW Committee of the South Texas Veterans Health Care System (STVHCS) noted that 40% of FPOWs in our region had no VA primary care or clinic assignment. In consideration of the commitment of the VA to care for FPOWs, the unique POW-related medical and psychological issues, the geriatric age of many FPOWs, and the surprising number of FPOWs currently not receiving VA care, we expanded the concept of the CBT team to create a specialized interdisciplinary FPOW Clinic to address the unique needs of this predominantly elderly population and to involve more FPOWs in the VA system.

The main purpose of this clinic was to advise FPOWs of all VA benefits and services to which they may be entitled by identifying overlooked FPOW presumptives. As the number of FPOWs continues to decrease, outreach to FPOWs and family members has become critical, especially as increased benefits and special services might be available to this increasingly dependent older population. An informal survey of FPOW advocates across the nation found that 21% of FPOWs had disability ratings from the VA of ≤ 60%, including some who had no VA disability rating at all. Thus, an additional goal of the project was to develop a clinic model that could be disseminated throughout the VHA.

Design

The design of the FPOW Clinic team is based on an interdisciplinary model that has proven successful in geriatric medicine.⁷ The team comprises a physician, a social worker, and a registered nurse.⁸ All members have expertise in geriatric medicine and specific training in FPOW-related issues by completing a VA employee education training session on FPOW case management. Completion of this training ensured that team members were:

• Familiar with the experiences of FPOWs as well as about the medical, psychosocial, and mental health conditions that affect FPOWs;
• Knowledgeable about FPOW presumptive conditions;
• Familiar with the VBA process for rating FPOW disability claims; and
• Capable of FPOW case coordination, workflow, and communications between the FPOW Clinic team and the VBA to avail FPOWs and their families of all eligible benefits.

In-person FPOW clinic visits and chart reviews helped identify overlooked FPOW benefits. To facilitate case management, a representative of the VBA attended the initial evaluation of each FPOW in the clinic to confirm any overlooked presumptive benefits and to familiarize FPOWs with the claims process. FPOWs were also given the choice to officially enroll in the FPOW clinic for primary care or to remain with their current health care provider. Special efforts were made to enroll those FPOWs who had no STVHCS assigned primary care clinic.

The clinic was scheduled for 4 hours every week. Initial patient visits were 2 hours each and consisted of separate evaluations by each of the 3 FPOW Clinic team members who then met as a team with the addition of the VBA representative. The purpose of this meeting was to discuss overlooked benefits, address any other specific issues noted, and to devise an appropriate interdisciplinary plan. Findings of overlooked benefits and other relevant outcomes then were conveyed to the FPOW. For FPOWs who opted to continue in the clinic for their primary care, subsequent appointments were 1 hour.

Implementation 

STVHCS FPOW advocates identified and sent letters to FPOWs announcing the opening of the clinic and its goals. Phone calls were made to each FPOW to address questions and to ascertain their interest. The FPOW advocates then worked directly with schedulers to make clinic appointments. Forty-one FPOWs responded to this initial invitation and attended the new clinic. Subsequently, this number increased through FPOW consults placed by STVHCS primary care providers.

The service-connected disability rating of clinic patients ranged from none (6% of attendees) to 100% (28% of attendees). For 34% of patients, clinic attendance resulted in identification application for overlooked presumptives. VBA evaluation resulted in increased service-connected disability ratings for nearly one-third of clinic patients. All clinic patients without a service-connected disability prior to FPOW clinic evaluation received an increased service-connected disability rating. Overall, 60% of the FPOWs who attended the clinic opted to receive their primary care at the FPOW clinic.

The FPOW Clinic successfully identified overlooked presumptives and facilitated the determination of appropriate service-connected disabilities. Interestingly, the FPOW Clinic encountered an unanticipated challenge to identifying overlooked FPOW benefits—veterans’ medical conditions that are listed by the VHA as being service-connected in the Computerized Patient Record System did not always reflect those listed officially in VBA records. This led to occasional identification of apparently overlooked FPOW presumptives that were already recognized by the VBA but not reflected in VHA records. This issue was addressed by ensuring that VBA representatives attended postclinic meetings with clinic staff and avoided the need to pursue supposedly unrecognized benefits that were recognized.

Telehealth 

At present, FPOWs from World War II outnumber those of all other conflicts; however, this group is rapidly dwindling in numbers. World War II FPOWs are aged > 85 years, and therefore among the most frail and dependent of veterans. Often they are homebound and unable to physically travel to clinics for assessment. To serve these veterans, we are modifying the FPOW Clinic to utilize telehealth. The Telehealth FPOW Clinic will obtain relevant data from review of the electronic health record and telehealth-based clinic visits. Telehealth also may be used for assessments of Vietnam War veterans (eg, Agent Orange exposure), atomic veterans, and Gulf War veterans. Once fully designed and implemented, we believe that telehealth will prove to be a cost-effective way to provide clinic benefits to rural and older veterans.

Conclusions

The VHA provides priority medical treatment to FPOWs as well as timely and appropriate assessment of their eligibility for veterans’ benefits. The complexities benefit programs established for FPOWs is often beyond the ken of VHA physicians, social workers, and nurses. Because of this unfamiliarity, referrals of eligible FPOWs to appropriate programs can be overlooked. We established a clinic-based interdisciplinary team (FPOW Clinic) that was fully trained in FPOW benefit programs to identify overlooked benefits for FPOWs and were able to increase the disability rating on approximately one-third of the FPOWs seen in the FPOW Clinic. A telehealth-based version of the FPOW clinic is now being developed.

Since the beginning of the American Republic, servicemen have been captured and held as prisoners of war (POWs), including > 130,000 in World War II , > 7,100 in the Korean War, > 700 in the Vietnam War, and 37 in Operation Desert Storm and recent conflicts.^1,2 Also, > 80 servicewomen have been held during these conflicts.^1-3 Of those living former POWs (FPOWs), almost all are geriatric (aged > 65 years) with a significant portion aged ≥ 85 years.

The physical hardships and psychological stress endured by FPOWs have lifelong deleterious sequelae on health and social functioning.^3-5 The experiences of FPOWs are associated with higher prevalence of chronic diseases and diminished functional performance in later life as demonstrated by a survey of FPOWs from World War II.⁴ The survey assessed health and functional status in a random sample of 101 FPOWs and a group of 107 non-POW combatants from the same military operations. FPOWs reported a higher mean number of somatic symptoms than did non-POWs (7.2 vs 5.4, respectively; P = .002), a higher mean number of diagnosed health conditions (9.4 vs 7.7, respectively; P < .001), and used a greater mean number of medications (4.5 vs 3.4, respectively; P = .001). Among 15 broad categories of diagnoses, differences were found in gastrointestinal disorders (FPOWs 63% vs non-POWs 49%, P = .032), musculoskeletal disorders (FPOWs 76% vs non-POWs 60%, P = .001), and cognitive disorders (FPOWs 31% vs non-POWs 15%, P = .006). FPOWs had a significantly higher proportion of 7 extrapyramidal signs and 6 signs relating to ataxia. On the Instrumental Activities of Daily Living scale, FPOWs were more likely to be impaired than were non-POWs (33% vs 17%, respectively; P = .01). In addition, FPOWs have an increased risk of developing dementia, and this risk is doubled in FPOWs with posttraumatic stress disorder (PTSD) compared with non-FPOWs without PTSD.⁵

These data indicate that FPOW status is associated with increased risk of disability and loss of independence. Federal statutes established the presumption of a relationship between FPOW status and many comorbidities for VA disability determinations in recognition of such data and to overcome lack of medical records during POW confinement and to accord benefit of the doubt where medical science cannot conclusively link disease etiology to FPOW status, to FPOWs.

Service-Connected Conditions

The historical development of conditions with a presumption of service connection for adjudication of VA compensation/disability claims began in 1921 with the Act to Establish a Veterans’ Bureau and to Improve the Facilities.¹ The act simplified and streamlined the claims adjudication process by eliminating the need to obtain evidence on the part of the veteran. The presumption of service connection also facilitated increased accuracy and consistency in adjudications by requiring similar treatment for similar claims. This “presumptive” process relieved claimants and VA of the necessity of producing direct evidence when it was impractical to do so.

In 1970, the first presumptives specific to FPOWs were legislatively established and covered 17 diseases for a FPOW who had been confined for ≥ 30 days (Pub. L. 91-376). The 30-day confinement requirement was later relaxed, and additional presumptives were established that related to diseases that were more common among FPOWs than they were among non-FPOWs. These disorders included traumatic arthritis, stroke, heart disease, osteoporosis, peripheral neuropathy, cold injuries, as well as a variety of digestive and neuropsychiatric disorders. If a FPOW is diagnosed as having ≥ 1 of these conditions and it is judged to be ≥ 10% disabling, the condition is presumed to be a sequelae of the POW experience, and it is classified as a service-connected disability (Table).

FPOW Care And Benefits Teams

Several Veterans Health Administration (VHA) directives have been issued, including the recent VHA directive 1650, which requires that each VHA medical facility have a special Care and Benefits Team (CBT) that is charged with the evaluation and treatment of FPOWs to ensure that “FPOWs receive the highest quality care and benefit services.”⁶ CBTs must be composed of a clinician trained in internal medicine or family practice; a clinician who is certified through the VA Office of Disability and Medical Assessment to conduct General Medical Compensation and Pension evaluations; a FPOW advocate who typically is a VHA clinical social worker; and a Veterans Benefits Administration (VBA) FPOW coordinator appointed by the local VBA regional office. CBTs can be expanded to include other members as needed. The CBTs are tasked with facilitating interactions between FPOWs, the VHA, and the VBA.

CBTs face several challenges in meeting their responsibilities. For example, the POW experience often results in psychological trauma that foments denial and distrust; hence, thoughtful sensitivity to the sequelae of captivity when approaching FPOWs about personal issues, such as health care, is required. Establishing trusting relationships with FPOWs is necessary if their needs are to be effectively addressed.

While the VHA is mandated to provide priority treatment for FPOWs, including hospital, nursing home, dental, and outpatient treatment, a significant number of FPOWs do not avail themselves of benefits to which they are entitled. Often these FPOWs have not used VA programs and facilities because they are uninformed or confused about VA benefits for FPOWs. As a result, referrals of eligible FPOWs to appropriate programs can be overlooked. Maximizing the service-connected disability rating of FPOWs not only impacts the disability pensions received by these veterans, but also impacts their eligibility for VHA programs, including long-term care and Dependency and Indemnity Compensation, a monthly benefit paid to spouses, children, and/or surviving parents.

