Article

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

The SARS-CoV-2 virus has resulted in > 778 million reported COVID-19 cases and > 7 million deaths worldwide. ¹ About 70% of the eligible US population has completed a primary COVID-19 vaccination series, yet only 17% have received an updated bivalent booster dose.² These immunization rates fall below the World Health Organization (WHO) target of 70%.³

Early in the pandemic, US Department of Veterans Affairs (VA) vaccination rates ranged from 46% to 71%.^4,5 Ensuring a high level of COVID-19 vaccination in the largest integrated US health care system aligns with the VA priority to provide high-quality, evidence-based care to a patient population that is older and has more comorbidities than the overall US population.^6-9

Vaccine hesitancy, defined as a “delay in acceptance or refusal of vaccination despite availability of vaccination service,” is a major contributor to suboptimal vaccination rates.^10-13 Previous studies used cluster analyses to identify the unique combinations of behavioral and social factors responsible for COVID-19 vaccine hesitancy.^10,11 Lack of perceived vaccine effectiveness and low perceived risk of the health consequences from COVID-19 infection were frequently identified in clusters where patients had the lowest intent for vaccination.^10,11 Similarly, low trust in health care practitioners (HCPs), government, and pharmaceutical companies diminished intent for vaccination in these clusters.¹⁰ These quantitative studies were limited by their exclusive focus on unvaccinated individuals, reliance on self-reported intent, and lack of assessment of a health care system with a COVID-19 vaccine delivery program designed to overcome barriers to health care access, such as the VA.

Prior qualitative studies of vaccine uptake in distinct veteran subgroups (ie, unhoused and in VA facilities with low vaccination rates) demonstrated that overriding medical priorities among the unhoused and vaccine safety concerns were associated with decreased vaccine uptake, and positive perceptions of HCPs and the health care system were associated with increased vaccine uptake.^11,12 However, these studies were conducted during periods of greater COVID-19 vaccine availability and acceptance, and prior to booster recommendations.^4,12,13

This mixed-methods quality improvement (QI) project assessed the barriers and facilitators of COVID-19 vaccination among veterans receiving primary care at a single VA health care facility. We assessed whether unique patient clusters could be identified based on COVID-19–related and vaccine-related thoughts and feelings and whether cluster membership was associated with COVID-19 vaccination. This analysis also explored how individuals’ beliefs and trust shaped motivations and hesitancies for vaccine uptake in quantitatively derived clusters with varying vaccination rates.

Methods

This QI project was conducted at the VA Pittsburgh Healthcare System (VAPHS), a tertiary care facility serving > 75,000 veterans in Pennsylvania, West Virginia, and Ohio. The VAPHS Institutional Review Board determined this QI study was exempt from review.^14-17 Participation was voluntary and had no bearing on VA health care or benefits. Financial support for the project, including key personnel and participant compensation, was provided by VAPHS. We followed the STROBE reporting guideline for cross-sectional studies and the COREQ checklist for qualitative research.^18,19

Quantitative Survey

The 32,271 veterans assigned to a VAPHS primary care HCP, effective April 1, 2020, were eligible. To ensure representation of subgroups underrecognized in research and/or QI projects, the sample included all 1980 female patients at VAPHS and a random sample of 500 White and 500 Hispanic and/or non-White men within 4 age categories (< 50, 50-64, 65-84, and > 84 years). For the < 50 years or > 84 years categories, all Hispanic and/or non-White men were included due to small sample sizes.^20-22 The nonrandom sampling frame comprised 1708 Hispanic and/or non-White men and 2000 White men. After assigning the 5688 potentially eligible individuals a unique identifier, 31 opted out, resulting in a final sample of 5657 individuals.

The 5657 individuals received a letter requesting their completion of a future questionnaire about COVID-19 infection and vaccines. An electronic Qualtrics questionnaire link was emailed to 3221 individuals; nonresponders received 2 follow-up email reminders. For the 2436 veterans without an email address on file, trained interviewers conducted phone surveys and entered responses. Those patients who completed the questionnaire could enter a drawing to win 1 of 100 cash prizes valued at $100. We collected questionnaire data from July to September 2021.

Questionnaire Items

We constructed a 60-item questionnaire based on prior research on COVID-19 vaccine hesitancy and the WHO Guidebook for Immunization Programs and Implementing Partners.^4,23-25 The WHO Guidebook comprises survey items organized within 4 domains reflecting the behavioral and social determinants of vaccination: thoughts and feelings; social processes; motivation and hesitancy; and practical factors.²³

Sociodemographic, clinical, and personal characteristics. The survey assessed respondent ethnicity and race and used these data to create a composite race and ethnicity variable. Highest educational level was also attained using 8 response options. The survey also assessed prior COVID-19 infection; prior receipt of vaccines for influenza, pneumonia, tetanus, or shingles; and presence of comorbidities that increase the risk of severe COVID-19 infection. We used administrative data from the VA Corporate Data Warehouse to determine respondent age, sex, geographic residence (urban, rural), and to fill in missing self-reported data on sex (n = 4) and ethnicity and race (n = 12). The survey assessed political views using a 5-point Likert scale (1, very liberal; 5, very conservative) and was collapsed into 3 categories (ie, very conservative or conservative, moderate, very liberal or liberal), with prefer not to answer reported separately

COVID-19 infection and vaccine. We asked veterans if they had ever been infected with COVID-19, whether they had been offered and/or received a COVID-19 vaccine, and type (Pfizer, Moderna, or Johnson & Johnson), and number of doses received. Positive vaccination status was defined as the receipt of ≥ 1 dose of a COVID-19 vaccine approved by the US Food and Drug Administration.

COVID-19 opinions. Respondents were asked about perceived risk of COVID-19 infection and related health outcomes, as well as beliefs about COVID-19 vaccines, using a 4-point Likert scale for all items: (1, not at all concerned; 4, very concerned). Respondents were asked about concerns related to COVID-19 infection and severe illness. They also were asked about vaccine-related short-term adverse effects (AEs) and long-term complications. Respondents were asked how effective they believed COVID-19 vaccines were at preventing infection, serious illness, or death. Unvaccinated and vaccinated veterans were asked similar items, with a qualifier of “before getting vaccinated…” for those who were vaccinated.

Social processes. Respondents were asked to rate their level of trust in various sources of COVID-19 vaccine information using a 4-point Likert scale (1, trust not at all; 4, trust very much). Respondents were asked whether community or religious leaders or close family or friends wanted them to get vaccinated (yes, no, or unsure).

Practical factors. Respondents were asked to rate the logistical difficulty of getting vaccinated or trying to get vaccinated using a 4-point Likert scale (1, not at all; 4, extremely).

Participants

Respondents were asked to participate in a follow-up qualitative interview. Among 293 participants who agreed, we sampled all 86 unvaccinated individuals regardless of cluster assignment, a random sample of 88 individuals in the cluster with the lowest vaccination rate, and all 33 vaccinated individuals in the cluster with the second-lowest vaccination rate. Forty-nine veterans completed qualitative interviews.

Two research staff trained in qualitative research completed telephone interviews, averaging 16.5 minutes (March to May 2022), using semistructured scripts to elicit vaccine-related motivations, hesitancies, or concerns. Interviews were recorded, transcribed, and deidentified. Participants provided written consent for recording and received $50 cash-equivalent compensation for interview completion.

Qualitative Interview Script

The interview script consisted of open-ended questions related to vaccine uptake across WHO domains.²³ Both unvaccinated and vaccinated respondents were asked similar questions and customized questions about boosters for the vaccinated subgroup. To assess motivations and hesitancies, respondents were asked how they made their decisions about vaccination and what they considered when deciding. Vaccinated participants were asked about motivations and overcoming concerns. Unvaccinated respondents were asked about reasons for concern. To assess social processes, the interviewers asked participants whose opinion or counsel they trusted when deciding whether to get vaccinated. Questions also focused on positive experiences and vaccination barriers. Vaccinated participants were asked what could have improved their vaccination experiences. Finally, the interviewers asked participants who received a complete primary vaccine series about their motivations and plans related to booster vaccines, and whether information about emerging COVID-19 variants influenced their decisions.

Data Analyses

This analysis used X² and Fisher exact tests to assess the associations among respondent characteristics, questionnaire responses, vaccination status, and cluster membership. Items phrased similarly were handled in a similar fashion for vaccinated and unvaccinated respondents.

Cluster analysis assessed the possible groupings in responses to the quantitative questionnaire items focused on thoughts and feelings about COVID-19 infection risk and severity, vaccine effectiveness, and vaccine safety. This analysis treated the items’ ordinal response categories as continuous. We performed factor analysis using principal component analysis to explore dimension reduction and account for covariance between items. Two principal components were calculated and applied k-means clustering, determining the number of clusters through agreement from the elbow, gap statistic, and silhouette methods.²⁶ Each cluster was named based on its unique pattern of responses to the items used to define them (eAppendix 1).

Multivariable logistic regression analyses assessed the independent association between cluster membership as the independent measure and vaccination status as the dependent measure, adjusting for respondent sociodemographic and personal characteristics and 2 measures of trust (ie, local VA HCP and the CDC). We selected these trust measures because they represent objective sources of medical information and were independently associated with COVID-19 vaccination status in a logistic regression model comprising all 6 trust items assessed.

This study defined statistical significance as a 2-tailed P value < .05. SAS 9.4 was used for all statistical analyses and Python 3.7.4 and the Scikit-learn package for cluster analyses.²⁷ For qualitative analyses, this study used an inductive thematic approach guided by conventional qualitative content analysis, NVivo 12 Plus for Windows to code and analyze interview transcripts.^28,29 We created an initial codebook based on 10 transcripts that were selected for high complexity and represented cluster membership and vaccination status.^30,31 After 2 qualitative staff developed the initial codebook, 11 of 49 (22%) transcripts were independently coded by a primary and secondary coder to ensure consistent code application. Both coders reviewed the cocoded transcripts and resolved all discrepancies through negotiated consensus.³² After the cocoding process was complete, the primary coder coded the remaining transcripts. The primary and secondary coder met as needed to review and discuss any questions that arose during the primary coder’s work.

Results

Of 5657 eligible participants, 1208 (21.4%) completed a questionnaire. Overall, 674 (55.8%) were aged < 65 years, 530 (43.9%) were women, 828 (68.5%) were non-Hispanic White, 303 (25.1%) were Black, and 47 (3.9%) were Hispanic, and 1034 (85.6%) were vaccinated (Table 1). Compared to the total sampled population, respondents were more often older, female, and White (eAppendix 2).

Cluster Membership

Four clusters were identified from 1183 (97.9%) participants who provided complete responses to 6 items assessing thoughts and feelings about COVID-19 infection and vaccines (Table 2). Of the 1183 respondents, 375 (31.7%) were Concerned Believers (cluster 1), 336 (28.4%) were Unconcerned Believers (cluster 2), 298 (25.2%) were Concerned Ambivalents (cluster 3), and 174 (14.7%) were Unconcerned Disbelievers (cluster 4). The Concerned Believers were moderately/ very concerned about COVID-19 infection (96.0%) and becoming very ill from infection (94.6%), believed the vaccine was moderately/very effective in preventing COVID-19 infection (100%) and severe illness or death from infection (98.7%), and had slight concern about short-term AEs (92.6%) or long-term complications (92.0%) from the vaccine. The Unconcerned Believers had no/slight concern about COVID-19 infection (76.5%) or becoming very ill (79.2%), believed the vaccine was effective in preventing infection (82.4%) and severe illness and death (83.6%), and had no/slight concern about short-term AEs (94.0%) or long-term complications (87.2%) from the vaccine. The Concerned Ambivalents were moderately/ very concerned about COVID-19 infection (94.3%) and becoming very ill (93.6%), believed the vaccine was moderately/very effective in preventing infection (86.6%) and severe illness or death (86.9%), and were moderately/very concerned about short-term AEs (81.9%) or long-term complications (89.3%) from the vaccine. The Unconcerned Disbelievers had no/slight concern about COVID-19 infection (90.8%) and becoming very ill (88.6%), believed the vaccine was not at all/slightly effective in preventing infection (90.3%) and severe illness or death (87.4%), and were moderately/very concerned about short-term AEs (52.8%) or long-term complications (75.9%) from the vaccine.