In 2013, the FPOW Committee of the South Texas Veterans Health Care System (STVHCS) noted that 40% of FPOWs in our region had no VA primary care or clinic assignment. In consideration of the commitment of the VA to care for FPOWs, the unique POW-related medical and psychological issues, the geriatric age of many FPOWs, and the surprising number of FPOWs currently not receiving VA care, we expanded the concept of the CBT team to create a specialized interdisciplinary FPOW Clinic to address the unique needs of this predominantly elderly population and to involve more FPOWs in the VA system.

The main purpose of this clinic was to advise FPOWs of all VA benefits and services to which they may be entitled by identifying overlooked FPOW presumptives. As the number of FPOWs continues to decrease, outreach to FPOWs and family members has become critical, especially as increased benefits and special services might be available to this increasingly dependent older population. An informal survey of FPOW advocates across the nation found that 21% of FPOWs had disability ratings from the VA of ≤ 60%, including some who had no VA disability rating at all. Thus, an additional goal of the project was to develop a clinic model that could be disseminated throughout the VHA.

Design

The design of the FPOW Clinic team is based on an interdisciplinary model that has proven successful in geriatric medicine.⁷ The team comprises a physician, a social worker, and a registered nurse.⁸ All members have expertise in geriatric medicine and specific training in FPOW-related issues by completing a VA employee education training session on FPOW case management. Completion of this training ensured that team members were:

• Familiar with the experiences of FPOWs as well as about the medical, psychosocial, and mental health conditions that affect FPOWs;
• Knowledgeable about FPOW presumptive conditions;
• Familiar with the VBA process for rating FPOW disability claims; and
• Capable of FPOW case coordination, workflow, and communications between the FPOW Clinic team and the VBA to avail FPOWs and their families of all eligible benefits.

In-person FPOW clinic visits and chart reviews helped identify overlooked FPOW benefits. To facilitate case management, a representative of the VBA attended the initial evaluation of each FPOW in the clinic to confirm any overlooked presumptive benefits and to familiarize FPOWs with the claims process. FPOWs were also given the choice to officially enroll in the FPOW clinic for primary care or to remain with their current health care provider. Special efforts were made to enroll those FPOWs who had no STVHCS assigned primary care clinic.

The clinic was scheduled for 4 hours every week. Initial patient visits were 2 hours each and consisted of separate evaluations by each of the 3 FPOW Clinic team members who then met as a team with the addition of the VBA representative. The purpose of this meeting was to discuss overlooked benefits, address any other specific issues noted, and to devise an appropriate interdisciplinary plan. Findings of overlooked benefits and other relevant outcomes then were conveyed to the FPOW. For FPOWs who opted to continue in the clinic for their primary care, subsequent appointments were 1 hour.

Implementation 

STVHCS FPOW advocates identified and sent letters to FPOWs announcing the opening of the clinic and its goals. Phone calls were made to each FPOW to address questions and to ascertain their interest. The FPOW advocates then worked directly with schedulers to make clinic appointments. Forty-one FPOWs responded to this initial invitation and attended the new clinic. Subsequently, this number increased through FPOW consults placed by STVHCS primary care providers.

The service-connected disability rating of clinic patients ranged from none (6% of attendees) to 100% (28% of attendees). For 34% of patients, clinic attendance resulted in identification application for overlooked presumptives. VBA evaluation resulted in increased service-connected disability ratings for nearly one-third of clinic patients. All clinic patients without a service-connected disability prior to FPOW clinic evaluation received an increased service-connected disability rating. Overall, 60% of the FPOWs who attended the clinic opted to receive their primary care at the FPOW clinic.

The FPOW Clinic successfully identified overlooked presumptives and facilitated the determination of appropriate service-connected disabilities. Interestingly, the FPOW Clinic encountered an unanticipated challenge to identifying overlooked FPOW benefits—veterans’ medical conditions that are listed by the VHA as being service-connected in the Computerized Patient Record System did not always reflect those listed officially in VBA records. This led to occasional identification of apparently overlooked FPOW presumptives that were already recognized by the VBA but not reflected in VHA records. This issue was addressed by ensuring that VBA representatives attended postclinic meetings with clinic staff and avoided the need to pursue supposedly unrecognized benefits that were recognized.

Telehealth 

At present, FPOWs from World War II outnumber those of all other conflicts; however, this group is rapidly dwindling in numbers. World War II FPOWs are aged > 85 years, and therefore among the most frail and dependent of veterans. Often they are homebound and unable to physically travel to clinics for assessment. To serve these veterans, we are modifying the FPOW Clinic to utilize telehealth. The Telehealth FPOW Clinic will obtain relevant data from review of the electronic health record and telehealth-based clinic visits. Telehealth also may be used for assessments of Vietnam War veterans (eg, Agent Orange exposure), atomic veterans, and Gulf War veterans. Once fully designed and implemented, we believe that telehealth will prove to be a cost-effective way to provide clinic benefits to rural and older veterans.

Conclusions

The VHA provides priority medical treatment to FPOWs as well as timely and appropriate assessment of their eligibility for veterans’ benefits. The complexities benefit programs established for FPOWs is often beyond the ken of VHA physicians, social workers, and nurses. Because of this unfamiliarity, referrals of eligible FPOWs to appropriate programs can be overlooked. We established a clinic-based interdisciplinary team (FPOW Clinic) that was fully trained in FPOW benefit programs to identify overlooked benefits for FPOWs and were able to increase the disability rating on approximately one-third of the FPOWs seen in the FPOW Clinic. A telehealth-based version of the FPOW clinic is now being developed.

Since the beginning of the American Republic, servicemen have been captured and held as prisoners of war (POWs), including > 130,000 in World War II , > 7,100 in the Korean War, > 700 in the Vietnam War, and 37 in Operation Desert Storm and recent conflicts.^1,2 Also, > 80 servicewomen have been held during these conflicts.^1-3 Of those living former POWs (FPOWs), almost all are geriatric (aged > 65 years) with a significant portion aged ≥ 85 years.

The physical hardships and psychological stress endured by FPOWs have lifelong deleterious sequelae on health and social functioning.^3-5 The experiences of FPOWs are associated with higher prevalence of chronic diseases and diminished functional performance in later life as demonstrated by a survey of FPOWs from World War II.⁴ The survey assessed health and functional status in a random sample of 101 FPOWs and a group of 107 non-POW combatants from the same military operations. FPOWs reported a higher mean number of somatic symptoms than did non-POWs (7.2 vs 5.4, respectively; P = .002), a higher mean number of diagnosed health conditions (9.4 vs 7.7, respectively; P < .001), and used a greater mean number of medications (4.5 vs 3.4, respectively; P = .001). Among 15 broad categories of diagnoses, differences were found in gastrointestinal disorders (FPOWs 63% vs non-POWs 49%, P = .032), musculoskeletal disorders (FPOWs 76% vs non-POWs 60%, P = .001), and cognitive disorders (FPOWs 31% vs non-POWs 15%, P = .006). FPOWs had a significantly higher proportion of 7 extrapyramidal signs and 6 signs relating to ataxia. On the Instrumental Activities of Daily Living scale, FPOWs were more likely to be impaired than were non-POWs (33% vs 17%, respectively; P = .01). In addition, FPOWs have an increased risk of developing dementia, and this risk is doubled in FPOWs with posttraumatic stress disorder (PTSD) compared with non-FPOWs without PTSD.⁵

These data indicate that FPOW status is associated with increased risk of disability and loss of independence. Federal statutes established the presumption of a relationship between FPOW status and many comorbidities for VA disability determinations in recognition of such data and to overcome lack of medical records during POW confinement and to accord benefit of the doubt where medical science cannot conclusively link disease etiology to FPOW status, to FPOWs.

Service-Connected Conditions

The historical development of conditions with a presumption of service connection for adjudication of VA compensation/disability claims began in 1921 with the Act to Establish a Veterans’ Bureau and to Improve the Facilities.¹ The act simplified and streamlined the claims adjudication process by eliminating the need to obtain evidence on the part of the veteran. The presumption of service connection also facilitated increased accuracy and consistency in adjudications by requiring similar treatment for similar claims. This “presumptive” process relieved claimants and VA of the necessity of producing direct evidence when it was impractical to do so.

In 1970, the first presumptives specific to FPOWs were legislatively established and covered 17 diseases for a FPOW who had been confined for ≥ 30 days (Pub. L. 91-376). The 30-day confinement requirement was later relaxed, and additional presumptives were established that related to diseases that were more common among FPOWs than they were among non-FPOWs. These disorders included traumatic arthritis, stroke, heart disease, osteoporosis, peripheral neuropathy, cold injuries, as well as a variety of digestive and neuropsychiatric disorders. If a FPOW is diagnosed as having ≥ 1 of these conditions and it is judged to be ≥ 10% disabling, the condition is presumed to be a sequelae of the POW experience, and it is classified as a service-connected disability (Table).

FPOW Care And Benefits Teams

Several Veterans Health Administration (VHA) directives have been issued, including the recent VHA directive 1650, which requires that each VHA medical facility have a special Care and Benefits Team (CBT) that is charged with the evaluation and treatment of FPOWs to ensure that “FPOWs receive the highest quality care and benefit services.”⁶ CBTs must be composed of a clinician trained in internal medicine or family practice; a clinician who is certified through the VA Office of Disability and Medical Assessment to conduct General Medical Compensation and Pension evaluations; a FPOW advocate who typically is a VHA clinical social worker; and a Veterans Benefits Administration (VBA) FPOW coordinator appointed by the local VBA regional office. CBTs can be expanded to include other members as needed. The CBTs are tasked with facilitating interactions between FPOWs, the VHA, and the VBA.

CBTs face several challenges in meeting their responsibilities. For example, the POW experience often results in psychological trauma that foments denial and distrust; hence, thoughtful sensitivity to the sequelae of captivity when approaching FPOWs about personal issues, such as health care, is required. Establishing trusting relationships with FPOWs is necessary if their needs are to be effectively addressed.

While the VHA is mandated to provide priority treatment for FPOWs, including hospital, nursing home, dental, and outpatient treatment, a significant number of FPOWs do not avail themselves of benefits to which they are entitled. Often these FPOWs have not used VA programs and facilities because they are uninformed or confused about VA benefits for FPOWs. As a result, referrals of eligible FPOWs to appropriate programs can be overlooked. Maximizing the service-connected disability rating of FPOWs not only impacts the disability pensions received by these veterans, but also impacts their eligibility for VHA programs, including long-term care and Dependency and Indemnity Compensation, a monthly benefit paid to spouses, children, and/or surviving parents.

In 2013, the FPOW Committee of the South Texas Veterans Health Care System (STVHCS) noted that 40% of FPOWs in our region had no VA primary care or clinic assignment. In consideration of the commitment of the VA to care for FPOWs, the unique POW-related medical and psychological issues, the geriatric age of many FPOWs, and the surprising number of FPOWs currently not receiving VA care, we expanded the concept of the CBT team to create a specialized interdisciplinary FPOW Clinic to address the unique needs of this predominantly elderly population and to involve more FPOWs in the VA system.

The main purpose of this clinic was to advise FPOWs of all VA benefits and services to which they may be entitled by identifying overlooked FPOW presumptives. As the number of FPOWs continues to decrease, outreach to FPOWs and family members has become critical, especially as increased benefits and special services might be available to this increasingly dependent older population. An informal survey of FPOW advocates across the nation found that 21% of FPOWs had disability ratings from the VA of ≤ 60%, including some who had no VA disability rating at all. Thus, an additional goal of the project was to develop a clinic model that could be disseminated throughout the VHA.

Design

The design of the FPOW Clinic team is based on an interdisciplinary model that has proven successful in geriatric medicine.⁷ The team comprises a physician, a social worker, and a registered nurse.⁸ All members have expertise in geriatric medicine and specific training in FPOW-related issues by completing a VA employee education training session on FPOW case management. Completion of this training ensured that team members were:

• Familiar with the experiences of FPOWs as well as about the medical, psychosocial, and mental health conditions that affect FPOWs;
• Knowledgeable about FPOW presumptive conditions;
• Familiar with the VBA process for rating FPOW disability claims; and
• Capable of FPOW case coordination, workflow, and communications between the FPOW Clinic team and the VBA to avail FPOWs and their families of all eligible benefits.

In-person FPOW clinic visits and chart reviews helped identify overlooked FPOW benefits. To facilitate case management, a representative of the VBA attended the initial evaluation of each FPOW in the clinic to confirm any overlooked presumptive benefits and to familiarize FPOWs with the claims process. FPOWs were also given the choice to officially enroll in the FPOW clinic for primary care or to remain with their current health care provider. Special efforts were made to enroll those FPOWs who had no STVHCS assigned primary care clinic.

The clinic was scheduled for 4 hours every week. Initial patient visits were 2 hours each and consisted of separate evaluations by each of the 3 FPOW Clinic team members who then met as a team with the addition of the VBA representative. The purpose of this meeting was to discuss overlooked benefits, address any other specific issues noted, and to devise an appropriate interdisciplinary plan. Findings of overlooked benefits and other relevant outcomes then were conveyed to the FPOW. For FPOWs who opted to continue in the clinic for their primary care, subsequent appointments were 1 hour.

Implementation 

STVHCS FPOW advocates identified and sent letters to FPOWs announcing the opening of the clinic and its goals. Phone calls were made to each FPOW to address questions and to ascertain their interest. The FPOW advocates then worked directly with schedulers to make clinic appointments. Forty-one FPOWs responded to this initial invitation and attended the new clinic. Subsequently, this number increased through FPOW consults placed by STVHCS primary care providers.

The service-connected disability rating of clinic patients ranged from none (6% of attendees) to 100% (28% of attendees). For 34% of patients, clinic attendance resulted in identification application for overlooked presumptives. VBA evaluation resulted in increased service-connected disability ratings for nearly one-third of clinic patients. All clinic patients without a service-connected disability prior to FPOW clinic evaluation received an increased service-connected disability rating. Overall, 60% of the FPOWs who attended the clinic opted to receive their primary care at the FPOW clinic.

The FPOW Clinic successfully identified overlooked presumptives and facilitated the determination of appropriate service-connected disabilities. Interestingly, the FPOW Clinic encountered an unanticipated challenge to identifying overlooked FPOW benefits—veterans’ medical conditions that are listed by the VHA as being service-connected in the Computerized Patient Record System did not always reflect those listed officially in VBA records. This led to occasional identification of apparently overlooked FPOW presumptives that were already recognized by the VBA but not reflected in VHA records. This issue was addressed by ensuring that VBA representatives attended postclinic meetings with clinic staff and avoided the need to pursue supposedly unrecognized benefits that were recognized.

Telehealth 

At present, FPOWs from World War II outnumber those of all other conflicts; however, this group is rapidly dwindling in numbers. World War II FPOWs are aged > 85 years, and therefore among the most frail and dependent of veterans. Often they are homebound and unable to physically travel to clinics for assessment. To serve these veterans, we are modifying the FPOW Clinic to utilize telehealth. The Telehealth FPOW Clinic will obtain relevant data from review of the electronic health record and telehealth-based clinic visits. Telehealth also may be used for assessments of Vietnam War veterans (eg, Agent Orange exposure), atomic veterans, and Gulf War veterans. Once fully designed and implemented, we believe that telehealth will prove to be a cost-effective way to provide clinic benefits to rural and older veterans.

Conclusions

The VHA provides priority medical treatment to FPOWs as well as timely and appropriate assessment of their eligibility for veterans’ benefits. The complexities benefit programs established for FPOWs is often beyond the ken of VHA physicians, social workers, and nurses. Because of this unfamiliarity, referrals of eligible FPOWs to appropriate programs can be overlooked. We established a clinic-based interdisciplinary team (FPOW Clinic) that was fully trained in FPOW benefit programs to identify overlooked benefits for FPOWs and were able to increase the disability rating on approximately one-third of the FPOWs seen in the FPOW Clinic. A telehealth-based version of the FPOW clinic is now being developed.

Patients being treated for RA or spondyloarthritis who develop symptoms of COVID-19 do not appear to be at higher risk of respiratory or life-threatening complications, results from a new study in Italy suggest.

Such patients, the study authors wrote, do not need to be taken off their immunosuppressive medications if they develop COVID-19 symptoms.

In a letter published in Annals of the Rheumatic Diseases, Sara Monti, MD, and colleagues in the rheumatology department of the Fondazione IRCCS Policlinico in San Matteo, Italy, described results from an observational cohort of 320 patients (68% women; mean age, 55 years) with RA or spondyloarthritis from a single outpatient clinic. The vast majority of subjects (92%) were taking biologic disease-modifying antirheumatic drugs (bDMARD), including tumor necrosis factor inhibitors, while the rest were taking targeted synthetic DMARDs (tsDMARD).

Four patients in the cohort developed laboratory-confirmed COVID-19; another four developed symptoms highly suggestive of the disease but did not receive confirmatory testing, and five had contact with a confirmed COVID-19 case but did not develop symptoms of COVID-19.

Among the eight confirmed and suspected COVID-19 patients, only one was hospitalized. All temporarily withdrew bDMARD or tsDMARD treatment at symptom onset.

“To date, there have been no significant relapses of the rheumatic disease,” Dr. Monti and colleagues reported. “None of the patients with a confirmed diagnosis of COVID-19 or with a highly suggestive clinical picture developed severe respiratory complications or died. Only one patient, aged 65, required admission to hospital and low-flow oxygen supplementation for a few days.”

The findings “do not allow any conclusions on the incidence rate of SARS-CoV-2 infection in patients with rheumatic diseases, nor on the overall outcome of immunocompromised patients affected by COVID-19,” the investigators cautioned, adding that such patients should receive careful attention and follow-up. “However, our preliminary experience shows that patients with chronic arthritis treated with bDMARDs or tsDMARDs do not seem to be at increased risk of respiratory or life-threatening complications from SARS-CoV-2, compared with the general population.”

Dr. Monti and colleagues noted that, during previous outbreaks of other coronaviruses, no increased mortality was reported for people taking immunosuppressive drugs for a range of conditions, including autoimmune diseases.

“These data can support rheumatologists [in] avoiding the unjustifiable preventive withdrawal of DMARDs, which could lead to an increased risk of relapses and morbidity from the chronic rheumatological condition,” the researchers concluded.

Dr. Monti and colleagues reported no outside funding or financial conflicts of interest.

SOURCE: Monti S et al. Ann Rheum Dis. 2020 April 2. doi: 10.1136/annrheumdis-2020-217424.

Patients being treated for RA or spondyloarthritis who develop symptoms of COVID-19 do not appear to be at higher risk of respiratory or life-threatening complications, results from a new study in Italy suggest.

Such patients, the study authors wrote, do not need to be taken off their immunosuppressive medications if they develop COVID-19 symptoms.

In a letter published in Annals of the Rheumatic Diseases, Sara Monti, MD, and colleagues in the rheumatology department of the Fondazione IRCCS Policlinico in San Matteo, Italy, described results from an observational cohort of 320 patients (68% women; mean age, 55 years) with RA or spondyloarthritis from a single outpatient clinic. The vast majority of subjects (92%) were taking biologic disease-modifying antirheumatic drugs (bDMARD), including tumor necrosis factor inhibitors, while the rest were taking targeted synthetic DMARDs (tsDMARD).

Four patients in the cohort developed laboratory-confirmed COVID-19; another four developed symptoms highly suggestive of the disease but did not receive confirmatory testing, and five had contact with a confirmed COVID-19 case but did not develop symptoms of COVID-19.

Among the eight confirmed and suspected COVID-19 patients, only one was hospitalized. All temporarily withdrew bDMARD or tsDMARD treatment at symptom onset.

“To date, there have been no significant relapses of the rheumatic disease,” Dr. Monti and colleagues reported. “None of the patients with a confirmed diagnosis of COVID-19 or with a highly suggestive clinical picture developed severe respiratory complications or died. Only one patient, aged 65, required admission to hospital and low-flow oxygen supplementation for a few days.”

The findings “do not allow any conclusions on the incidence rate of SARS-CoV-2 infection in patients with rheumatic diseases, nor on the overall outcome of immunocompromised patients affected by COVID-19,” the investigators cautioned, adding that such patients should receive careful attention and follow-up. “However, our preliminary experience shows that patients with chronic arthritis treated with bDMARDs or tsDMARDs do not seem to be at increased risk of respiratory or life-threatening complications from SARS-CoV-2, compared with the general population.”