Cluster Membership

Respondent age, race and ethnicity, and political viewpoints differed significantly by cluster (P < .001). Compared with the other clusters, the Concerned Believer cluster was older (55.5% age ≥ 65 years vs 16.7%-48.0%) and more frequently reported liberal political views (28.8% vs 4.6%-15.1%). In contrast, the Unconcerned Disbeliever cluster was younger (83.4% age ≤ 64 years vs 44.5%-56.8%) and more frequently reported conservative political views (37.9% vs 17.1%-26.8%) than the other clusters. Whereas the Concerned Ambivalent cluster had the highest proportion of Black (37.7%) and the lowest proportion of White respondents (57.6%), the Unconcerned Disbelievers cluster had the lowest proportion of Black respondents (14.5%) and the highest proportion of White respondents (77.9%). The Unconcerned Disbelievers cluster were significantly less likely to trust COVID-19 vaccine information from any source and to believe those close to them wanted them to get vaccinated.

Association of Cluster Membership and COVID-19 Vaccination

COVID-19 vaccination rates varied more than 3-fold (P < .001) by cluster, with 29.9% of Unconcerned Disbelievers, 93.3% of Concerned Ambivalents, 93.5% of Unconcerned Believers, and 98.9% of Concerned Believers reporting being vaccinated. (Figure). Cluster membership was independently associated with vaccination, with adjusted odds ratios (AORs) of 12.0 (95% CI, 6.1-23.8) for the Concerned Ambivalent, 13.0 (95% CI, 6.9-24.5) for Unconcerned Believer, and 48.6 (95% CI, 15.5-152.1) for Concerned Believer clusters (Table 3). Respondent trust in COVID-19 vaccine information from their VA HCP (AOR 2.1; 95% CI, 1.6-2.8) and the CDC (AOR 1.6; 95% CI, 1.2-2.1) were independently associated with vaccination status, while the remaining respondent sociodemographic or personal characteristics were not.

Qualitative Interview Participants

A 49-participant convenience sample completed interviews, including 30 Concerned Ambivalent, 17 Unconcerned Disbeliever, and 2 Unconcerned Believer respondents cluster. The data were not calculated for Unconcerned Believers due to the small sample size. Interview participants were more likely to be younger, female, non-Hispanic, White, less educated, and more politically conservative than the questionnaire respondents as a whole (Appendix). The vaccination rate for the interview participants was 73.5%, ranging from 29.9% in the Unconcerned Disbeliever to 93.3% in the Concerned Ambivalent cluster. Qualitative themes and participant quotes for Concerned Ambivalent and Unconcerned Disbeliever respondents are in eAppendix 3.

Motivations. Wanting personal protection from becoming infected or severely ill from COVID-19 (63.8%), caregiver wanting to protect others (17.0%), and employment vaccine requirements (14.9%) were frequent motivations for vaccination. Whereas personal protection (90.0%) and protection of others (23.3%) were identified more frequently in the Concerned Ambivalents cluster, employment vaccine requirements (35.3%) were more frequently identified in the Unconcerned Disbelievers cluster.

Hesitancies or concerns. Lack of sufficient information related to rapid vaccine development (55.3%), vaccine AEs (38.3%), and low confidence in vaccine efficacy (23.4%) were frequent concerns or hesitancies about vaccination. Unconcerned Disbelievers expressed higher levels of concern about the vaccine’s rapid development (82.4%), low perceived vaccine efficacy (47.1%), and a lack of trust in governmental vaccine promotion (23.5%) than did the Concerned Ambivalents.

Overcoming concerns. Not wanting to get sick or die from infection coupled with an understanding that vaccine benefits exceed risks (23.4%) and receiving information from a trusted source (10.6%) were common ways of overcoming concerns for vaccination. Although the Unconcerned Disbelievers infrequently identified reasons for overcoming concerns, they identified employment requirements (17.6%) as a reason for vaccination despite concerns. They also identified seeing others with positive vaccine experiences and pressure from family or friends as ways of overcoming concerns (11.8% each).

Social influences. Family members or partners (38.3%), personal opinions (38.3%), and HCPs (23.4%) were frequent social influences for vaccination. Concerned Ambivalents mentioned family members and partners (46.7%), HCPs (26.7%), and friends (20.0%) as common influences, while Unconcerned Disbelievers more frequently relied on their opinion (41.2%) and quoted specific scientifically reputable data sources (17.6%) to guide vaccine decision-making, although it is unclear whether these sources were accessed directly or if this information was obtained indirectly through scientifically unvetted data platforms.

Practical factors. Most participants had positive vaccination experiences (68.1%), determined mainly by the Concerned Ambivalents (90.0%), who were more highly vaccinated. Barriers to vaccination were reported by 9 (19.1%) participants, driven by those in the Concerned Ambivalent cluster (26.7%). Eight (17.0%) participants suggested improvements for vaccination processes, with similar overall reporting frequencies across clusters.

COVID-19 boosters and variants. Wanting continued protection from COVID-19 (36.2%), recommendations from a doctor or trusted source (17.0%), and news about emerging variants (10.6%) were frequent motivations for receiving a vaccine booster (eAppendix 4). These motivations were largely driven by the Concerned Ambivalents, of whom 25 of 30 were booster eligible and 24 received a booster dose. Belief that boosters were unnecessary (8.5%), concerns about efficacy (6.4%), and concerns about AEs (6.4%) were frequently identified hesitancies. These concerns were expressed largely by the Unconcerned Disbelievers, of whom 7 of 17 were booster dose eligible, but only 1 received a dose.

Evolving knowledge about variants was not a major concern overall and did not change existing opinions about the vaccine (36.2%). Concerned Ambivalents believed vaccination provided extra protection against variants (36.7%) and the emergence of variants served as a reminder of the ongoing pandemic (30.0%). In contrast, Unconcerned Disbelievers believed that the threat of variants was overblown (35.3%) and mutations are to be expected (17.6%).

Discussion

This study used a complementary mixed-methods approach to understand the motivations, hesitancies, and social and practical drivers of COVID-19 vaccine uptake among VA beneficiaries. Our quantitative analyses identified 4 distinct clusters based on respondents’ opinions on COVID-19 infection severity and vaccine effectiveness and safety. Veterans in 3 clusters were 12 to 49 times more likely to be vaccinated than those in the remaining cluster, even when controlling for baseline respondent characteristics and level of trust in credible sources of COVID-19 information. The observed vaccination rate of nearly 86% was higher than the contemporaneous national average of 62% for vaccine-eligible individuals, likely reflecting the comprehensive VA vaccine promotion strategies tailored to a patient demographic with a high COVID-19 risk profile.^2,10

This cluster analyses demonstrated the importance of thoughts and feelings about COVID-19 infection and vaccination as influential social and behavioral drivers of vaccine uptake. These opinions help explain the strong association between cluster membership and vaccination status in this multivariable modeling. The cluster composition was consistent with findings from studies of nonveteran populations that identified perceived vulnerability to COVID-19 infection, beliefs in vaccine effectiveness, and adherence with protective behaviors during the pandemic as contributors to vaccine uptake.^13,33 Qualitative themes showed that personal protection, protecting others, and vaccine mandates were frequent motivators for vaccination. Whereas protection of self and others from COVID-19 infection were more often expressed by the highly vaccinated Concerned Ambivalents, employment and travel vaccine mandates were more often identified by Unconcerned Disbelievers, who had a lower vaccination rate. Among Unconcerned Disbelievers, an employer vaccine requirement was the most frequent qualitative theme for overcoming vaccination concerns.

In addition to cluster membership, our modeling showed that trust in local VA HCPs and the CDC were independently associated with COVID-19 vaccination, which has been found in prior research.²⁰ This qualitative analyses regarding vaccine hesitancy identified trust-related concerns that were more frequently expressed by Unconcerned Disbelievers than Concerned Ambivalents. Concerns included the rapid development of the vaccines potentially limiting the generation of scientifically sound effectiveness and safety data, and potential biases involving the entities promoting vaccine uptake.

Whereas the Concerned Believers, Unconcerned Believers, and Concerned Ambivalents all had high COVID-19 vaccination rates (≥ 93%), the decision-making pathways to vaccine uptake likely differ by their concerns about COVID-19 infection and perceptions of vaccine safety and effectiveness. For example, this mixed-methods analysis consistently showed that people in the Concerned Ambivalent cluster were positively motivated by concerns about COVID-19 infection and severity and beliefs about vaccine effectiveness that were tempered by concerns about vaccine AEs. For this cluster, their frequent thematic expression that the benefits of the vaccine exceed the risks, and the positive social influences of family, friends, and HCPs may explain their high vaccination rate.

Such insights into how the patterns of COVID-19–related thoughts and feelings vary across clusters can be used to design interventions to encourage initial and booster doses of COVID-19 vaccines. For example, messaging that highlights the infectivity and severity of COVID-19 and the potential for persistent negative health outcomes associated with long COVID could reinforce the beliefs of Concerned Believers and Concerned Ambivalents, and such messaging could also be used as a targeted intervention for Unconcerned Believers who expressed fewer concerns about the health consequences of COVID-19.23 Likewise, messaging about the safety profile of COVID-19 vaccines may reduce vaccine hesitancy for Concerned Ambivalents. Importantly, purposeful attention to health equity, community engagement, and involvement of racially diverse HCPs in patient discussions represent successful strategies to increase COVID-19 vaccine uptake among Black individuals, who were disproportionately represented in the Concerned Ambivalent cluster and may possess higher levels of mistrust due to racism experienced within the health care system.²⁴

Our findings suggest that the greatest challenge for overcoming vaccine hesitancy is for individuals in the suboptimally vaccinated (30%) Unconcerned Disbeliever cluster. These individuals had low levels of concern about COVID-19 infection and severity, high levels of concern about vaccine safety, low perceived vaccine effectiveness, and low levels of trust in all information sources about COVID-19. While the Unconcerned Disbelievers cited scientifically reputable data sources, we were unable to verify whether participants accessed these reputable sources of information directly or obtained such information indirectly through potentially biased online sources. Nearly half of this cluster trusted their VA HCP and believed their community or religious leaders would want them to get vaccinated. This qualitative analyses found that Unconcerned Disbelievers relied on personal beliefs for vaccine decision-making more than Concerned Ambivalents. While Unconcerned Disbelievers were less likely to be socially influenced by family, friends, or religious leaders, they still acknowledged some impact from these sources. These findings suggest that addressing vaccine hesitancy among Unconcerned Disbelievers may require a multifaceted approach that respects their reliance on personal research while also leveraging the potential social influences. This approach supports the promising, previously reported practices of harnessing the social influences of HCPs and other community and religious leaders to promote vaccine uptake among Unconcerned Disbelievers.^34,35 One evidence-based approach to effectively change patient health care behaviors is through motivational interviewing strategies that use open-ended questions, nonjudgmental interactions, and collaborative decision-making when discussing the risks and benefits of vaccination.^21,22

Limitations

This study was conducted at a single VA health care facility and our sampling technique was nonrandom, suggesting that these results may not be generalizable to all veterans or non-VA patient populations. The 21% questionnaire response rate could have introduced selection bias into the respondent sample. All questionnaire data were self-reported, including vaccination status. Finally, the qualitative interviews consisted of a small number of unvaccinated individuals in 2 clusters (ie, Concerned Ambivalents and Unconcerned Disbelievers) and may not have reached thematic saturation in these subgroups.

Conclusions

Quantitative analyses identified 4 clusters based on individual thoughts and feelings about COVID-19 infection and vaccines. Cluster membership and levels of trust in COVID-19 information sources were independently associated with vaccination. Understanding the quantitative patterns of thoughts and beliefs across clusters, enriched by common qualitative themes for vaccine hesitancy, help inform tailored interventions to augment COVID-19 vaccine uptake and highlight the importance of targeted, trust-based communication and culturally sensitive interventions to enhance vaccine uptake across diverse populations.

The SARS-CoV-2 virus has resulted in > 778 million reported COVID-19 cases and > 7 million deaths worldwide. ¹ About 70% of the eligible US population has completed a primary COVID-19 vaccination series, yet only 17% have received an updated bivalent booster dose.² These immunization rates fall below the World Health Organization (WHO) target of 70%.³

Early in the pandemic, US Department of Veterans Affairs (VA) vaccination rates ranged from 46% to 71%.^4,5 Ensuring a high level of COVID-19 vaccination in the largest integrated US health care system aligns with the VA priority to provide high-quality, evidence-based care to a patient population that is older and has more comorbidities than the overall US population.^6-9

Vaccine hesitancy, defined as a “delay in acceptance or refusal of vaccination despite availability of vaccination service,” is a major contributor to suboptimal vaccination rates.^10-13 Previous studies used cluster analyses to identify the unique combinations of behavioral and social factors responsible for COVID-19 vaccine hesitancy.^10,11 Lack of perceived vaccine effectiveness and low perceived risk of the health consequences from COVID-19 infection were frequently identified in clusters where patients had the lowest intent for vaccination.^10,11 Similarly, low trust in health care practitioners (HCPs), government, and pharmaceutical companies diminished intent for vaccination in these clusters.¹⁰ These quantitative studies were limited by their exclusive focus on unvaccinated individuals, reliance on self-reported intent, and lack of assessment of a health care system with a COVID-19 vaccine delivery program designed to overcome barriers to health care access, such as the VA.

Prior qualitative studies of vaccine uptake in distinct veteran subgroups (ie, unhoused and in VA facilities with low vaccination rates) demonstrated that overriding medical priorities among the unhoused and vaccine safety concerns were associated with decreased vaccine uptake, and positive perceptions of HCPs and the health care system were associated with increased vaccine uptake.^11,12 However, these studies were conducted during periods of greater COVID-19 vaccine availability and acceptance, and prior to booster recommendations.^4,12,13

This mixed-methods quality improvement (QI) project assessed the barriers and facilitators of COVID-19 vaccination among veterans receiving primary care at a single VA health care facility. We assessed whether unique patient clusters could be identified based on COVID-19–related and vaccine-related thoughts and feelings and whether cluster membership was associated with COVID-19 vaccination. This analysis also explored how individuals’ beliefs and trust shaped motivations and hesitancies for vaccine uptake in quantitatively derived clusters with varying vaccination rates.

Methods

This QI project was conducted at the VA Pittsburgh Healthcare System (VAPHS), a tertiary care facility serving > 75,000 veterans in Pennsylvania, West Virginia, and Ohio. The VAPHS Institutional Review Board determined this QI study was exempt from review.^14-17 Participation was voluntary and had no bearing on VA health care or benefits. Financial support for the project, including key personnel and participant compensation, was provided by VAPHS. We followed the STROBE reporting guideline for cross-sectional studies and the COREQ checklist for qualitative research.^18,19

Quantitative Survey

The 32,271 veterans assigned to a VAPHS primary care HCP, effective April 1, 2020, were eligible. To ensure representation of subgroups underrecognized in research and/or QI projects, the sample included all 1980 female patients at VAPHS and a random sample of 500 White and 500 Hispanic and/or non-White men within 4 age categories (< 50, 50-64, 65-84, and > 84 years). For the < 50 years or > 84 years categories, all Hispanic and/or non-White men were included due to small sample sizes.^20-22 The nonrandom sampling frame comprised 1708 Hispanic and/or non-White men and 2000 White men. After assigning the 5688 potentially eligible individuals a unique identifier, 31 opted out, resulting in a final sample of 5657 individuals.

The 5657 individuals received a letter requesting their completion of a future questionnaire about COVID-19 infection and vaccines. An electronic Qualtrics questionnaire link was emailed to 3221 individuals; nonresponders received 2 follow-up email reminders. For the 2436 veterans without an email address on file, trained interviewers conducted phone surveys and entered responses. Those patients who completed the questionnaire could enter a drawing to win 1 of 100 cash prizes valued at $100. We collected questionnaire data from July to September 2021.

Questionnaire Items

We constructed a 60-item questionnaire based on prior research on COVID-19 vaccine hesitancy and the WHO Guidebook for Immunization Programs and Implementing Partners.^4,23-25 The WHO Guidebook comprises survey items organized within 4 domains reflecting the behavioral and social determinants of vaccination: thoughts and feelings; social processes; motivation and hesitancy; and practical factors.²³

Sociodemographic, clinical, and personal characteristics. The survey assessed respondent ethnicity and race and used these data to create a composite race and ethnicity variable. Highest educational level was also attained using 8 response options. The survey also assessed prior COVID-19 infection; prior receipt of vaccines for influenza, pneumonia, tetanus, or shingles; and presence of comorbidities that increase the risk of severe COVID-19 infection. We used administrative data from the VA Corporate Data Warehouse to determine respondent age, sex, geographic residence (urban, rural), and to fill in missing self-reported data on sex (n = 4) and ethnicity and race (n = 12). The survey assessed political views using a 5-point Likert scale (1, very liberal; 5, very conservative) and was collapsed into 3 categories (ie, very conservative or conservative, moderate, very liberal or liberal), with prefer not to answer reported separately

COVID-19 infection and vaccine. We asked veterans if they had ever been infected with COVID-19, whether they had been offered and/or received a COVID-19 vaccine, and type (Pfizer, Moderna, or Johnson & Johnson), and number of doses received. Positive vaccination status was defined as the receipt of ≥ 1 dose of a COVID-19 vaccine approved by the US Food and Drug Administration.

COVID-19 opinions. Respondents were asked about perceived risk of COVID-19 infection and related health outcomes, as well as beliefs about COVID-19 vaccines, using a 4-point Likert scale for all items: (1, not at all concerned; 4, very concerned). Respondents were asked about concerns related to COVID-19 infection and severe illness. They also were asked about vaccine-related short-term adverse effects (AEs) and long-term complications. Respondents were asked how effective they believed COVID-19 vaccines were at preventing infection, serious illness, or death. Unvaccinated and vaccinated veterans were asked similar items, with a qualifier of “before getting vaccinated…” for those who were vaccinated.

Social processes. Respondents were asked to rate their level of trust in various sources of COVID-19 vaccine information using a 4-point Likert scale (1, trust not at all; 4, trust very much). Respondents were asked whether community or religious leaders or close family or friends wanted them to get vaccinated (yes, no, or unsure).

Practical factors. Respondents were asked to rate the logistical difficulty of getting vaccinated or trying to get vaccinated using a 4-point Likert scale (1, not at all; 4, extremely).

Participants

Respondents were asked to participate in a follow-up qualitative interview. Among 293 participants who agreed, we sampled all 86 unvaccinated individuals regardless of cluster assignment, a random sample of 88 individuals in the cluster with the lowest vaccination rate, and all 33 vaccinated individuals in the cluster with the second-lowest vaccination rate. Forty-nine veterans completed qualitative interviews.

Two research staff trained in qualitative research completed telephone interviews, averaging 16.5 minutes (March to May 2022), using semistructured scripts to elicit vaccine-related motivations, hesitancies, or concerns. Interviews were recorded, transcribed, and deidentified. Participants provided written consent for recording and received $50 cash-equivalent compensation for interview completion.

Qualitative Interview Script

The interview script consisted of open-ended questions related to vaccine uptake across WHO domains.²³ Both unvaccinated and vaccinated respondents were asked similar questions and customized questions about boosters for the vaccinated subgroup. To assess motivations and hesitancies, respondents were asked how they made their decisions about vaccination and what they considered when deciding. Vaccinated participants were asked about motivations and overcoming concerns. Unvaccinated respondents were asked about reasons for concern. To assess social processes, the interviewers asked participants whose opinion or counsel they trusted when deciding whether to get vaccinated. Questions also focused on positive experiences and vaccination barriers. Vaccinated participants were asked what could have improved their vaccination experiences. Finally, the interviewers asked participants who received a complete primary vaccine series about their motivations and plans related to booster vaccines, and whether information about emerging COVID-19 variants influenced their decisions.

Data Analyses

This analysis used X² and Fisher exact tests to assess the associations among respondent characteristics, questionnaire responses, vaccination status, and cluster membership. Items phrased similarly were handled in a similar fashion for vaccinated and unvaccinated respondents.

Cluster analysis assessed the possible groupings in responses to the quantitative questionnaire items focused on thoughts and feelings about COVID-19 infection risk and severity, vaccine effectiveness, and vaccine safety. This analysis treated the items’ ordinal response categories as continuous. We performed factor analysis using principal component analysis to explore dimension reduction and account for covariance between items. Two principal components were calculated and applied k-means clustering, determining the number of clusters through agreement from the elbow, gap statistic, and silhouette methods.²⁶ Each cluster was named based on its unique pattern of responses to the items used to define them (eAppendix 1).

Multivariable logistic regression analyses assessed the independent association between cluster membership as the independent measure and vaccination status as the dependent measure, adjusting for respondent sociodemographic and personal characteristics and 2 measures of trust (ie, local VA HCP and the CDC). We selected these trust measures because they represent objective sources of medical information and were independently associated with COVID-19 vaccination status in a logistic regression model comprising all 6 trust items assessed.

This study defined statistical significance as a 2-tailed P value < .05. SAS 9.4 was used for all statistical analyses and Python 3.7.4 and the Scikit-learn package for cluster analyses.²⁷ For qualitative analyses, this study used an inductive thematic approach guided by conventional qualitative content analysis, NVivo 12 Plus for Windows to code and analyze interview transcripts.^28,29 We created an initial codebook based on 10 transcripts that were selected for high complexity and represented cluster membership and vaccination status.^30,31 After 2 qualitative staff developed the initial codebook, 11 of 49 (22%) transcripts were independently coded by a primary and secondary coder to ensure consistent code application. Both coders reviewed the cocoded transcripts and resolved all discrepancies through negotiated consensus.³² After the cocoding process was complete, the primary coder coded the remaining transcripts. The primary and secondary coder met as needed to review and discuss any questions that arose during the primary coder’s work.

Results

Of 5657 eligible participants, 1208 (21.4%) completed a questionnaire. Overall, 674 (55.8%) were aged < 65 years, 530 (43.9%) were women, 828 (68.5%) were non-Hispanic White, 303 (25.1%) were Black, and 47 (3.9%) were Hispanic, and 1034 (85.6%) were vaccinated (Table 1). Compared to the total sampled population, respondents were more often older, female, and White (eAppendix 2).

Cluster Membership

Four clusters were identified from 1183 (97.9%) participants who provided complete responses to 6 items assessing thoughts and feelings about COVID-19 infection and vaccines (Table 2). Of the 1183 respondents, 375 (31.7%) were Concerned Believers (cluster 1), 336 (28.4%) were Unconcerned Believers (cluster 2), 298 (25.2%) were Concerned Ambivalents (cluster 3), and 174 (14.7%) were Unconcerned Disbelievers (cluster 4). The Concerned Believers were moderately/ very concerned about COVID-19 infection (96.0%) and becoming very ill from infection (94.6%), believed the vaccine was moderately/very effective in preventing COVID-19 infection (100%) and severe illness or death from infection (98.7%), and had slight concern about short-term AEs (92.6%) or long-term complications (92.0%) from the vaccine. The Unconcerned Believers had no/slight concern about COVID-19 infection (76.5%) or becoming very ill (79.2%), believed the vaccine was effective in preventing infection (82.4%) and severe illness and death (83.6%), and had no/slight concern about short-term AEs (94.0%) or long-term complications (87.2%) from the vaccine. The Concerned Ambivalents were moderately/ very concerned about COVID-19 infection (94.3%) and becoming very ill (93.6%), believed the vaccine was moderately/very effective in preventing infection (86.6%) and severe illness or death (86.9%), and were moderately/very concerned about short-term AEs (81.9%) or long-term complications (89.3%) from the vaccine. The Unconcerned Disbelievers had no/slight concern about COVID-19 infection (90.8%) and becoming very ill (88.6%), believed the vaccine was not at all/slightly effective in preventing infection (90.3%) and severe illness or death (87.4%), and were moderately/very concerned about short-term AEs (52.8%) or long-term complications (75.9%) from the vaccine.

Cluster Membership

Respondent age, race and ethnicity, and political viewpoints differed significantly by cluster (P < .001). Compared with the other clusters, the Concerned Believer cluster was older (55.5% age ≥ 65 years vs 16.7%-48.0%) and more frequently reported liberal political views (28.8% vs 4.6%-15.1%). In contrast, the Unconcerned Disbeliever cluster was younger (83.4% age ≤ 64 years vs 44.5%-56.8%) and more frequently reported conservative political views (37.9% vs 17.1%-26.8%) than the other clusters. Whereas the Concerned Ambivalent cluster had the highest proportion of Black (37.7%) and the lowest proportion of White respondents (57.6%), the Unconcerned Disbelievers cluster had the lowest proportion of Black respondents (14.5%) and the highest proportion of White respondents (77.9%). The Unconcerned Disbelievers cluster were significantly less likely to trust COVID-19 vaccine information from any source and to believe those close to them wanted them to get vaccinated.