Dr. Monti and colleagues noted that, during previous outbreaks of other coronaviruses, no increased mortality was reported for people taking immunosuppressive drugs for a range of conditions, including autoimmune diseases.

“These data can support rheumatologists [in] avoiding the unjustifiable preventive withdrawal of DMARDs, which could lead to an increased risk of relapses and morbidity from the chronic rheumatological condition,” the researchers concluded.

Dr. Monti and colleagues reported no outside funding or financial conflicts of interest.

SOURCE: Monti S et al. Ann Rheum Dis. 2020 April 2. doi: 10.1136/annrheumdis-2020-217424.

Patients being treated for RA or spondyloarthritis who develop symptoms of COVID-19 do not appear to be at higher risk of respiratory or life-threatening complications, results from a new study in Italy suggest.

Such patients, the study authors wrote, do not need to be taken off their immunosuppressive medications if they develop COVID-19 symptoms.

In a letter published in Annals of the Rheumatic Diseases, Sara Monti, MD, and colleagues in the rheumatology department of the Fondazione IRCCS Policlinico in San Matteo, Italy, described results from an observational cohort of 320 patients (68% women; mean age, 55 years) with RA or spondyloarthritis from a single outpatient clinic. The vast majority of subjects (92%) were taking biologic disease-modifying antirheumatic drugs (bDMARD), including tumor necrosis factor inhibitors, while the rest were taking targeted synthetic DMARDs (tsDMARD).

Four patients in the cohort developed laboratory-confirmed COVID-19; another four developed symptoms highly suggestive of the disease but did not receive confirmatory testing, and five had contact with a confirmed COVID-19 case but did not develop symptoms of COVID-19.

Among the eight confirmed and suspected COVID-19 patients, only one was hospitalized. All temporarily withdrew bDMARD or tsDMARD treatment at symptom onset.

“To date, there have been no significant relapses of the rheumatic disease,” Dr. Monti and colleagues reported. “None of the patients with a confirmed diagnosis of COVID-19 or with a highly suggestive clinical picture developed severe respiratory complications or died. Only one patient, aged 65, required admission to hospital and low-flow oxygen supplementation for a few days.”

The findings “do not allow any conclusions on the incidence rate of SARS-CoV-2 infection in patients with rheumatic diseases, nor on the overall outcome of immunocompromised patients affected by COVID-19,” the investigators cautioned, adding that such patients should receive careful attention and follow-up. “However, our preliminary experience shows that patients with chronic arthritis treated with bDMARDs or tsDMARDs do not seem to be at increased risk of respiratory or life-threatening complications from SARS-CoV-2, compared with the general population.”

Dr. Monti and colleagues noted that, during previous outbreaks of other coronaviruses, no increased mortality was reported for people taking immunosuppressive drugs for a range of conditions, including autoimmune diseases.

“These data can support rheumatologists [in] avoiding the unjustifiable preventive withdrawal of DMARDs, which could lead to an increased risk of relapses and morbidity from the chronic rheumatological condition,” the researchers concluded.

Dr. Monti and colleagues reported no outside funding or financial conflicts of interest.

SOURCE: Monti S et al. Ann Rheum Dis. 2020 April 2. doi: 10.1136/annrheumdis-2020-217424.

More than three-quarters of cancer clinical research programs have experienced operational changes during the COVID-19 pandemic, according to a survey conducted by the Association of Community Cancer Centers (ACCC) during a recent webinar.

The webinar included insights into how some cancer research programs have adapted to the pandemic, a review of guidance for conducting cancer trials during this time, and a discussion of how the cancer research landscape may be affected by COVID-19 going forward.

The webinar was led by Randall A. Oyer, MD, president of the ACCC and medical director of the oncology program at Penn Medicine Lancaster General Health in Pennsylvania.

The impact of COVID-19 on cancer research

Dr. Oyer observed that planning and implementation for COVID-19–related illness at U.S. health care institutions has had a predictable effect of limiting patient access and staff availability for nonessential services.

Coronavirus-related exposure and/or illness has relegated cancer research to a lower-level priority. As a result, ACCC institutions have made adjustments in their cancer research programs, including moving clinical research coordinators off-campus and deploying them in clinical areas.

New clinical trials have not been opened. In some cases, new accruals have been halted, particularly for registry, prevention, and symptom control trials.

Standards that have changed and those that have not

Guidance documents for conducting clinical trials during the pandemic have been developed by the Food and Drug Administration, the National Cancer Institute’s Cancer Therapy Evaluation Program and Central Institutional Review Board, and the National Institutes of Health’s Office of Extramural Research. Industry sponsors and parent institutions of research programs have also disseminated guidance.

Among other topics, guidance documents have addressed:

• How COVID-19-related protocol deviations will be judged at monitoring visits and audits
• Missed office visits and endpoint evaluations
• Providing investigational oral medications to patients via mail and potential issues of medication unavailability
• Processes for patients to have interim visits with providers at external institutions, including providers who may not be personally engaged in or credentialed for the research trial
• Potential delays in submitting protocol amendments for institutional review board (IRB) review
• Recommendations for patients confirmed or suspected of having a coronavirus infection.

Dr. Oyer emphasized that patient safety must remain the highest priority for patient management, on or off study. He advised continuing investigational therapy when potential benefit from treatment is anticipated and identifying alternative methods to face-to-face visits for monitoring and access to treatment.

Dr. Oyer urged programs to:

• Maintain good clinical practice standards
• Consult with sponsors and IRBs when questions arise but implement changes that affect patient safety prior to IRB review if necessary
• Document all deviations and COVID-19 related adaptations in a log or spreadsheet in anticipation of future questions from sponsors, monitors, and other entities.

New questions and considerations

In the short-term, Dr. Oyer predicts fewer available trials and a decreased rate of accrual to existing studies. This may result in delays in trial completion and the possibility of redesign for some trials.

He predicts the emergence of COVID-19-focused research questions, including those assessing the course of coronavirus infection in various malignant settings and the impact of cancer-directed treatments and supportive care interventions (e.g., treatment for graft-versus-host disease) on response to COVID-19.

To facilitate developing a clinically and research-relevant database, Dr. Oyer stressed the importance of documentation in the research record, reporting infections as serious adverse events. Documentation should specify whether the infection was confirmed or suspected coronavirus or related to another organism.

In general, when coronavirus infection is strongly suspected, Dr. Oyer said investigational treatments should be interrupted, but study-specific criteria will be forthcoming on that issue.
 

Looking to the future

For patients with advanced cancers, clinical trials provide an important option for hope and clinical benefit. Disrupting the conduct of clinical trials could endanger the lives of participants and delay the emergence of promising treatments and diagnostic tests.

When the coronavirus pandemic recedes, advancing knowledge and treatments for cancer will demand renewed commitment across the oncology care community.

Going forward, Dr. Oyer advised that clinical research staff protect their own health and the safety of trial participants. He encouraged programs to work with sponsors and IRBs to solve logistical problems and clarify individual issues.

He was optimistic that resumption of more normal conduct of studies will enable the successful completion of ongoing trials, enhanced by the creative solutions that were devised during the crisis and by additional prospective, clinically annotated, carefully recorded data from academic and community research sites.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

More than three-quarters of cancer clinical research programs have experienced operational changes during the COVID-19 pandemic, according to a survey conducted by the Association of Community Cancer Centers (ACCC) during a recent webinar.

The webinar included insights into how some cancer research programs have adapted to the pandemic, a review of guidance for conducting cancer trials during this time, and a discussion of how the cancer research landscape may be affected by COVID-19 going forward.

The webinar was led by Randall A. Oyer, MD, president of the ACCC and medical director of the oncology program at Penn Medicine Lancaster General Health in Pennsylvania.

The impact of COVID-19 on cancer research

Dr. Oyer observed that planning and implementation for COVID-19–related illness at U.S. health care institutions has had a predictable effect of limiting patient access and staff availability for nonessential services.

Coronavirus-related exposure and/or illness has relegated cancer research to a lower-level priority. As a result, ACCC institutions have made adjustments in their cancer research programs, including moving clinical research coordinators off-campus and deploying them in clinical areas.

New clinical trials have not been opened. In some cases, new accruals have been halted, particularly for registry, prevention, and symptom control trials.

Standards that have changed and those that have not

Guidance documents for conducting clinical trials during the pandemic have been developed by the Food and Drug Administration, the National Cancer Institute’s Cancer Therapy Evaluation Program and Central Institutional Review Board, and the National Institutes of Health’s Office of Extramural Research. Industry sponsors and parent institutions of research programs have also disseminated guidance.

Among other topics, guidance documents have addressed:

• How COVID-19-related protocol deviations will be judged at monitoring visits and audits
• Missed office visits and endpoint evaluations
• Providing investigational oral medications to patients via mail and potential issues of medication unavailability
• Processes for patients to have interim visits with providers at external institutions, including providers who may not be personally engaged in or credentialed for the research trial
• Potential delays in submitting protocol amendments for institutional review board (IRB) review
• Recommendations for patients confirmed or suspected of having a coronavirus infection.

Dr. Oyer emphasized that patient safety must remain the highest priority for patient management, on or off study. He advised continuing investigational therapy when potential benefit from treatment is anticipated and identifying alternative methods to face-to-face visits for monitoring and access to treatment.

Dr. Oyer urged programs to:

• Maintain good clinical practice standards
• Consult with sponsors and IRBs when questions arise but implement changes that affect patient safety prior to IRB review if necessary
• Document all deviations and COVID-19 related adaptations in a log or spreadsheet in anticipation of future questions from sponsors, monitors, and other entities.

New questions and considerations

In the short-term, Dr. Oyer predicts fewer available trials and a decreased rate of accrual to existing studies. This may result in delays in trial completion and the possibility of redesign for some trials.

He predicts the emergence of COVID-19-focused research questions, including those assessing the course of coronavirus infection in various malignant settings and the impact of cancer-directed treatments and supportive care interventions (e.g., treatment for graft-versus-host disease) on response to COVID-19.

To facilitate developing a clinically and research-relevant database, Dr. Oyer stressed the importance of documentation in the research record, reporting infections as serious adverse events. Documentation should specify whether the infection was confirmed or suspected coronavirus or related to another organism.