Association of Cluster Membership and COVID-19 Vaccination

COVID-19 vaccination rates varied more than 3-fold (P < .001) by cluster, with 29.9% of Unconcerned Disbelievers, 93.3% of Concerned Ambivalents, 93.5% of Unconcerned Believers, and 98.9% of Concerned Believers reporting being vaccinated. (Figure). Cluster membership was independently associated with vaccination, with adjusted odds ratios (AORs) of 12.0 (95% CI, 6.1-23.8) for the Concerned Ambivalent, 13.0 (95% CI, 6.9-24.5) for Unconcerned Believer, and 48.6 (95% CI, 15.5-152.1) for Concerned Believer clusters (Table 3). Respondent trust in COVID-19 vaccine information from their VA HCP (AOR 2.1; 95% CI, 1.6-2.8) and the CDC (AOR 1.6; 95% CI, 1.2-2.1) were independently associated with vaccination status, while the remaining respondent sociodemographic or personal characteristics were not.

Qualitative Interview Participants

A 49-participant convenience sample completed interviews, including 30 Concerned Ambivalent, 17 Unconcerned Disbeliever, and 2 Unconcerned Believer respondents cluster. The data were not calculated for Unconcerned Believers due to the small sample size. Interview participants were more likely to be younger, female, non-Hispanic, White, less educated, and more politically conservative than the questionnaire respondents as a whole (Appendix). The vaccination rate for the interview participants was 73.5%, ranging from 29.9% in the Unconcerned Disbeliever to 93.3% in the Concerned Ambivalent cluster. Qualitative themes and participant quotes for Concerned Ambivalent and Unconcerned Disbeliever respondents are in eAppendix 3.

Motivations. Wanting personal protection from becoming infected or severely ill from COVID-19 (63.8%), caregiver wanting to protect others (17.0%), and employment vaccine requirements (14.9%) were frequent motivations for vaccination. Whereas personal protection (90.0%) and protection of others (23.3%) were identified more frequently in the Concerned Ambivalents cluster, employment vaccine requirements (35.3%) were more frequently identified in the Unconcerned Disbelievers cluster.

Hesitancies or concerns. Lack of sufficient information related to rapid vaccine development (55.3%), vaccine AEs (38.3%), and low confidence in vaccine efficacy (23.4%) were frequent concerns or hesitancies about vaccination. Unconcerned Disbelievers expressed higher levels of concern about the vaccine’s rapid development (82.4%), low perceived vaccine efficacy (47.1%), and a lack of trust in governmental vaccine promotion (23.5%) than did the Concerned Ambivalents.

Overcoming concerns. Not wanting to get sick or die from infection coupled with an understanding that vaccine benefits exceed risks (23.4%) and receiving information from a trusted source (10.6%) were common ways of overcoming concerns for vaccination. Although the Unconcerned Disbelievers infrequently identified reasons for overcoming concerns, they identified employment requirements (17.6%) as a reason for vaccination despite concerns. They also identified seeing others with positive vaccine experiences and pressure from family or friends as ways of overcoming concerns (11.8% each).

Social influences. Family members or partners (38.3%), personal opinions (38.3%), and HCPs (23.4%) were frequent social influences for vaccination. Concerned Ambivalents mentioned family members and partners (46.7%), HCPs (26.7%), and friends (20.0%) as common influences, while Unconcerned Disbelievers more frequently relied on their opinion (41.2%) and quoted specific scientifically reputable data sources (17.6%) to guide vaccine decision-making, although it is unclear whether these sources were accessed directly or if this information was obtained indirectly through scientifically unvetted data platforms.

Practical factors. Most participants had positive vaccination experiences (68.1%), determined mainly by the Concerned Ambivalents (90.0%), who were more highly vaccinated. Barriers to vaccination were reported by 9 (19.1%) participants, driven by those in the Concerned Ambivalent cluster (26.7%). Eight (17.0%) participants suggested improvements for vaccination processes, with similar overall reporting frequencies across clusters.

COVID-19 boosters and variants. Wanting continued protection from COVID-19 (36.2%), recommendations from a doctor or trusted source (17.0%), and news about emerging variants (10.6%) were frequent motivations for receiving a vaccine booster (eAppendix 4). These motivations were largely driven by the Concerned Ambivalents, of whom 25 of 30 were booster eligible and 24 received a booster dose. Belief that boosters were unnecessary (8.5%), concerns about efficacy (6.4%), and concerns about AEs (6.4%) were frequently identified hesitancies. These concerns were expressed largely by the Unconcerned Disbelievers, of whom 7 of 17 were booster dose eligible, but only 1 received a dose.

Evolving knowledge about variants was not a major concern overall and did not change existing opinions about the vaccine (36.2%). Concerned Ambivalents believed vaccination provided extra protection against variants (36.7%) and the emergence of variants served as a reminder of the ongoing pandemic (30.0%). In contrast, Unconcerned Disbelievers believed that the threat of variants was overblown (35.3%) and mutations are to be expected (17.6%).

Discussion

This study used a complementary mixed-methods approach to understand the motivations, hesitancies, and social and practical drivers of COVID-19 vaccine uptake among VA beneficiaries. Our quantitative analyses identified 4 distinct clusters based on respondents’ opinions on COVID-19 infection severity and vaccine effectiveness and safety. Veterans in 3 clusters were 12 to 49 times more likely to be vaccinated than those in the remaining cluster, even when controlling for baseline respondent characteristics and level of trust in credible sources of COVID-19 information. The observed vaccination rate of nearly 86% was higher than the contemporaneous national average of 62% for vaccine-eligible individuals, likely reflecting the comprehensive VA vaccine promotion strategies tailored to a patient demographic with a high COVID-19 risk profile.^2,10

This cluster analyses demonstrated the importance of thoughts and feelings about COVID-19 infection and vaccination as influential social and behavioral drivers of vaccine uptake. These opinions help explain the strong association between cluster membership and vaccination status in this multivariable modeling. The cluster composition was consistent with findings from studies of nonveteran populations that identified perceived vulnerability to COVID-19 infection, beliefs in vaccine effectiveness, and adherence with protective behaviors during the pandemic as contributors to vaccine uptake.^13,33 Qualitative themes showed that personal protection, protecting others, and vaccine mandates were frequent motivators for vaccination. Whereas protection of self and others from COVID-19 infection were more often expressed by the highly vaccinated Concerned Ambivalents, employment and travel vaccine mandates were more often identified by Unconcerned Disbelievers, who had a lower vaccination rate. Among Unconcerned Disbelievers, an employer vaccine requirement was the most frequent qualitative theme for overcoming vaccination concerns.

In addition to cluster membership, our modeling showed that trust in local VA HCPs and the CDC were independently associated with COVID-19 vaccination, which has been found in prior research.²⁰ This qualitative analyses regarding vaccine hesitancy identified trust-related concerns that were more frequently expressed by Unconcerned Disbelievers than Concerned Ambivalents. Concerns included the rapid development of the vaccines potentially limiting the generation of scientifically sound effectiveness and safety data, and potential biases involving the entities promoting vaccine uptake.

Whereas the Concerned Believers, Unconcerned Believers, and Concerned Ambivalents all had high COVID-19 vaccination rates (≥ 93%), the decision-making pathways to vaccine uptake likely differ by their concerns about COVID-19 infection and perceptions of vaccine safety and effectiveness. For example, this mixed-methods analysis consistently showed that people in the Concerned Ambivalent cluster were positively motivated by concerns about COVID-19 infection and severity and beliefs about vaccine effectiveness that were tempered by concerns about vaccine AEs. For this cluster, their frequent thematic expression that the benefits of the vaccine exceed the risks, and the positive social influences of family, friends, and HCPs may explain their high vaccination rate.

Such insights into how the patterns of COVID-19–related thoughts and feelings vary across clusters can be used to design interventions to encourage initial and booster doses of COVID-19 vaccines. For example, messaging that highlights the infectivity and severity of COVID-19 and the potential for persistent negative health outcomes associated with long COVID could reinforce the beliefs of Concerned Believers and Concerned Ambivalents, and such messaging could also be used as a targeted intervention for Unconcerned Believers who expressed fewer concerns about the health consequences of COVID-19.23 Likewise, messaging about the safety profile of COVID-19 vaccines may reduce vaccine hesitancy for Concerned Ambivalents. Importantly, purposeful attention to health equity, community engagement, and involvement of racially diverse HCPs in patient discussions represent successful strategies to increase COVID-19 vaccine uptake among Black individuals, who were disproportionately represented in the Concerned Ambivalent cluster and may possess higher levels of mistrust due to racism experienced within the health care system.²⁴

Our findings suggest that the greatest challenge for overcoming vaccine hesitancy is for individuals in the suboptimally vaccinated (30%) Unconcerned Disbeliever cluster. These individuals had low levels of concern about COVID-19 infection and severity, high levels of concern about vaccine safety, low perceived vaccine effectiveness, and low levels of trust in all information sources about COVID-19. While the Unconcerned Disbelievers cited scientifically reputable data sources, we were unable to verify whether participants accessed these reputable sources of information directly or obtained such information indirectly through potentially biased online sources. Nearly half of this cluster trusted their VA HCP and believed their community or religious leaders would want them to get vaccinated. This qualitative analyses found that Unconcerned Disbelievers relied on personal beliefs for vaccine decision-making more than Concerned Ambivalents. While Unconcerned Disbelievers were less likely to be socially influenced by family, friends, or religious leaders, they still acknowledged some impact from these sources. These findings suggest that addressing vaccine hesitancy among Unconcerned Disbelievers may require a multifaceted approach that respects their reliance on personal research while also leveraging the potential social influences. This approach supports the promising, previously reported practices of harnessing the social influences of HCPs and other community and religious leaders to promote vaccine uptake among Unconcerned Disbelievers.^34,35 One evidence-based approach to effectively change patient health care behaviors is through motivational interviewing strategies that use open-ended questions, nonjudgmental interactions, and collaborative decision-making when discussing the risks and benefits of vaccination.^21,22

Limitations

This study was conducted at a single VA health care facility and our sampling technique was nonrandom, suggesting that these results may not be generalizable to all veterans or non-VA patient populations. The 21% questionnaire response rate could have introduced selection bias into the respondent sample. All questionnaire data were self-reported, including vaccination status. Finally, the qualitative interviews consisted of a small number of unvaccinated individuals in 2 clusters (ie, Concerned Ambivalents and Unconcerned Disbelievers) and may not have reached thematic saturation in these subgroups.

Conclusions

Quantitative analyses identified 4 clusters based on individual thoughts and feelings about COVID-19 infection and vaccines. Cluster membership and levels of trust in COVID-19 information sources were independently associated with vaccination. Understanding the quantitative patterns of thoughts and beliefs across clusters, enriched by common qualitative themes for vaccine hesitancy, help inform tailored interventions to augment COVID-19 vaccine uptake and highlight the importance of targeted, trust-based communication and culturally sensitive interventions to enhance vaccine uptake across diverse populations.

The SARS-CoV-2 virus has resulted in > 778 million reported COVID-19 cases and > 7 million deaths worldwide. ¹ About 70% of the eligible US population has completed a primary COVID-19 vaccination series, yet only 17% have received an updated bivalent booster dose.² These immunization rates fall below the World Health Organization (WHO) target of 70%.³

Early in the pandemic, US Department of Veterans Affairs (VA) vaccination rates ranged from 46% to 71%.^4,5 Ensuring a high level of COVID-19 vaccination in the largest integrated US health care system aligns with the VA priority to provide high-quality, evidence-based care to a patient population that is older and has more comorbidities than the overall US population.^6-9

Vaccine hesitancy, defined as a “delay in acceptance or refusal of vaccination despite availability of vaccination service,” is a major contributor to suboptimal vaccination rates.^10-13 Previous studies used cluster analyses to identify the unique combinations of behavioral and social factors responsible for COVID-19 vaccine hesitancy.^10,11 Lack of perceived vaccine effectiveness and low perceived risk of the health consequences from COVID-19 infection were frequently identified in clusters where patients had the lowest intent for vaccination.^10,11 Similarly, low trust in health care practitioners (HCPs), government, and pharmaceutical companies diminished intent for vaccination in these clusters.¹⁰ These quantitative studies were limited by their exclusive focus on unvaccinated individuals, reliance on self-reported intent, and lack of assessment of a health care system with a COVID-19 vaccine delivery program designed to overcome barriers to health care access, such as the VA.

Prior qualitative studies of vaccine uptake in distinct veteran subgroups (ie, unhoused and in VA facilities with low vaccination rates) demonstrated that overriding medical priorities among the unhoused and vaccine safety concerns were associated with decreased vaccine uptake, and positive perceptions of HCPs and the health care system were associated with increased vaccine uptake.^11,12 However, these studies were conducted during periods of greater COVID-19 vaccine availability and acceptance, and prior to booster recommendations.^4,12,13

This mixed-methods quality improvement (QI) project assessed the barriers and facilitators of COVID-19 vaccination among veterans receiving primary care at a single VA health care facility. We assessed whether unique patient clusters could be identified based on COVID-19–related and vaccine-related thoughts and feelings and whether cluster membership was associated with COVID-19 vaccination. This analysis also explored how individuals’ beliefs and trust shaped motivations and hesitancies for vaccine uptake in quantitatively derived clusters with varying vaccination rates.