In general, when coronavirus infection is strongly suspected, Dr. Oyer said investigational treatments should be interrupted, but study-specific criteria will be forthcoming on that issue.
 

Looking to the future

For patients with advanced cancers, clinical trials provide an important option for hope and clinical benefit. Disrupting the conduct of clinical trials could endanger the lives of participants and delay the emergence of promising treatments and diagnostic tests.

When the coronavirus pandemic recedes, advancing knowledge and treatments for cancer will demand renewed commitment across the oncology care community.

Going forward, Dr. Oyer advised that clinical research staff protect their own health and the safety of trial participants. He encouraged programs to work with sponsors and IRBs to solve logistical problems and clarify individual issues.

He was optimistic that resumption of more normal conduct of studies will enable the successful completion of ongoing trials, enhanced by the creative solutions that were devised during the crisis and by additional prospective, clinically annotated, carefully recorded data from academic and community research sites.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

More than three-quarters of cancer clinical research programs have experienced operational changes during the COVID-19 pandemic, according to a survey conducted by the Association of Community Cancer Centers (ACCC) during a recent webinar.

The webinar included insights into how some cancer research programs have adapted to the pandemic, a review of guidance for conducting cancer trials during this time, and a discussion of how the cancer research landscape may be affected by COVID-19 going forward.

The webinar was led by Randall A. Oyer, MD, president of the ACCC and medical director of the oncology program at Penn Medicine Lancaster General Health in Pennsylvania.

The impact of COVID-19 on cancer research

Dr. Oyer observed that planning and implementation for COVID-19–related illness at U.S. health care institutions has had a predictable effect of limiting patient access and staff availability for nonessential services.

Coronavirus-related exposure and/or illness has relegated cancer research to a lower-level priority. As a result, ACCC institutions have made adjustments in their cancer research programs, including moving clinical research coordinators off-campus and deploying them in clinical areas.

New clinical trials have not been opened. In some cases, new accruals have been halted, particularly for registry, prevention, and symptom control trials.

Standards that have changed and those that have not

Guidance documents for conducting clinical trials during the pandemic have been developed by the Food and Drug Administration, the National Cancer Institute’s Cancer Therapy Evaluation Program and Central Institutional Review Board, and the National Institutes of Health’s Office of Extramural Research. Industry sponsors and parent institutions of research programs have also disseminated guidance.

Among other topics, guidance documents have addressed:

• How COVID-19-related protocol deviations will be judged at monitoring visits and audits
• Missed office visits and endpoint evaluations
• Providing investigational oral medications to patients via mail and potential issues of medication unavailability
• Processes for patients to have interim visits with providers at external institutions, including providers who may not be personally engaged in or credentialed for the research trial
• Potential delays in submitting protocol amendments for institutional review board (IRB) review
• Recommendations for patients confirmed or suspected of having a coronavirus infection.

Dr. Oyer emphasized that patient safety must remain the highest priority for patient management, on or off study. He advised continuing investigational therapy when potential benefit from treatment is anticipated and identifying alternative methods to face-to-face visits for monitoring and access to treatment.

Dr. Oyer urged programs to:

• Maintain good clinical practice standards
• Consult with sponsors and IRBs when questions arise but implement changes that affect patient safety prior to IRB review if necessary
• Document all deviations and COVID-19 related adaptations in a log or spreadsheet in anticipation of future questions from sponsors, monitors, and other entities.

New questions and considerations

In the short-term, Dr. Oyer predicts fewer available trials and a decreased rate of accrual to existing studies. This may result in delays in trial completion and the possibility of redesign for some trials.

He predicts the emergence of COVID-19-focused research questions, including those assessing the course of coronavirus infection in various malignant settings and the impact of cancer-directed treatments and supportive care interventions (e.g., treatment for graft-versus-host disease) on response to COVID-19.

To facilitate developing a clinically and research-relevant database, Dr. Oyer stressed the importance of documentation in the research record, reporting infections as serious adverse events. Documentation should specify whether the infection was confirmed or suspected coronavirus or related to another organism.

In general, when coronavirus infection is strongly suspected, Dr. Oyer said investigational treatments should be interrupted, but study-specific criteria will be forthcoming on that issue.
 

Looking to the future

For patients with advanced cancers, clinical trials provide an important option for hope and clinical benefit. Disrupting the conduct of clinical trials could endanger the lives of participants and delay the emergence of promising treatments and diagnostic tests.

When the coronavirus pandemic recedes, advancing knowledge and treatments for cancer will demand renewed commitment across the oncology care community.

Going forward, Dr. Oyer advised that clinical research staff protect their own health and the safety of trial participants. He encouraged programs to work with sponsors and IRBs to solve logistical problems and clarify individual issues.

He was optimistic that resumption of more normal conduct of studies will enable the successful completion of ongoing trials, enhanced by the creative solutions that were devised during the crisis and by additional prospective, clinically annotated, carefully recorded data from academic and community research sites.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

The coronavirus disease 2019 (COVID-19) pandemic affects us in many ways. Pediatric patients, interestingly, are largely unaffected clinically by this disease. Less than 1% of documented infections occur in children under 10 years old, according to a review of over 72,000 cases from China.¹ In that review, most children were asymptomatic or had mild illness, only three required intensive care, and only one death had been reported as of March 10, 2020. This is in stark contrast to the shocking morbidity and mortality statistics we are becoming all too familiar with on the adult side.

From a social standpoint, however, our pediatric patients’ lives have been turned upside down. Their schedules and routines upended, their education and friendships interrupted, and many are likely experiencing real anxiety and fear.² For countless children, school is a major source of social, emotional, and nutritional support that has been cut off. Some will lose parents, grandparents, or other loved ones to this disease. Parents will lose jobs and will be unable to afford necessities. Pediatric patients will experience delays of procedures or treatments because of the pandemic. Some have projected that rates of child abuse will increase as has been reported during natural disasters.³

Pediatricians around the country are coming together to tackle these issues in creative ways, including the rapid expansion of virtual/telehealth programs. The school systems are developing strategies to deliver online content, and even food, to their students’ homes. Hopefully these tactics will mitigate some of the potential effects on the mental and physical well-being of these patients.

How about my kids? Will they be all right? I am lucky that my husband and I will have jobs throughout this ordeal. Unfortunately, given my role as a hospitalist and my husband’s as a pulmonary/critical care physician, these same jobs that will keep our kids nourished and supported pose the greatest threat to them. As health care workers, we are worried about protecting our families, which may include vulnerable members. The Spanish health ministry announced that medical professionals account for approximately one in eight documented COVID-19 infections in Spain.⁴ With inadequate supplies of personal protective equipment (PPE) in our own nation, we are concerned that our statistics could be similar.

There are multiple strategies to protect ourselves and our families during this difficult time. First, appropriate PPE is essential and integrity with the process must be maintained always. Hospital leaders can protect us by tirelessly working to acquire PPE. In Grand Rapids, Mich., our health system has partnered with multiple local manufacturing companies, including Steelcase, who are producing PPE for our workforce.⁵ Leaders can diligently update their system’s PPE recommendations to be in line with the latest CDC recommendations and disseminate the information regularly. Hospitalists should frequently check with their Infection Prevention department to make sure they understand if there have been any changes to the recommendations. Innovative solutions for sterilization of PPE, stethoscopes, badges and other equipment, such as with the use of UV boxes or hydrogen peroxide vapor,⁶ should be explored to minimize contamination. Hospitalists should bring a set of clothes and shoes to change into upon arrival to work and to change out of prior to leaving the hospital.

We must also keep our heads strong. Currently the anxiety amongst physicians is palpable but there is solidarity. Hospital leaders must ensure that hospitalists have easy access to free mental health resources, such as virtual counseling. Wellness teams must rise to the occasion with innovative tactics to support us. For example, Spectrum Health’s wellness team is sponsoring a blog where physicians can discuss COVID-19–related challenges openly. Hospitalist leaders should ensure that there is a structure for debriefing after critical incidents, which are sure to increase in frequency. Email lists and discussion boards sponsored by professional society also provide a collaborative venue for some of these discussions. We must take advantage of these resources and communicate with each other.

For me, in the end it comes back to the kids. My kids and most pediatric patients are not likely to be hospitalized from COVID-19, but they are also not immune to the toll that fighting this pandemic will take on our families. We took an oath to protect our patients, but what do we owe to our own children? At a minimum we can optimize how we protect ourselves every day, both physically and mentally. As we come together as a strong community to fight this pandemic, in addition to saving lives, we are working to ensure that, in the end, the kids will be all right.
 

Dr. Hadley is chief of pediatric hospital medicine at Spectrum Health/Helen DeVos Children’s Hospital in Grand Rapids, Mich., and clinical assistant professor at Michigan State University, East Lansing.

References

1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648.

2. Hagan JF Jr; American Academy of Pediatrics Committee on Psychosocial Aspects of Child and Family Health; Task Force on Terrorism. Psychosocial implications of disaster or terrorism on children: A guide for the pediatrician. Pediatrics. 2005;116(3):787-795.

3. Gearhart S et al. The impact of natural disasters on domestic violence: An analysis of reports of simple assault in Florida (1997-2007). Violence Gend. 2018 Jun. doi: 10.1089/vio.2017.0077.

4. Minder R, Peltier E. Virus knocks thousands of health workers out of action in Europe. The New York Times. March 24, 2020.

5. McVicar B. West Michigan businesses hustle to produce medical supplies amid coronavirus pandemic. MLive. March 25, 2020.

6. Kenney PA et al. Hydrogen Peroxide Vapor sterilization of N95 respirators for reuse. medRxiv preprint. 2020 Mar. doi: 10.1101/2020.03.24.20041087.
 

The coronavirus disease 2019 (COVID-19) pandemic affects us in many ways. Pediatric patients, interestingly, are largely unaffected clinically by this disease. Less than 1% of documented infections occur in children under 10 years old, according to a review of over 72,000 cases from China.¹ In that review, most children were asymptomatic or had mild illness, only three required intensive care, and only one death had been reported as of March 10, 2020. This is in stark contrast to the shocking morbidity and mortality statistics we are becoming all too familiar with on the adult side.