Methods

This QI project was conducted at the VA Pittsburgh Healthcare System (VAPHS), a tertiary care facility serving > 75,000 veterans in Pennsylvania, West Virginia, and Ohio. The VAPHS Institutional Review Board determined this QI study was exempt from review.^14-17 Participation was voluntary and had no bearing on VA health care or benefits. Financial support for the project, including key personnel and participant compensation, was provided by VAPHS. We followed the STROBE reporting guideline for cross-sectional studies and the COREQ checklist for qualitative research.^18,19

Quantitative Survey

The 32,271 veterans assigned to a VAPHS primary care HCP, effective April 1, 2020, were eligible. To ensure representation of subgroups underrecognized in research and/or QI projects, the sample included all 1980 female patients at VAPHS and a random sample of 500 White and 500 Hispanic and/or non-White men within 4 age categories (< 50, 50-64, 65-84, and > 84 years). For the < 50 years or > 84 years categories, all Hispanic and/or non-White men were included due to small sample sizes.^20-22 The nonrandom sampling frame comprised 1708 Hispanic and/or non-White men and 2000 White men. After assigning the 5688 potentially eligible individuals a unique identifier, 31 opted out, resulting in a final sample of 5657 individuals.

The 5657 individuals received a letter requesting their completion of a future questionnaire about COVID-19 infection and vaccines. An electronic Qualtrics questionnaire link was emailed to 3221 individuals; nonresponders received 2 follow-up email reminders. For the 2436 veterans without an email address on file, trained interviewers conducted phone surveys and entered responses. Those patients who completed the questionnaire could enter a drawing to win 1 of 100 cash prizes valued at $100. We collected questionnaire data from July to September 2021.

Questionnaire Items

We constructed a 60-item questionnaire based on prior research on COVID-19 vaccine hesitancy and the WHO Guidebook for Immunization Programs and Implementing Partners.^4,23-25 The WHO Guidebook comprises survey items organized within 4 domains reflecting the behavioral and social determinants of vaccination: thoughts and feelings; social processes; motivation and hesitancy; and practical factors.²³

Sociodemographic, clinical, and personal characteristics. The survey assessed respondent ethnicity and race and used these data to create a composite race and ethnicity variable. Highest educational level was also attained using 8 response options. The survey also assessed prior COVID-19 infection; prior receipt of vaccines for influenza, pneumonia, tetanus, or shingles; and presence of comorbidities that increase the risk of severe COVID-19 infection. We used administrative data from the VA Corporate Data Warehouse to determine respondent age, sex, geographic residence (urban, rural), and to fill in missing self-reported data on sex (n = 4) and ethnicity and race (n = 12). The survey assessed political views using a 5-point Likert scale (1, very liberal; 5, very conservative) and was collapsed into 3 categories (ie, very conservative or conservative, moderate, very liberal or liberal), with prefer not to answer reported separately

COVID-19 infection and vaccine. We asked veterans if they had ever been infected with COVID-19, whether they had been offered and/or received a COVID-19 vaccine, and type (Pfizer, Moderna, or Johnson & Johnson), and number of doses received. Positive vaccination status was defined as the receipt of ≥ 1 dose of a COVID-19 vaccine approved by the US Food and Drug Administration.

COVID-19 opinions. Respondents were asked about perceived risk of COVID-19 infection and related health outcomes, as well as beliefs about COVID-19 vaccines, using a 4-point Likert scale for all items: (1, not at all concerned; 4, very concerned). Respondents were asked about concerns related to COVID-19 infection and severe illness. They also were asked about vaccine-related short-term adverse effects (AEs) and long-term complications. Respondents were asked how effective they believed COVID-19 vaccines were at preventing infection, serious illness, or death. Unvaccinated and vaccinated veterans were asked similar items, with a qualifier of “before getting vaccinated…” for those who were vaccinated.

Social processes. Respondents were asked to rate their level of trust in various sources of COVID-19 vaccine information using a 4-point Likert scale (1, trust not at all; 4, trust very much). Respondents were asked whether community or religious leaders or close family or friends wanted them to get vaccinated (yes, no, or unsure).

Practical factors. Respondents were asked to rate the logistical difficulty of getting vaccinated or trying to get vaccinated using a 4-point Likert scale (1, not at all; 4, extremely).

Participants

Respondents were asked to participate in a follow-up qualitative interview. Among 293 participants who agreed, we sampled all 86 unvaccinated individuals regardless of cluster assignment, a random sample of 88 individuals in the cluster with the lowest vaccination rate, and all 33 vaccinated individuals in the cluster with the second-lowest vaccination rate. Forty-nine veterans completed qualitative interviews.

Two research staff trained in qualitative research completed telephone interviews, averaging 16.5 minutes (March to May 2022), using semistructured scripts to elicit vaccine-related motivations, hesitancies, or concerns. Interviews were recorded, transcribed, and deidentified. Participants provided written consent for recording and received $50 cash-equivalent compensation for interview completion.

Qualitative Interview Script

The interview script consisted of open-ended questions related to vaccine uptake across WHO domains.²³ Both unvaccinated and vaccinated respondents were asked similar questions and customized questions about boosters for the vaccinated subgroup. To assess motivations and hesitancies, respondents were asked how they made their decisions about vaccination and what they considered when deciding. Vaccinated participants were asked about motivations and overcoming concerns. Unvaccinated respondents were asked about reasons for concern. To assess social processes, the interviewers asked participants whose opinion or counsel they trusted when deciding whether to get vaccinated. Questions also focused on positive experiences and vaccination barriers. Vaccinated participants were asked what could have improved their vaccination experiences. Finally, the interviewers asked participants who received a complete primary vaccine series about their motivations and plans related to booster vaccines, and whether information about emerging COVID-19 variants influenced their decisions.

Data Analyses

This analysis used X² and Fisher exact tests to assess the associations among respondent characteristics, questionnaire responses, vaccination status, and cluster membership. Items phrased similarly were handled in a similar fashion for vaccinated and unvaccinated respondents.

Cluster analysis assessed the possible groupings in responses to the quantitative questionnaire items focused on thoughts and feelings about COVID-19 infection risk and severity, vaccine effectiveness, and vaccine safety. This analysis treated the items’ ordinal response categories as continuous. We performed factor analysis using principal component analysis to explore dimension reduction and account for covariance between items. Two principal components were calculated and applied k-means clustering, determining the number of clusters through agreement from the elbow, gap statistic, and silhouette methods.²⁶ Each cluster was named based on its unique pattern of responses to the items used to define them (eAppendix 1).

Multivariable logistic regression analyses assessed the independent association between cluster membership as the independent measure and vaccination status as the dependent measure, adjusting for respondent sociodemographic and personal characteristics and 2 measures of trust (ie, local VA HCP and the CDC). We selected these trust measures because they represent objective sources of medical information and were independently associated with COVID-19 vaccination status in a logistic regression model comprising all 6 trust items assessed.

This study defined statistical significance as a 2-tailed P value < .05. SAS 9.4 was used for all statistical analyses and Python 3.7.4 and the Scikit-learn package for cluster analyses.²⁷ For qualitative analyses, this study used an inductive thematic approach guided by conventional qualitative content analysis, NVivo 12 Plus for Windows to code and analyze interview transcripts.^28,29 We created an initial codebook based on 10 transcripts that were selected for high complexity and represented cluster membership and vaccination status.^30,31 After 2 qualitative staff developed the initial codebook, 11 of 49 (22%) transcripts were independently coded by a primary and secondary coder to ensure consistent code application. Both coders reviewed the cocoded transcripts and resolved all discrepancies through negotiated consensus.³² After the cocoding process was complete, the primary coder coded the remaining transcripts. The primary and secondary coder met as needed to review and discuss any questions that arose during the primary coder’s work.

Results

Of 5657 eligible participants, 1208 (21.4%) completed a questionnaire. Overall, 674 (55.8%) were aged < 65 years, 530 (43.9%) were women, 828 (68.5%) were non-Hispanic White, 303 (25.1%) were Black, and 47 (3.9%) were Hispanic, and 1034 (85.6%) were vaccinated (Table 1). Compared to the total sampled population, respondents were more often older, female, and White (eAppendix 2).

Cluster Membership

Four clusters were identified from 1183 (97.9%) participants who provided complete responses to 6 items assessing thoughts and feelings about COVID-19 infection and vaccines (Table 2). Of the 1183 respondents, 375 (31.7%) were Concerned Believers (cluster 1), 336 (28.4%) were Unconcerned Believers (cluster 2), 298 (25.2%) were Concerned Ambivalents (cluster 3), and 174 (14.7%) were Unconcerned Disbelievers (cluster 4). The Concerned Believers were moderately/ very concerned about COVID-19 infection (96.0%) and becoming very ill from infection (94.6%), believed the vaccine was moderately/very effective in preventing COVID-19 infection (100%) and severe illness or death from infection (98.7%), and had slight concern about short-term AEs (92.6%) or long-term complications (92.0%) from the vaccine. The Unconcerned Believers had no/slight concern about COVID-19 infection (76.5%) or becoming very ill (79.2%), believed the vaccine was effective in preventing infection (82.4%) and severe illness and death (83.6%), and had no/slight concern about short-term AEs (94.0%) or long-term complications (87.2%) from the vaccine. The Concerned Ambivalents were moderately/ very concerned about COVID-19 infection (94.3%) and becoming very ill (93.6%), believed the vaccine was moderately/very effective in preventing infection (86.6%) and severe illness or death (86.9%), and were moderately/very concerned about short-term AEs (81.9%) or long-term complications (89.3%) from the vaccine. The Unconcerned Disbelievers had no/slight concern about COVID-19 infection (90.8%) and becoming very ill (88.6%), believed the vaccine was not at all/slightly effective in preventing infection (90.3%) and severe illness or death (87.4%), and were moderately/very concerned about short-term AEs (52.8%) or long-term complications (75.9%) from the vaccine.

Cluster Membership

Respondent age, race and ethnicity, and political viewpoints differed significantly by cluster (P < .001). Compared with the other clusters, the Concerned Believer cluster was older (55.5% age ≥ 65 years vs 16.7%-48.0%) and more frequently reported liberal political views (28.8% vs 4.6%-15.1%). In contrast, the Unconcerned Disbeliever cluster was younger (83.4% age ≤ 64 years vs 44.5%-56.8%) and more frequently reported conservative political views (37.9% vs 17.1%-26.8%) than the other clusters. Whereas the Concerned Ambivalent cluster had the highest proportion of Black (37.7%) and the lowest proportion of White respondents (57.6%), the Unconcerned Disbelievers cluster had the lowest proportion of Black respondents (14.5%) and the highest proportion of White respondents (77.9%). The Unconcerned Disbelievers cluster were significantly less likely to trust COVID-19 vaccine information from any source and to believe those close to them wanted them to get vaccinated.

Association of Cluster Membership and COVID-19 Vaccination

COVID-19 vaccination rates varied more than 3-fold (P < .001) by cluster, with 29.9% of Unconcerned Disbelievers, 93.3% of Concerned Ambivalents, 93.5% of Unconcerned Believers, and 98.9% of Concerned Believers reporting being vaccinated. (Figure). Cluster membership was independently associated with vaccination, with adjusted odds ratios (AORs) of 12.0 (95% CI, 6.1-23.8) for the Concerned Ambivalent, 13.0 (95% CI, 6.9-24.5) for Unconcerned Believer, and 48.6 (95% CI, 15.5-152.1) for Concerned Believer clusters (Table 3). Respondent trust in COVID-19 vaccine information from their VA HCP (AOR 2.1; 95% CI, 1.6-2.8) and the CDC (AOR 1.6; 95% CI, 1.2-2.1) were independently associated with vaccination status, while the remaining respondent sociodemographic or personal characteristics were not.

Qualitative Interview Participants

A 49-participant convenience sample completed interviews, including 30 Concerned Ambivalent, 17 Unconcerned Disbeliever, and 2 Unconcerned Believer respondents cluster. The data were not calculated for Unconcerned Believers due to the small sample size. Interview participants were more likely to be younger, female, non-Hispanic, White, less educated, and more politically conservative than the questionnaire respondents as a whole (Appendix). The vaccination rate for the interview participants was 73.5%, ranging from 29.9% in the Unconcerned Disbeliever to 93.3% in the Concerned Ambivalent cluster. Qualitative themes and participant quotes for Concerned Ambivalent and Unconcerned Disbeliever respondents are in eAppendix 3.