From a social standpoint, however, our pediatric patients’ lives have been turned upside down. Their schedules and routines upended, their education and friendships interrupted, and many are likely experiencing real anxiety and fear.² For countless children, school is a major source of social, emotional, and nutritional support that has been cut off. Some will lose parents, grandparents, or other loved ones to this disease. Parents will lose jobs and will be unable to afford necessities. Pediatric patients will experience delays of procedures or treatments because of the pandemic. Some have projected that rates of child abuse will increase as has been reported during natural disasters.³

Pediatricians around the country are coming together to tackle these issues in creative ways, including the rapid expansion of virtual/telehealth programs. The school systems are developing strategies to deliver online content, and even food, to their students’ homes. Hopefully these tactics will mitigate some of the potential effects on the mental and physical well-being of these patients.

How about my kids? Will they be all right? I am lucky that my husband and I will have jobs throughout this ordeal. Unfortunately, given my role as a hospitalist and my husband’s as a pulmonary/critical care physician, these same jobs that will keep our kids nourished and supported pose the greatest threat to them. As health care workers, we are worried about protecting our families, which may include vulnerable members. The Spanish health ministry announced that medical professionals account for approximately one in eight documented COVID-19 infections in Spain.⁴ With inadequate supplies of personal protective equipment (PPE) in our own nation, we are concerned that our statistics could be similar.

There are multiple strategies to protect ourselves and our families during this difficult time. First, appropriate PPE is essential and integrity with the process must be maintained always. Hospital leaders can protect us by tirelessly working to acquire PPE. In Grand Rapids, Mich., our health system has partnered with multiple local manufacturing companies, including Steelcase, who are producing PPE for our workforce.⁵ Leaders can diligently update their system’s PPE recommendations to be in line with the latest CDC recommendations and disseminate the information regularly. Hospitalists should frequently check with their Infection Prevention department to make sure they understand if there have been any changes to the recommendations. Innovative solutions for sterilization of PPE, stethoscopes, badges and other equipment, such as with the use of UV boxes or hydrogen peroxide vapor,⁶ should be explored to minimize contamination. Hospitalists should bring a set of clothes and shoes to change into upon arrival to work and to change out of prior to leaving the hospital.

We must also keep our heads strong. Currently the anxiety amongst physicians is palpable but there is solidarity. Hospital leaders must ensure that hospitalists have easy access to free mental health resources, such as virtual counseling. Wellness teams must rise to the occasion with innovative tactics to support us. For example, Spectrum Health’s wellness team is sponsoring a blog where physicians can discuss COVID-19–related challenges openly. Hospitalist leaders should ensure that there is a structure for debriefing after critical incidents, which are sure to increase in frequency. Email lists and discussion boards sponsored by professional society also provide a collaborative venue for some of these discussions. We must take advantage of these resources and communicate with each other.

For me, in the end it comes back to the kids. My kids and most pediatric patients are not likely to be hospitalized from COVID-19, but they are also not immune to the toll that fighting this pandemic will take on our families. We took an oath to protect our patients, but what do we owe to our own children? At a minimum we can optimize how we protect ourselves every day, both physically and mentally. As we come together as a strong community to fight this pandemic, in addition to saving lives, we are working to ensure that, in the end, the kids will be all right.
 

Dr. Hadley is chief of pediatric hospital medicine at Spectrum Health/Helen DeVos Children’s Hospital in Grand Rapids, Mich., and clinical assistant professor at Michigan State University, East Lansing.

References

1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648.

2. Hagan JF Jr; American Academy of Pediatrics Committee on Psychosocial Aspects of Child and Family Health; Task Force on Terrorism. Psychosocial implications of disaster or terrorism on children: A guide for the pediatrician. Pediatrics. 2005;116(3):787-795.

3. Gearhart S et al. The impact of natural disasters on domestic violence: An analysis of reports of simple assault in Florida (1997-2007). Violence Gend. 2018 Jun. doi: 10.1089/vio.2017.0077.

4. Minder R, Peltier E. Virus knocks thousands of health workers out of action in Europe. The New York Times. March 24, 2020.

5. McVicar B. West Michigan businesses hustle to produce medical supplies amid coronavirus pandemic. MLive. March 25, 2020.

6. Kenney PA et al. Hydrogen Peroxide Vapor sterilization of N95 respirators for reuse. medRxiv preprint. 2020 Mar. doi: 10.1101/2020.03.24.20041087.
 

The coronavirus disease 2019 (COVID-19) pandemic affects us in many ways. Pediatric patients, interestingly, are largely unaffected clinically by this disease. Less than 1% of documented infections occur in children under 10 years old, according to a review of over 72,000 cases from China.¹ In that review, most children were asymptomatic or had mild illness, only three required intensive care, and only one death had been reported as of March 10, 2020. This is in stark contrast to the shocking morbidity and mortality statistics we are becoming all too familiar with on the adult side.

From a social standpoint, however, our pediatric patients’ lives have been turned upside down. Their schedules and routines upended, their education and friendships interrupted, and many are likely experiencing real anxiety and fear.² For countless children, school is a major source of social, emotional, and nutritional support that has been cut off. Some will lose parents, grandparents, or other loved ones to this disease. Parents will lose jobs and will be unable to afford necessities. Pediatric patients will experience delays of procedures or treatments because of the pandemic. Some have projected that rates of child abuse will increase as has been reported during natural disasters.³

Pediatricians around the country are coming together to tackle these issues in creative ways, including the rapid expansion of virtual/telehealth programs. The school systems are developing strategies to deliver online content, and even food, to their students’ homes. Hopefully these tactics will mitigate some of the potential effects on the mental and physical well-being of these patients.

How about my kids? Will they be all right? I am lucky that my husband and I will have jobs throughout this ordeal. Unfortunately, given my role as a hospitalist and my husband’s as a pulmonary/critical care physician, these same jobs that will keep our kids nourished and supported pose the greatest threat to them. As health care workers, we are worried about protecting our families, which may include vulnerable members. The Spanish health ministry announced that medical professionals account for approximately one in eight documented COVID-19 infections in Spain.⁴ With inadequate supplies of personal protective equipment (PPE) in our own nation, we are concerned that our statistics could be similar.

There are multiple strategies to protect ourselves and our families during this difficult time. First, appropriate PPE is essential and integrity with the process must be maintained always. Hospital leaders can protect us by tirelessly working to acquire PPE. In Grand Rapids, Mich., our health system has partnered with multiple local manufacturing companies, including Steelcase, who are producing PPE for our workforce.⁵ Leaders can diligently update their system’s PPE recommendations to be in line with the latest CDC recommendations and disseminate the information regularly. Hospitalists should frequently check with their Infection Prevention department to make sure they understand if there have been any changes to the recommendations. Innovative solutions for sterilization of PPE, stethoscopes, badges and other equipment, such as with the use of UV boxes or hydrogen peroxide vapor,⁶ should be explored to minimize contamination. Hospitalists should bring a set of clothes and shoes to change into upon arrival to work and to change out of prior to leaving the hospital.

We must also keep our heads strong. Currently the anxiety amongst physicians is palpable but there is solidarity. Hospital leaders must ensure that hospitalists have easy access to free mental health resources, such as virtual counseling. Wellness teams must rise to the occasion with innovative tactics to support us. For example, Spectrum Health’s wellness team is sponsoring a blog where physicians can discuss COVID-19–related challenges openly. Hospitalist leaders should ensure that there is a structure for debriefing after critical incidents, which are sure to increase in frequency. Email lists and discussion boards sponsored by professional society also provide a collaborative venue for some of these discussions. We must take advantage of these resources and communicate with each other.

For me, in the end it comes back to the kids. My kids and most pediatric patients are not likely to be hospitalized from COVID-19, but they are also not immune to the toll that fighting this pandemic will take on our families. We took an oath to protect our patients, but what do we owe to our own children? At a minimum we can optimize how we protect ourselves every day, both physically and mentally. As we come together as a strong community to fight this pandemic, in addition to saving lives, we are working to ensure that, in the end, the kids will be all right.
 

Dr. Hadley is chief of pediatric hospital medicine at Spectrum Health/Helen DeVos Children’s Hospital in Grand Rapids, Mich., and clinical assistant professor at Michigan State University, East Lansing.

References

1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648.

2. Hagan JF Jr; American Academy of Pediatrics Committee on Psychosocial Aspects of Child and Family Health; Task Force on Terrorism. Psychosocial implications of disaster or terrorism on children: A guide for the pediatrician. Pediatrics. 2005;116(3):787-795.

3. Gearhart S et al. The impact of natural disasters on domestic violence: An analysis of reports of simple assault in Florida (1997-2007). Violence Gend. 2018 Jun. doi: 10.1089/vio.2017.0077.

4. Minder R, Peltier E. Virus knocks thousands of health workers out of action in Europe. The New York Times. March 24, 2020.

5. McVicar B. West Michigan businesses hustle to produce medical supplies amid coronavirus pandemic. MLive. March 25, 2020.

6. Kenney PA et al. Hydrogen Peroxide Vapor sterilization of N95 respirators for reuse. medRxiv preprint. 2020 Mar. doi: 10.1101/2020.03.24.20041087.
 

The pandemic of coronavirus disease 2019 (COVID-19) is confronting the modern world like nothing else before. With over 20 million individuals expected to require hospitalization in the US, this health crisis may become a generation-defining moment for healthcare systems and the field of hospital medicine.¹ The specific challenges facing hospital medicine are comparable to running a sprint and a marathon—at the same time. For the sprint underway, hospitalists must learn to respond to a rapidly changing environment in which critical decisions are made within hours and days. At the same time, hospitalists need to plan for the marathon of increased clinical needs over the coming months, the possibility of burnout, and concerns about staff well-­being. Although runners typically focus on either the sprint or the marathon, healthcare systems and hospital medicine providers will need to simultaneously prepare for both types of races.

Over the past several weeks, hospital medicine leaders have been rapidly responding to an evolving crisis. Leaders and clinicians are quickly learning how to restructure clinical operations, negotiate the short supply of personal protective equipment (PPE), and manage delays in COVID-19 testing. In these areas, our hospitalist group has experienced a steep learning curve. In addition to the strategies outlined in the Table, we will share here our experiences and insights on managing and preparing for the COVID-19 pandemic.