Motivations. Wanting personal protection from becoming infected or severely ill from COVID-19 (63.8%), caregiver wanting to protect others (17.0%), and employment vaccine requirements (14.9%) were frequent motivations for vaccination. Whereas personal protection (90.0%) and protection of others (23.3%) were identified more frequently in the Concerned Ambivalents cluster, employment vaccine requirements (35.3%) were more frequently identified in the Unconcerned Disbelievers cluster.

Hesitancies or concerns. Lack of sufficient information related to rapid vaccine development (55.3%), vaccine AEs (38.3%), and low confidence in vaccine efficacy (23.4%) were frequent concerns or hesitancies about vaccination. Unconcerned Disbelievers expressed higher levels of concern about the vaccine’s rapid development (82.4%), low perceived vaccine efficacy (47.1%), and a lack of trust in governmental vaccine promotion (23.5%) than did the Concerned Ambivalents.

Overcoming concerns. Not wanting to get sick or die from infection coupled with an understanding that vaccine benefits exceed risks (23.4%) and receiving information from a trusted source (10.6%) were common ways of overcoming concerns for vaccination. Although the Unconcerned Disbelievers infrequently identified reasons for overcoming concerns, they identified employment requirements (17.6%) as a reason for vaccination despite concerns. They also identified seeing others with positive vaccine experiences and pressure from family or friends as ways of overcoming concerns (11.8% each).

Social influences. Family members or partners (38.3%), personal opinions (38.3%), and HCPs (23.4%) were frequent social influences for vaccination. Concerned Ambivalents mentioned family members and partners (46.7%), HCPs (26.7%), and friends (20.0%) as common influences, while Unconcerned Disbelievers more frequently relied on their opinion (41.2%) and quoted specific scientifically reputable data sources (17.6%) to guide vaccine decision-making, although it is unclear whether these sources were accessed directly or if this information was obtained indirectly through scientifically unvetted data platforms.

Practical factors. Most participants had positive vaccination experiences (68.1%), determined mainly by the Concerned Ambivalents (90.0%), who were more highly vaccinated. Barriers to vaccination were reported by 9 (19.1%) participants, driven by those in the Concerned Ambivalent cluster (26.7%). Eight (17.0%) participants suggested improvements for vaccination processes, with similar overall reporting frequencies across clusters.

COVID-19 boosters and variants. Wanting continued protection from COVID-19 (36.2%), recommendations from a doctor or trusted source (17.0%), and news about emerging variants (10.6%) were frequent motivations for receiving a vaccine booster (eAppendix 4). These motivations were largely driven by the Concerned Ambivalents, of whom 25 of 30 were booster eligible and 24 received a booster dose. Belief that boosters were unnecessary (8.5%), concerns about efficacy (6.4%), and concerns about AEs (6.4%) were frequently identified hesitancies. These concerns were expressed largely by the Unconcerned Disbelievers, of whom 7 of 17 were booster dose eligible, but only 1 received a dose.

Evolving knowledge about variants was not a major concern overall and did not change existing opinions about the vaccine (36.2%). Concerned Ambivalents believed vaccination provided extra protection against variants (36.7%) and the emergence of variants served as a reminder of the ongoing pandemic (30.0%). In contrast, Unconcerned Disbelievers believed that the threat of variants was overblown (35.3%) and mutations are to be expected (17.6%).

Discussion

This study used a complementary mixed-methods approach to understand the motivations, hesitancies, and social and practical drivers of COVID-19 vaccine uptake among VA beneficiaries. Our quantitative analyses identified 4 distinct clusters based on respondents’ opinions on COVID-19 infection severity and vaccine effectiveness and safety. Veterans in 3 clusters were 12 to 49 times more likely to be vaccinated than those in the remaining cluster, even when controlling for baseline respondent characteristics and level of trust in credible sources of COVID-19 information. The observed vaccination rate of nearly 86% was higher than the contemporaneous national average of 62% for vaccine-eligible individuals, likely reflecting the comprehensive VA vaccine promotion strategies tailored to a patient demographic with a high COVID-19 risk profile.^2,10

This cluster analyses demonstrated the importance of thoughts and feelings about COVID-19 infection and vaccination as influential social and behavioral drivers of vaccine uptake. These opinions help explain the strong association between cluster membership and vaccination status in this multivariable modeling. The cluster composition was consistent with findings from studies of nonveteran populations that identified perceived vulnerability to COVID-19 infection, beliefs in vaccine effectiveness, and adherence with protective behaviors during the pandemic as contributors to vaccine uptake.^13,33 Qualitative themes showed that personal protection, protecting others, and vaccine mandates were frequent motivators for vaccination. Whereas protection of self and others from COVID-19 infection were more often expressed by the highly vaccinated Concerned Ambivalents, employment and travel vaccine mandates were more often identified by Unconcerned Disbelievers, who had a lower vaccination rate. Among Unconcerned Disbelievers, an employer vaccine requirement was the most frequent qualitative theme for overcoming vaccination concerns.

In addition to cluster membership, our modeling showed that trust in local VA HCPs and the CDC were independently associated with COVID-19 vaccination, which has been found in prior research.²⁰ This qualitative analyses regarding vaccine hesitancy identified trust-related concerns that were more frequently expressed by Unconcerned Disbelievers than Concerned Ambivalents. Concerns included the rapid development of the vaccines potentially limiting the generation of scientifically sound effectiveness and safety data, and potential biases involving the entities promoting vaccine uptake.

Whereas the Concerned Believers, Unconcerned Believers, and Concerned Ambivalents all had high COVID-19 vaccination rates (≥ 93%), the decision-making pathways to vaccine uptake likely differ by their concerns about COVID-19 infection and perceptions of vaccine safety and effectiveness. For example, this mixed-methods analysis consistently showed that people in the Concerned Ambivalent cluster were positively motivated by concerns about COVID-19 infection and severity and beliefs about vaccine effectiveness that were tempered by concerns about vaccine AEs. For this cluster, their frequent thematic expression that the benefits of the vaccine exceed the risks, and the positive social influences of family, friends, and HCPs may explain their high vaccination rate.

Such insights into how the patterns of COVID-19–related thoughts and feelings vary across clusters can be used to design interventions to encourage initial and booster doses of COVID-19 vaccines. For example, messaging that highlights the infectivity and severity of COVID-19 and the potential for persistent negative health outcomes associated with long COVID could reinforce the beliefs of Concerned Believers and Concerned Ambivalents, and such messaging could also be used as a targeted intervention for Unconcerned Believers who expressed fewer concerns about the health consequences of COVID-19.23 Likewise, messaging about the safety profile of COVID-19 vaccines may reduce vaccine hesitancy for Concerned Ambivalents. Importantly, purposeful attention to health equity, community engagement, and involvement of racially diverse HCPs in patient discussions represent successful strategies to increase COVID-19 vaccine uptake among Black individuals, who were disproportionately represented in the Concerned Ambivalent cluster and may possess higher levels of mistrust due to racism experienced within the health care system.²⁴

Our findings suggest that the greatest challenge for overcoming vaccine hesitancy is for individuals in the suboptimally vaccinated (30%) Unconcerned Disbeliever cluster. These individuals had low levels of concern about COVID-19 infection and severity, high levels of concern about vaccine safety, low perceived vaccine effectiveness, and low levels of trust in all information sources about COVID-19. While the Unconcerned Disbelievers cited scientifically reputable data sources, we were unable to verify whether participants accessed these reputable sources of information directly or obtained such information indirectly through potentially biased online sources. Nearly half of this cluster trusted their VA HCP and believed their community or religious leaders would want them to get vaccinated. This qualitative analyses found that Unconcerned Disbelievers relied on personal beliefs for vaccine decision-making more than Concerned Ambivalents. While Unconcerned Disbelievers were less likely to be socially influenced by family, friends, or religious leaders, they still acknowledged some impact from these sources. These findings suggest that addressing vaccine hesitancy among Unconcerned Disbelievers may require a multifaceted approach that respects their reliance on personal research while also leveraging the potential social influences. This approach supports the promising, previously reported practices of harnessing the social influences of HCPs and other community and religious leaders to promote vaccine uptake among Unconcerned Disbelievers.^34,35 One evidence-based approach to effectively change patient health care behaviors is through motivational interviewing strategies that use open-ended questions, nonjudgmental interactions, and collaborative decision-making when discussing the risks and benefits of vaccination.^21,22

Limitations

This study was conducted at a single VA health care facility and our sampling technique was nonrandom, suggesting that these results may not be generalizable to all veterans or non-VA patient populations. The 21% questionnaire response rate could have introduced selection bias into the respondent sample. All questionnaire data were self-reported, including vaccination status. Finally, the qualitative interviews consisted of a small number of unvaccinated individuals in 2 clusters (ie, Concerned Ambivalents and Unconcerned Disbelievers) and may not have reached thematic saturation in these subgroups.

Conclusions

Quantitative analyses identified 4 clusters based on individual thoughts and feelings about COVID-19 infection and vaccines. Cluster membership and levels of trust in COVID-19 information sources were independently associated with vaccination. Understanding the quantitative patterns of thoughts and beliefs across clusters, enriched by common qualitative themes for vaccine hesitancy, help inform tailored interventions to augment COVID-19 vaccine uptake and highlight the importance of targeted, trust-based communication and culturally sensitive interventions to enhance vaccine uptake across diverse populations.

The better part of valor is discretion.

Henry IV, Part 1 by William Shakespeare¹

This is the second part of an exploration of the phenomenon of stolen valor, where individuals claim military exploits or acts of heroism that are either fabricated or exaggerated, and/or awards and medals they did not earn.² In June, I focused on the unsettling story of Sarah Cavanaugh, a young US Department of Veterans Affairs (VA) social worker who posed as a decorated, heroic, and seriously wounded Marine veteran for years. Cavanaugh’s manipulative masquerade allowed her to receive coveted spots in veteran recovery programs, thousands of dollars in fraudulent donations, the leadership of a local Veterans of Foreign Wars post, and eventually a federal conviction and prison sentence.³ The first column focused on the legal history of stolen valor; this editorial analyzes the clinical import and ethical impact of the behavior of military imposters. Military imposters are the culprits who steal valor.

It would be easy and perhaps reassuring to assume that stolen valor has emerged as another deplorable example of a national culture in which the betrayal of trust in human beings and loss of faith in institutions and aspirations has reached a nadir. Ironically, stolen valor is inextricably linked to the founding of the United States. When General George Washington inaugurated the American military tradition of awarding decorations to honor the bravery and sacrifices of the patriot Army, he anticipated military imposters. He tried to deter stolen valor through the threat of chastisement: “Should any who are not entitled to these honors have the insolence to assume the badges of them, they shall be severely punished,” Washington warned.⁴

It is plausible to think such despicable conduct occurs only as the ugly side of the beauty of our unparalleled national freedom, but this is a mistake. Cases of stolen valor have been reported in many countries around the world, with some of the most infamous found in the United Kingdom.⁵

While many brazen military imposters like Cavanaugh never serve, there is a small subset who honorably wore a uniform yet embellish their service record with secret missions and meritorious gallantry that purportedly earned them high rank and even higher awards. A most puzzling and disturbing example of this group is an allegation that surfaced when celebrated Navy SEAL Chris Kyle declared in American Sniper that he had won 3 additional combat awards for combat valor in addition to the Silver Star and 3 Bronze Stars actually listed in his service record.⁶

The fact that for centuries stolen valor has plagued multiple nations suggests, at least to this psychiatrically trained mind, that something deeper and darker in human nature than profit alone drives military imposters. Philosopher Verna Gehring has distilled these less tangible motivations into the concept of virtue imposters. According to Gehring, military phonies are a notorious exemplar: “The military phony adopts a past not her own, acts of courage she did not perform—she impersonates the heroic character and virtues she does not possess.”⁷ There could be no more apposite depiction of Cavanaugh, other military imposters, or a legion of other offenders of honor. ⁸

As with Cavanaugh, financial gain is a byproduct of the machinations of military imposters and is usually secondary to the pursuit of nonmaterial rewards such as power, influence, admiration, emulation, empathy, and charity. Gehring contends, and I agree, that virtue imposters are more pernicious and culpable than the plethora of more prosaic scammers and swindlers who use deceit primarily as a means of economic exploitation: “The virtue impostor by contrast plays on people’s better natures—their generosity, humility, and their need for heroes.”⁷

Military imposters cause real and lasting harm. Every veteran who exaggerates claims or scams the VA unjustly steals human and monetary resources from other deserving veterans whose integrity would not permit them to break the rules.⁹ Yet, even more harmful is the potential damage to therapeutic relationships: federal practitioners may become skeptical of a veteran’s history even when there is little to no grounds for suspicion. Veterans, in turn, may experience a breach of trust and betrayal not only from health care professionals and VA leaders but from their brothers and sisters in arms. On an ever-wider scale, every military impostor who is exposed may diminish the respect and honor all veterans have earned. 