Communication Is Central

During the sprint, focused, regular communication is imperative to ameliorate anxiety and fear. A study of crisis communication after 9/11 found that, for employees, good communication from leadership was one of the most valued factors.² Communications experts also note that, in times of crisis, leaders have a special role in communication, specifically around demystifying the situation, providing hope, and maintaining transparency.³

Mental bandwidth may be limited in a stressful environment, so efforts should be taken to maximize the value of each communication. Information on hospital metrics should be provided regularly, including the number of COVID-19 cases, the status of clinical services and staffing, hospital capacity, and resource availability.⁴ Although the ubiquity and ease of email is convenient, recognize that providers are likely receiving email updates from multiple layers within your healthcare organization. To guard against losing important information, we use the same templated format for daily email updates with changes highlighted, which allows busy clinicians to digest pertinent information easily.⁵ Finally, consider having a single individual be responsible for collating COVID-19–related emails sent to your group. Although clinicians may want to share the most recent studies or their clinical experiences with a group email, instead have them send this information to a single individual who can organize these materials and share them on a regular basis.

To keep two-way communication channels open in a busy, asynchronous environment, consider having a centralized shared document in which providers can give real-time feedback to capture on-the-ground experiences or share questions they would like answered. Within our group, we found that centralizing our conversation in a shared document eliminated redundancy, focused our meetings, and kept everyone up to date. Additionally, regularly scheduled meetings may need to be adapted to a remote format (eg, Zoom, WebEx) as clinicians are asked to work from home when not on clinical service. Finally, recognize that virtual meetings require a different skill set than that required by in-person meetings, including reestablishment of social norms and technology preparation.⁶

Optimize Your Staffing

Hospital volumes could increase to as high as 270% of current hospital bed capacities during this pandemic.¹ This surge is further complicated by the effort involved in caring for these patients, given their increased medical complexity, the use of new protocols, and the extra time needed to update staff and family. As the workload intensifies, staffing models and operations will also need to adapt.

First, optimize your inpatient resources based on the changes your hospital system is making. For instance, as elective surgeries were cancelled, we dissolved our surgical comanagement and consult services to better accommodate our hospitals’ needs. Further, consider using advanced practice providers (eg, physician assistants and nurse practitioners) released from their clinical duties to help with inpatient care in the event of a surge. If your hospital has trainees (eg, residents or fellows), consider reassigning those whose rotations have been postponed to newly created inpatient teams; trainees often have strong institutional knowledge and understanding of hospital protocols and resources.

Second, use hospitalists for their most relevant skills. Hospitalists are pluripotent clinicians who are comfortable with high-­acuity patients and can fit into a myriad of clinical positions. The initial instinct at our institution was to mobilize hospitalists across all areas of increasing needs in the hospital (eg, screening clinics,⁷ advice phone lines for patients, or in the Emergency Department), but we quickly recognized that the hospitalist group is a finite resource. We focused our hospitalists’ clinical work on the expanding inpatient needs and allowed other outpatient or procedure-based specialties that have less inpatient experience to fill the broader institutional gaps.

Finally, consider long-term implications of staffing decisions. Leaders are making challenging coverage decisions that can affect the morale and autonomy of staff. Does backup staffing happen on a volunteer basis? Who fills the need—those with less clinical time or those with fewer personal obligations? When a staffing model is challenged and your group is making such decisions, engaged communication again becomes paramount.

Experts believe that we are only at the beginning of this crisis, one for which we don’t know what the end looks like or when it will come. With this in mind, hospital medicine leadership must plan for the long-term implications of the lengthy race ahead. Recognizing that morale, motivation, and burnout will be issues to deal with on the horizon, a focus on sustainability and wellness will become increasingly important as the marathon continues. To date, we’ve found the following principles to be helpful.

Delegate Responsibilities

Hospitals will not be able to survive COVID-19 through the efforts of single individuals. Instead, consider creating “operational champion” roles for frontline clinicians. These individuals can lead in specific areas (eg, PPE, updates on COVID-19 testing, discharge protocols) and act as conduits for information, updates, and resources for your group. At our institution, such operational meetings and activities take hours out of each day. By creating a breadth of leadership roles, our group has spread the operational workload while still allowing clinicians to care for patients, avoid burnout, and build autonomy and opportunities for both personal and professional growth. While for most institutions, these positions are temporary and not compensated with salary or time, the contribution to the group should be recognized both now and in the future.

Focus on Wellness

Providers are battling a laundry list of both clinical and personal stressors. The Centers for Disease Control and Prevention has already recognized that stress and mental health are going to be large hurdles for both patients and providers during this crisis.⁸ From the beginning, hospitalist leadership should be attuned to physician wellness and be aware that burnout, mental and physical exhaustion, and the possibility of contracting COVID-19 will be issues in the coming weeks and months. Volunteerism is built into the physician’s work ethic, but we must be mindful about its cost for long-term staffing demands. In addition, scarce medical resources add an additional moral strain for clinicians as they face tough allocation decisions, as we’ve seen with our Italian colleagues.⁹

As regular meetings around COVID-19 have become commonplace, we’ve made sure to set aside defined time for staff to discuss and reflect on their experiences. Doing so has allowed our clinicians to feel heard and to acknowledge the difficulties they are facing in their clinical duties. Leaders should also consider frequent check-ins with individual providers. At our institution, the first positive COVID-19 patient did not radically change any protocol that was in place, but a check-in with the hospitalist on service that day proved helpful for a debrief and processing opportunity. Individual conversations can help those on the front lines feel supported and remind them they are not operating alone in an anonymous vacuum.

Continue by celebrating small victories because this marathon is not going to end with an obvious finish line or a singular moment in which everyone can rejoice. A negative test, a patient with a good outcome, and a donation of PPE are all opportunities to celebrate. It may be what keeps us going when there is no end in sight. We have relied on these celebrations and moments of levity as an integral part of our regular group meetings.

At the end of this pandemic, just as we hope that our social distancing feels like an overreaction, we similarly hope that our sprint to build capacity ends up being unnecessary as well. As we wrote this Perspectives piece, uncertainty about the extent, length, and impact of this pandemic still existed. By the time it is published it may be that the sprint is over, and the marathon is beginning. Or, if our wildest hopes come true, there will be no marathon to run at all.

The pandemic of coronavirus disease 2019 (COVID-19) is confronting the modern world like nothing else before. With over 20 million individuals expected to require hospitalization in the US, this health crisis may become a generation-defining moment for healthcare systems and the field of hospital medicine.¹ The specific challenges facing hospital medicine are comparable to running a sprint and a marathon—at the same time. For the sprint underway, hospitalists must learn to respond to a rapidly changing environment in which critical decisions are made within hours and days. At the same time, hospitalists need to plan for the marathon of increased clinical needs over the coming months, the possibility of burnout, and concerns about staff well-­being. Although runners typically focus on either the sprint or the marathon, healthcare systems and hospital medicine providers will need to simultaneously prepare for both types of races.

Over the past several weeks, hospital medicine leaders have been rapidly responding to an evolving crisis. Leaders and clinicians are quickly learning how to restructure clinical operations, negotiate the short supply of personal protective equipment (PPE), and manage delays in COVID-19 testing. In these areas, our hospitalist group has experienced a steep learning curve. In addition to the strategies outlined in the Table, we will share here our experiences and insights on managing and preparing for the COVID-19 pandemic.

Communication Is Central

During the sprint, focused, regular communication is imperative to ameliorate anxiety and fear. A study of crisis communication after 9/11 found that, for employees, good communication from leadership was one of the most valued factors.² Communications experts also note that, in times of crisis, leaders have a special role in communication, specifically around demystifying the situation, providing hope, and maintaining transparency.³

Mental bandwidth may be limited in a stressful environment, so efforts should be taken to maximize the value of each communication. Information on hospital metrics should be provided regularly, including the number of COVID-19 cases, the status of clinical services and staffing, hospital capacity, and resource availability.⁴ Although the ubiquity and ease of email is convenient, recognize that providers are likely receiving email updates from multiple layers within your healthcare organization. To guard against losing important information, we use the same templated format for daily email updates with changes highlighted, which allows busy clinicians to digest pertinent information easily.⁵ Finally, consider having a single individual be responsible for collating COVID-19–related emails sent to your group. Although clinicians may want to share the most recent studies or their clinical experiences with a group email, instead have them send this information to a single individual who can organize these materials and share them on a regular basis.

To keep two-way communication channels open in a busy, asynchronous environment, consider having a centralized shared document in which providers can give real-time feedback to capture on-the-ground experiences or share questions they would like answered. Within our group, we found that centralizing our conversation in a shared document eliminated redundancy, focused our meetings, and kept everyone up to date. Additionally, regularly scheduled meetings may need to be adapted to a remote format (eg, Zoom, WebEx) as clinicians are asked to work from home when not on clinical service. Finally, recognize that virtual meetings require a different skill set than that required by in-person meetings, including reestablishment of social norms and technology preparation.⁶

Optimize Your Staffing

Hospital volumes could increase to as high as 270% of current hospital bed capacities during this pandemic.¹ This surge is further complicated by the effort involved in caring for these patients, given their increased medical complexity, the use of new protocols, and the extra time needed to update staff and family. As the workload intensifies, staffing models and operations will also need to adapt.

First, optimize your inpatient resources based on the changes your hospital system is making. For instance, as elective surgeries were cancelled, we dissolved our surgical comanagement and consult services to better accommodate our hospitals’ needs. Further, consider using advanced practice providers (eg, physician assistants and nurse practitioners) released from their clinical duties to help with inpatient care in the event of a surge. If your hospital has trainees (eg, residents or fellows), consider reassigning those whose rotations have been postponed to newly created inpatient teams; trainees often have strong institutional knowledge and understanding of hospital protocols and resources.

Second, use hospitalists for their most relevant skills. Hospitalists are pluripotent clinicians who are comfortable with high-­acuity patients and can fit into a myriad of clinical positions. The initial instinct at our institution was to mobilize hospitalists across all areas of increasing needs in the hospital (eg, screening clinics,⁷ advice phone lines for patients, or in the Emergency Department), but we quickly recognized that the hospitalist group is a finite resource. We focused our hospitalists’ clinical work on the expanding inpatient needs and allowed other outpatient or procedure-based specialties that have less inpatient experience to fill the broader institutional gaps.

Finally, consider long-term implications of staffing decisions. Leaders are making challenging coverage decisions that can affect the morale and autonomy of staff. Does backup staffing happen on a volunteer basis? Who fills the need—those with less clinical time or those with fewer personal obligations? When a staffing model is challenged and your group is making such decisions, engaged communication again becomes paramount.