It is clear, then, why a small group of former service members has adopted the cause of uncovering military imposters and adroitly using the media to identify signs of stolen valor.¹⁰ Yet deception mars even these mostly well-intentioned campaigns, as some more zealous stolen valor hunters may make allegations that turn out to be false.¹¹ Nevertheless, 500 years ago and in a very different context Shakespeare was, right on the mark: the better part of valor is discretion in describing one’s achievements, in relying on the veracity of our veteran’s narratives, and when there are sound reasons to do so verifying the truth of what our patients, friends, and even family tell us about their time in the military.¹

The better part of valor is discretion.

Henry IV, Part 1 by William Shakespeare¹

This is the second part of an exploration of the phenomenon of stolen valor, where individuals claim military exploits or acts of heroism that are either fabricated or exaggerated, and/or awards and medals they did not earn.² In June, I focused on the unsettling story of Sarah Cavanaugh, a young US Department of Veterans Affairs (VA) social worker who posed as a decorated, heroic, and seriously wounded Marine veteran for years. Cavanaugh’s manipulative masquerade allowed her to receive coveted spots in veteran recovery programs, thousands of dollars in fraudulent donations, the leadership of a local Veterans of Foreign Wars post, and eventually a federal conviction and prison sentence.³ The first column focused on the legal history of stolen valor; this editorial analyzes the clinical import and ethical impact of the behavior of military imposters. Military imposters are the culprits who steal valor.

It would be easy and perhaps reassuring to assume that stolen valor has emerged as another deplorable example of a national culture in which the betrayal of trust in human beings and loss of faith in institutions and aspirations has reached a nadir. Ironically, stolen valor is inextricably linked to the founding of the United States. When General George Washington inaugurated the American military tradition of awarding decorations to honor the bravery and sacrifices of the patriot Army, he anticipated military imposters. He tried to deter stolen valor through the threat of chastisement: “Should any who are not entitled to these honors have the insolence to assume the badges of them, they shall be severely punished,” Washington warned.⁴

It is plausible to think such despicable conduct occurs only as the ugly side of the beauty of our unparalleled national freedom, but this is a mistake. Cases of stolen valor have been reported in many countries around the world, with some of the most infamous found in the United Kingdom.⁵

While many brazen military imposters like Cavanaugh never serve, there is a small subset who honorably wore a uniform yet embellish their service record with secret missions and meritorious gallantry that purportedly earned them high rank and even higher awards. A most puzzling and disturbing example of this group is an allegation that surfaced when celebrated Navy SEAL Chris Kyle declared in American Sniper that he had won 3 additional combat awards for combat valor in addition to the Silver Star and 3 Bronze Stars actually listed in his service record.⁶

The fact that for centuries stolen valor has plagued multiple nations suggests, at least to this psychiatrically trained mind, that something deeper and darker in human nature than profit alone drives military imposters. Philosopher Verna Gehring has distilled these less tangible motivations into the concept of virtue imposters. According to Gehring, military phonies are a notorious exemplar: “The military phony adopts a past not her own, acts of courage she did not perform—she impersonates the heroic character and virtues she does not possess.”⁷ There could be no more apposite depiction of Cavanaugh, other military imposters, or a legion of other offenders of honor. ⁸

As with Cavanaugh, financial gain is a byproduct of the machinations of military imposters and is usually secondary to the pursuit of nonmaterial rewards such as power, influence, admiration, emulation, empathy, and charity. Gehring contends, and I agree, that virtue imposters are more pernicious and culpable than the plethora of more prosaic scammers and swindlers who use deceit primarily as a means of economic exploitation: “The virtue impostor by contrast plays on people’s better natures—their generosity, humility, and their need for heroes.”⁷

Military imposters cause real and lasting harm. Every veteran who exaggerates claims or scams the VA unjustly steals human and monetary resources from other deserving veterans whose integrity would not permit them to break the rules.⁹ Yet, even more harmful is the potential damage to therapeutic relationships: federal practitioners may become skeptical of a veteran’s history even when there is little to no grounds for suspicion. Veterans, in turn, may experience a breach of trust and betrayal not only from health care professionals and VA leaders but from their brothers and sisters in arms. On an ever-wider scale, every military impostor who is exposed may diminish the respect and honor all veterans have earned. 

It is clear, then, why a small group of former service members has adopted the cause of uncovering military imposters and adroitly using the media to identify signs of stolen valor.¹⁰ Yet deception mars even these mostly well-intentioned campaigns, as some more zealous stolen valor hunters may make allegations that turn out to be false.¹¹ Nevertheless, 500 years ago and in a very different context Shakespeare was, right on the mark: the better part of valor is discretion in describing one’s achievements, in relying on the veracity of our veteran’s narratives, and when there are sound reasons to do so verifying the truth of what our patients, friends, and even family tell us about their time in the military.¹

The better part of valor is discretion.

Henry IV, Part 1 by William Shakespeare¹

This is the second part of an exploration of the phenomenon of stolen valor, where individuals claim military exploits or acts of heroism that are either fabricated or exaggerated, and/or awards and medals they did not earn.² In June, I focused on the unsettling story of Sarah Cavanaugh, a young US Department of Veterans Affairs (VA) social worker who posed as a decorated, heroic, and seriously wounded Marine veteran for years. Cavanaugh’s manipulative masquerade allowed her to receive coveted spots in veteran recovery programs, thousands of dollars in fraudulent donations, the leadership of a local Veterans of Foreign Wars post, and eventually a federal conviction and prison sentence.³ The first column focused on the legal history of stolen valor; this editorial analyzes the clinical import and ethical impact of the behavior of military imposters. Military imposters are the culprits who steal valor.

It would be easy and perhaps reassuring to assume that stolen valor has emerged as another deplorable example of a national culture in which the betrayal of trust in human beings and loss of faith in institutions and aspirations has reached a nadir. Ironically, stolen valor is inextricably linked to the founding of the United States. When General George Washington inaugurated the American military tradition of awarding decorations to honor the bravery and sacrifices of the patriot Army, he anticipated military imposters. He tried to deter stolen valor through the threat of chastisement: “Should any who are not entitled to these honors have the insolence to assume the badges of them, they shall be severely punished,” Washington warned.⁴

It is plausible to think such despicable conduct occurs only as the ugly side of the beauty of our unparalleled national freedom, but this is a mistake. Cases of stolen valor have been reported in many countries around the world, with some of the most infamous found in the United Kingdom.⁵

While many brazen military imposters like Cavanaugh never serve, there is a small subset who honorably wore a uniform yet embellish their service record with secret missions and meritorious gallantry that purportedly earned them high rank and even higher awards. A most puzzling and disturbing example of this group is an allegation that surfaced when celebrated Navy SEAL Chris Kyle declared in American Sniper that he had won 3 additional combat awards for combat valor in addition to the Silver Star and 3 Bronze Stars actually listed in his service record.⁶

The fact that for centuries stolen valor has plagued multiple nations suggests, at least to this psychiatrically trained mind, that something deeper and darker in human nature than profit alone drives military imposters. Philosopher Verna Gehring has distilled these less tangible motivations into the concept of virtue imposters. According to Gehring, military phonies are a notorious exemplar: “The military phony adopts a past not her own, acts of courage she did not perform—she impersonates the heroic character and virtues she does not possess.”⁷ There could be no more apposite depiction of Cavanaugh, other military imposters, or a legion of other offenders of honor. ⁸

As with Cavanaugh, financial gain is a byproduct of the machinations of military imposters and is usually secondary to the pursuit of nonmaterial rewards such as power, influence, admiration, emulation, empathy, and charity. Gehring contends, and I agree, that virtue imposters are more pernicious and culpable than the plethora of more prosaic scammers and swindlers who use deceit primarily as a means of economic exploitation: “The virtue impostor by contrast plays on people’s better natures—their generosity, humility, and their need for heroes.”⁷

Military imposters cause real and lasting harm. Every veteran who exaggerates claims or scams the VA unjustly steals human and monetary resources from other deserving veterans whose integrity would not permit them to break the rules.⁹ Yet, even more harmful is the potential damage to therapeutic relationships: federal practitioners may become skeptical of a veteran’s history even when there is little to no grounds for suspicion. Veterans, in turn, may experience a breach of trust and betrayal not only from health care professionals and VA leaders but from their brothers and sisters in arms. On an ever-wider scale, every military impostor who is exposed may diminish the respect and honor all veterans have earned. 

It is clear, then, why a small group of former service members has adopted the cause of uncovering military imposters and adroitly using the media to identify signs of stolen valor.¹⁰ Yet deception mars even these mostly well-intentioned campaigns, as some more zealous stolen valor hunters may make allegations that turn out to be false.¹¹ Nevertheless, 500 years ago and in a very different context Shakespeare was, right on the mark: the better part of valor is discretion in describing one’s achievements, in relying on the veracity of our veteran’s narratives, and when there are sound reasons to do so verifying the truth of what our patients, friends, and even family tell us about their time in the military.¹

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

The treatment of metastatic solid tumors has been based historically on systemic therapies, with the goal of delaying progression and extend life as long as possible, with tolerable treatment-related adverse events. Some exceptions were made for local treatment with surgery or radiotherapy (RT), often for patients with a single metastasis. A 1939 report describes a patient with renal adenocarcinoma and a solitary lung metastasis who underwent RT to the lung lesion after nephrectomy and subsequently partial lobectomy after the metastatic lesion progressed. The authors argued that if a metastasis appears solitary and accessible, it is plausible to remove it in addition to the primary growth.¹

In 1995 Hellman and Weichselbaum proposed oligometastatic disease (OMD). They reasoned that malignancy exists along a spectrum from localized disease to widely disseminated disease, with OMD existing in between with a still-restricted tumor metastatic capacity. Appropriately selected patients with OMD may be candidates for prolonged disease-free survival or cure with the addition of local therapy to systemic therapy.²

The EORTC 4004 phase 2 randomized control trial (RCT) analyzed radiofrequency ablation (RFA) for colorectal liver metastases with systemic therapy vs systemic therapy alone for patients with ≤ 9 liver lesions.³ Systemic therapyconsisted of 5-FU/leucovorin/oxaliplatin, with bevacizumab added to the regimen 3.5 years into the study, per updated standard- of-care. This trial was the first to demonstrate the benefit of aggressive local treatment vs system treatment alone for OMD with a progression-free survival (PFS) benefit (16.8 vs 9.9 months; hazard ratio [HR], 0.63; P = .03) and overall survival (OS) benefit (45.3 vs 40.5 months; HR, 0.74; P = .02) with the addition of local treatment with RFA.

Since the presentations of the SABR-COMET phase 2 RCT and another study by Gomez et al at the American Society for Radiation Oncology (ASTRO) 2018 annual meeting, the paradigm for offering local RT for OMD has rapidly evolved. Both studies found PFS and OS benefits of RT for patients with OMD.^4,5 Additional RCTs have since demonstrated that for properly selected patients with OMD, aggressive local RT improved PFS and OS.^6-9 These small studies have led to larger RCTs to better understand who benefits from local consolidative treatment, particularly RT.^10,11

There is a large degree of heterogeneity in how oncologists define and approach OMD treatment. The 2020 European Society for Radiotherapy and Oncology (ESTRO) and ASTRO consensus guidelines defined the OMD state as 1 to 5 metastatic lesions for which all metastatic sites are safely treatable.¹² The purpose of this study was to evaluate perceptions and practice patterns among radiation oncologists and medical oncologists regarding the use of local RT for OMD across the Veterans Health Administration (VHA).

Methods

A 12-question survey was developed by the VHA Palliative Radiotherapy Task Force using the ESTRO-ASTRO consensus guidelines to define OMD. The survey was emailed to the VHA radiation oncology and medical oncology listservs on August 1, 2023. These listservs consist of physicians in these specialties either directly employed by the VHA or serve in its facilities as contractors. The original response closure date was August 11, 2023, but it was extended to August 18, 2023, to increase responses. No incentives were offered to respondents. Two email reminders were sent to the medical oncology listserv and 3 to the radiation oncology listserv. Descriptive statistics and X² tests were used for data analysis. The impact of specialty and presence of an on-site department of radiation oncology were reviewed. This project was approved by the VHA National Oncology Program and National Radiation Oncology Program.