Experts believe that we are only at the beginning of this crisis, one for which we don’t know what the end looks like or when it will come. With this in mind, hospital medicine leadership must plan for the long-term implications of the lengthy race ahead. Recognizing that morale, motivation, and burnout will be issues to deal with on the horizon, a focus on sustainability and wellness will become increasingly important as the marathon continues. To date, we’ve found the following principles to be helpful.

Delegate Responsibilities

Hospitals will not be able to survive COVID-19 through the efforts of single individuals. Instead, consider creating “operational champion” roles for frontline clinicians. These individuals can lead in specific areas (eg, PPE, updates on COVID-19 testing, discharge protocols) and act as conduits for information, updates, and resources for your group. At our institution, such operational meetings and activities take hours out of each day. By creating a breadth of leadership roles, our group has spread the operational workload while still allowing clinicians to care for patients, avoid burnout, and build autonomy and opportunities for both personal and professional growth. While for most institutions, these positions are temporary and not compensated with salary or time, the contribution to the group should be recognized both now and in the future.

Focus on Wellness

Providers are battling a laundry list of both clinical and personal stressors. The Centers for Disease Control and Prevention has already recognized that stress and mental health are going to be large hurdles for both patients and providers during this crisis.⁸ From the beginning, hospitalist leadership should be attuned to physician wellness and be aware that burnout, mental and physical exhaustion, and the possibility of contracting COVID-19 will be issues in the coming weeks and months. Volunteerism is built into the physician’s work ethic, but we must be mindful about its cost for long-term staffing demands. In addition, scarce medical resources add an additional moral strain for clinicians as they face tough allocation decisions, as we’ve seen with our Italian colleagues.⁹

As regular meetings around COVID-19 have become commonplace, we’ve made sure to set aside defined time for staff to discuss and reflect on their experiences. Doing so has allowed our clinicians to feel heard and to acknowledge the difficulties they are facing in their clinical duties. Leaders should also consider frequent check-ins with individual providers. At our institution, the first positive COVID-19 patient did not radically change any protocol that was in place, but a check-in with the hospitalist on service that day proved helpful for a debrief and processing opportunity. Individual conversations can help those on the front lines feel supported and remind them they are not operating alone in an anonymous vacuum.

Continue by celebrating small victories because this marathon is not going to end with an obvious finish line or a singular moment in which everyone can rejoice. A negative test, a patient with a good outcome, and a donation of PPE are all opportunities to celebrate. It may be what keeps us going when there is no end in sight. We have relied on these celebrations and moments of levity as an integral part of our regular group meetings.

At the end of this pandemic, just as we hope that our social distancing feels like an overreaction, we similarly hope that our sprint to build capacity ends up being unnecessary as well. As we wrote this Perspectives piece, uncertainty about the extent, length, and impact of this pandemic still existed. By the time it is published it may be that the sprint is over, and the marathon is beginning. Or, if our wildest hopes come true, there will be no marathon to run at all.

The pandemic of coronavirus disease 2019 (COVID-19) is confronting the modern world like nothing else before. With over 20 million individuals expected to require hospitalization in the US, this health crisis may become a generation-defining moment for healthcare systems and the field of hospital medicine.¹ The specific challenges facing hospital medicine are comparable to running a sprint and a marathon—at the same time. For the sprint underway, hospitalists must learn to respond to a rapidly changing environment in which critical decisions are made within hours and days. At the same time, hospitalists need to plan for the marathon of increased clinical needs over the coming months, the possibility of burnout, and concerns about staff well-­being. Although runners typically focus on either the sprint or the marathon, healthcare systems and hospital medicine providers will need to simultaneously prepare for both types of races.

Over the past several weeks, hospital medicine leaders have been rapidly responding to an evolving crisis. Leaders and clinicians are quickly learning how to restructure clinical operations, negotiate the short supply of personal protective equipment (PPE), and manage delays in COVID-19 testing. In these areas, our hospitalist group has experienced a steep learning curve. In addition to the strategies outlined in the Table, we will share here our experiences and insights on managing and preparing for the COVID-19 pandemic.

Communication Is Central

During the sprint, focused, regular communication is imperative to ameliorate anxiety and fear. A study of crisis communication after 9/11 found that, for employees, good communication from leadership was one of the most valued factors.² Communications experts also note that, in times of crisis, leaders have a special role in communication, specifically around demystifying the situation, providing hope, and maintaining transparency.³

Mental bandwidth may be limited in a stressful environment, so efforts should be taken to maximize the value of each communication. Information on hospital metrics should be provided regularly, including the number of COVID-19 cases, the status of clinical services and staffing, hospital capacity, and resource availability.⁴ Although the ubiquity and ease of email is convenient, recognize that providers are likely receiving email updates from multiple layers within your healthcare organization. To guard against losing important information, we use the same templated format for daily email updates with changes highlighted, which allows busy clinicians to digest pertinent information easily.⁵ Finally, consider having a single individual be responsible for collating COVID-19–related emails sent to your group. Although clinicians may want to share the most recent studies or their clinical experiences with a group email, instead have them send this information to a single individual who can organize these materials and share them on a regular basis.

To keep two-way communication channels open in a busy, asynchronous environment, consider having a centralized shared document in which providers can give real-time feedback to capture on-the-ground experiences or share questions they would like answered. Within our group, we found that centralizing our conversation in a shared document eliminated redundancy, focused our meetings, and kept everyone up to date. Additionally, regularly scheduled meetings may need to be adapted to a remote format (eg, Zoom, WebEx) as clinicians are asked to work from home when not on clinical service. Finally, recognize that virtual meetings require a different skill set than that required by in-person meetings, including reestablishment of social norms and technology preparation.⁶

Optimize Your Staffing

Hospital volumes could increase to as high as 270% of current hospital bed capacities during this pandemic.¹ This surge is further complicated by the effort involved in caring for these patients, given their increased medical complexity, the use of new protocols, and the extra time needed to update staff and family. As the workload intensifies, staffing models and operations will also need to adapt.

First, optimize your inpatient resources based on the changes your hospital system is making. For instance, as elective surgeries were cancelled, we dissolved our surgical comanagement and consult services to better accommodate our hospitals’ needs. Further, consider using advanced practice providers (eg, physician assistants and nurse practitioners) released from their clinical duties to help with inpatient care in the event of a surge. If your hospital has trainees (eg, residents or fellows), consider reassigning those whose rotations have been postponed to newly created inpatient teams; trainees often have strong institutional knowledge and understanding of hospital protocols and resources.

Second, use hospitalists for their most relevant skills. Hospitalists are pluripotent clinicians who are comfortable with high-­acuity patients and can fit into a myriad of clinical positions. The initial instinct at our institution was to mobilize hospitalists across all areas of increasing needs in the hospital (eg, screening clinics,⁷ advice phone lines for patients, or in the Emergency Department), but we quickly recognized that the hospitalist group is a finite resource. We focused our hospitalists’ clinical work on the expanding inpatient needs and allowed other outpatient or procedure-based specialties that have less inpatient experience to fill the broader institutional gaps.

Finally, consider long-term implications of staffing decisions. Leaders are making challenging coverage decisions that can affect the morale and autonomy of staff. Does backup staffing happen on a volunteer basis? Who fills the need—those with less clinical time or those with fewer personal obligations? When a staffing model is challenged and your group is making such decisions, engaged communication again becomes paramount.

Experts believe that we are only at the beginning of this crisis, one for which we don’t know what the end looks like or when it will come. With this in mind, hospital medicine leadership must plan for the long-term implications of the lengthy race ahead. Recognizing that morale, motivation, and burnout will be issues to deal with on the horizon, a focus on sustainability and wellness will become increasingly important as the marathon continues. To date, we’ve found the following principles to be helpful.

Delegate Responsibilities

Hospitals will not be able to survive COVID-19 through the efforts of single individuals. Instead, consider creating “operational champion” roles for frontline clinicians. These individuals can lead in specific areas (eg, PPE, updates on COVID-19 testing, discharge protocols) and act as conduits for information, updates, and resources for your group. At our institution, such operational meetings and activities take hours out of each day. By creating a breadth of leadership roles, our group has spread the operational workload while still allowing clinicians to care for patients, avoid burnout, and build autonomy and opportunities for both personal and professional growth. While for most institutions, these positions are temporary and not compensated with salary or time, the contribution to the group should be recognized both now and in the future.

Focus on Wellness

Providers are battling a laundry list of both clinical and personal stressors. The Centers for Disease Control and Prevention has already recognized that stress and mental health are going to be large hurdles for both patients and providers during this crisis.⁸ From the beginning, hospitalist leadership should be attuned to physician wellness and be aware that burnout, mental and physical exhaustion, and the possibility of contracting COVID-19 will be issues in the coming weeks and months. Volunteerism is built into the physician’s work ethic, but we must be mindful about its cost for long-term staffing demands. In addition, scarce medical resources add an additional moral strain for clinicians as they face tough allocation decisions, as we’ve seen with our Italian colleagues.⁹

As regular meetings around COVID-19 have become commonplace, we’ve made sure to set aside defined time for staff to discuss and reflect on their experiences. Doing so has allowed our clinicians to feel heard and to acknowledge the difficulties they are facing in their clinical duties. Leaders should also consider frequent check-ins with individual providers. At our institution, the first positive COVID-19 patient did not radically change any protocol that was in place, but a check-in with the hospitalist on service that day proved helpful for a debrief and processing opportunity. Individual conversations can help those on the front lines feel supported and remind them they are not operating alone in an anonymous vacuum.

Continue by celebrating small victories because this marathon is not going to end with an obvious finish line or a singular moment in which everyone can rejoice. A negative test, a patient with a good outcome, and a donation of PPE are all opportunities to celebrate. It may be what keeps us going when there is no end in sight. We have relied on these celebrations and moments of levity as an integral part of our regular group meetings.

At the end of this pandemic, just as we hope that our social distancing feels like an overreaction, we similarly hope that our sprint to build capacity ends up being unnecessary as well. As we wrote this Perspectives piece, uncertainty about the extent, length, and impact of this pandemic still existed. By the time it is published it may be that the sprint is over, and the marathon is beginning. Or, if our wildest hopes come true, there will be no marathon to run at all.