Results

The survey was sent to 125 radiation oncologists and 515 medical oncologists and 106 were completed for a 16.6% response rate. There were 59 (55.7%) radiation oncologist responses and 47 (44.3%) medical oncologist responses. Most (96.2%) respondents were board-certified, and 84 (79.2%) were affiliated with an academic center. Not every respondent answered every question (Table).

All respondents (n = 105) indicated there is a potential benefit of high-dose RT for appropriately selected cases. Ninety-four oncologists (88.7%) believed that RT for OMD contributes to cure (88.1% of radiation oncologists, 89.4% of medical oncologists; P = .84) for appropriately selected cases. Some respondents who did not believe RT for OMD contributes to cure added comments about other perceived benefits, such as local disease control for palliation, delaying systemic therapy with its associated toxicities, and prolongation of disease-free survival or OS. A higher percentage of respondents with academic affiliations believed high-dose RT contributes to cure, although this difference did not reach statistical significance (Figure 1).

Fifty-five respondents (51.9%; 55.2% radiation oncologists vs 50.0% medical oncologists; P = .60) responded that local RT for OMD treatment should not be limited by primary tumor type. Of respondents who responded that OMD treatment should be limited based on the type of primary tumor, many provided comments that argued there was a benefit for non-small cell lung cancer (NSCLC), prostate adenocarcinoma (PCa), and colorectal cancer.

The definition of how many metastatic lesions qualify as OMD varied. A total of 48.6% of respondents defined OMD as ≤ 3 lesions and 42.9% answered ≤ 5 lesions. A majority of radiation oncologists (55.2%) classified ≤ 5 lesions as OMD, whereas a majority of medical oncologists (66.0%) considered ≤ 3 lesions as OMD (P = .006) (Figure 2).

Thirty-six medical oncologists (76.6%) report having an on-site department of radiation oncology (Figure 3). This subgroup was more likely to consider local RT potentially curative compared with their medical oncology peers without on-site radiation oncology (94.4% vs 72.7%; P = .04).

Case Management

The 3 clinical cases demonstrated the heterogeneity of management approaches for OMD. The first described a man aged 65 years with PCa and 2 asymptomatic pelvic bone metastases. Ninety-three respondents (90.3%) recommended RT at the primary site and 74.8% recommended RT to both the primary site and metastatic foci. Sixty-three respondents (67.7%) recommended a STAMPEDE-compatible dose, and 30 (32.3%) recommended a definitive dose.

The second clinical case was a 60-year-old man with a cT1N2M1 NSCLC, with a solitary metastatic focus to the left iliac wing. Fifty-eight respondents (54.7%) recommended upfront systemic chemotherapy and the option of local therapy to the chest and metastatic focus after initial chemotherapy; 28 respondents (26.4%) recommended upfront chemoradiation to the chest and definitive radiation to the left iliac wing metastasis.

The third clinical case described a male aged 70 years with a history of a treated base of tongue squamous cell carcinoma, with a solitary metastatic focus within the right lung. Respondents could pick multiple treatment options and 85 (81.7%) favored upfront definitive local therapy with surgery or stereotactic body radiotherapy (SBRT), rather than upfront chemotherapy, with future consideration for local treatment. About half of respondents (51.8%) recommended SBRT and 41.2% would let the patient decide between surgery or SBRT. Additionally, 39.6% included in their patient counselling that the treatment may be for curative intent.

Discussion

The use of local treatment to increased PFS, OS, or even cure treatment for OMD has become more accepted since the 2018 ASTRO meeting.^4,5 Palma et al analyzed a controlled primary malignancy of any histology and ≤ 5 metastatic lesions, with all lesions amenable to SBRT.⁴ With a median follow-up of 51 months when comparing the standard-of-care (SOC) arm and the SBRT arm, the 5-year PFS was not reached and the 5-year OS rates were 17.7% and 42.3% (P = .006), respectively. In the SBRT arm, about 1 in 5 patients survived > 5 years without a recurrence or disease progression, vs 0 patients in the control arm. There was a 29% rate of grade 2 or higher toxicity in the SBRT arm, including 3 deaths that were likely due to treatment. Subsequent trials, such as the phase 3 SABR-COMET-3 (1-3 metastases), phase 3 SABR-COMET-10 (4-10 metastases), and phase 1 ARREST (> 10 metastases) trials, have been specifically designed to minimize treatment-related toxicities.^13-15

Gomez et al analyzed patients at 3 sites with a controlled NSCLC primary tumor and ≤ 3 metastases.⁵ At a follow-up of 38.8 months, the PFS was 4.4 months in the SOC arm vs 14.2 months in the RT and/or surgery local treatment arm (P = .02). There was also an OS benefit of 17.0 vs 41.2 months (P = .02), respectively.

Several RCTs soon followed that demonstrated improved PFS and OS with local radiotherapy for OMD; however, total metastatic ablation of the foci is necessary to attain these PFS and OS benefits.^6-9 Still, an oncologic benefit has yet to be proven. The randomized NRGBR002 study phase 2/3 trial for oligometastatic breast cancer included patients with ≤ 4 extracranial metastases and controlled primary disease to metastasis-directed therapy (SBRT and/ or surgical resection) and systemic therapy vs systemic therapy alone.¹⁰ The study did not demonstrate improved PFS or OS at 3 years. However, for most breast cancers, especially with the rapid advancements in systemic therapy that have been achieved, longer follow-up may be necessary to detect a significant difference.

The prospective single-arm phase 2 SABR-5 trial retrospectively demonstrated important lessons about the timing of SBRT and systemic therapy.¹¹ This study included patients with ≤ 5 metastases of any histology, and they received SBRT to all lesions. SABR-5 retrospectively compared patients who received upfront systemic therapy followed by SBRT vs another cohort that first received SBRT and did not receive systemic therapy until there was disease progression. Patients with oligo-progression were excluded, as it demonstrated systemic drug resistance. At a median follow-up time of 34 months, delayed systemic treatment was associated with shorter PFS (23 vs 34 months, respectively; P = .001), but not worse 3-year OS (80% vs 85%, respectively; P = .66). In addition, the delayed systemic treatment arm demonstrated a reduced risk of grade 2 or higher SBRT-related toxicity (odds ratio, 0.35; P < .001).

Similarly, the STOMP phase 2 trial analyzed the role of metastasis-directed therapy (MDT) in delaying initiation of androgen deprivation therapy (ADT) in a randomized phase 2 trial.¹⁶ This study included patients with asymptomatic PCa with a biochemical recurrence after primary treatment, 1 to 3 extracranial metastatic lesions, and serum testosterone levels > 50 ng/mL. Sixty-two patients were randomized 1:1 to either MDT (SBRT or surgery) of all lesions or surveillance. The 5-year ADT-free survival was 34% for MDT vs 8% for surveillance (P = .06).

VHA Radiation Oncology

The VHA has 138 departments of medical oncology, but only 41 departments of radiation oncology. Compared with medical oncologists without an on-site radiation oncology department, those with on-site departments were more likely to believe that local RT was potentially curative (94.4% vs 72.7%, respectively; P = .04). This finding suggests that a cancer center that includes both specialties has closer collaboration, which results in greater inclination to embrace local RT for OMD, as it has demonstrated PFS and OS benefits.

The radiation and medical oncologists surveyed had statistically significant differences in response by specialty regarding the maximal number of lesions still believed to constitute OMD. Most radiation oncologists classified ≤ 5 lesions as OMD, whereas most medical oncologists classified ≤ 3 lesions as OMD. This difference is not unexpected. There is no universally agreed-upon definition of OMD, and criteria differ across studies.

While the SABR-COMET trial did include ≤ 5 metastatic lesions, it was a phase 2 RCT, making subgroup analysis difficult. Ongoing phase 3 trials that are more specific in the number of metastases, comparing 1 to 3 vs 4 to 10 metastases (SABR-COMET-3 and SABR-COMET-10, respectively).^13,14 There is even an ongoing phase 1 trial (ARREST) studying the potential benefits of treating (“restraining”) > 10 metastases, if dosimetrically feasible.¹⁵ Within the VHA, VA STARPORT is investigating MDT for recurrent or de novo hormone-sensitive metastatic PCa.¹⁷ The ongoing HALT phase 2/3 trial focuses on patients with actionable mutations to help determine management of oligo-progression in mutation-positive NSCLC.¹⁸

There was no significant difference by specialty in who responded that offering local RT for OMD treatment should not be limited by histology (55.2% of radiation oncologists and 50.0% of medical oncologists; P = .60). Oncologists could make the argument that some histologies (eg, pancreatic adenocarcinomas) have such poor prognoses that local RT would not meaningfully affect oncologic outcomes, while potentially adding toxicity, whereas others could point to improved systemic therapy regimens and the low toxicity rates with careful hypofractionation regimens. Of note, the 41-patient phase 2 EXTEND trial for pancreatic ductal adenocarcinoma suggested an oncologic benefit to MDT, with far better PFS and no grade ≥ 3 toxicities related to MDT.¹⁹ About half of respondents for each specialty believed the primary histology should affect the decision. Further clarification may emerge from phase 3 trials.

Of note, a 2023 study of 44 radiation and medical oncologists at 2 Harvard Medical School-affiliated hospitals found that for synchronous OMD, 50.0% of medical oncologists and 5.3% (P < .01) of radiation oncologists recommended systemic treatment, suggesting a greater divergence in approach than found in this study.²⁰

Limitations

The response rate of 17.0% raised a potential for selection bias, but this rate is expected for a nonincentivized medical survey. A study by the American Board of Internal Medicine with 11 surveys and 6 weekly email contacts only generated a 23.7% response rate, while another study among physicians demonstrated a 4.5% response rate for email-based contact and 11.8% for mail-based contact.^21,22 We could have asked participants questions regarding demographics and geography to ensure the survey represented a diverse sample of the medical community, although additional questions would likely suppress the response rate. Additional data collection about respondents may elucidate the rationale for differences in their responses, especially between the specialties. In a planned subsequent survey in several years, the question on the number of lesions that qualifies as OMD may be amended to reflect the context and dosimetry for the maximal number of metastases constituting OMD; the joint ESTRO-ASTRO consensus defined OMD as 1 to 5 metastatic lesions, but in which all metastatic sites must be safely treatable.¹² Also, fewer example cases could be included to simplify the survey and boost response rates. A future survey may ask about the timing of SBRT and systemic therapy, and whether SBRT can safely delay systemic therapy.

Conclusions

Survey results demonstrated significant confidence among both radiation oncologists and medical oncologists that local RT for OMD improves outcomes, which is encouraging and a reflection of the recent evidence-based paradigm shift in viewing metastatic disease as a spectrum. However, there is a difference between radiation oncologists and medical oncologists in how they define OMD, and preferred treatment of the sample cases presented revealed nuanced differences by specialty. Close collaboration with radiation oncologists influences the belief of medical oncologists in the beneficial role of RT for OMD. As more phase 3 data for OMD local treatments emerge, additional investigation is needed on how beliefs and practice patterns evolve among radiation and medical oncologists.

The treatment of metastatic solid tumors has been based historically on systemic therapies, with the goal of delaying progression and extend life as long as possible, with tolerable treatment-related adverse events. Some exceptions were made for local treatment with surgery or radiotherapy (RT), often for patients with a single metastasis. A 1939 report describes a patient with renal adenocarcinoma and a solitary lung metastasis who underwent RT to the lung lesion after nephrectomy and subsequently partial lobectomy after the metastatic lesion progressed. The authors argued that if a metastasis appears solitary and accessible, it is plausible to remove it in addition to the primary growth.¹

In 1995 Hellman and Weichselbaum proposed oligometastatic disease (OMD). They reasoned that malignancy exists along a spectrum from localized disease to widely disseminated disease, with OMD existing in between with a still-restricted tumor metastatic capacity. Appropriately selected patients with OMD may be candidates for prolonged disease-free survival or cure with the addition of local therapy to systemic therapy.²

The EORTC 4004 phase 2 randomized control trial (RCT) analyzed radiofrequency ablation (RFA) for colorectal liver metastases with systemic therapy vs systemic therapy alone for patients with ≤ 9 liver lesions.³ Systemic therapyconsisted of 5-FU/leucovorin/oxaliplatin, with bevacizumab added to the regimen 3.5 years into the study, per updated standard- of-care. This trial was the first to demonstrate the benefit of aggressive local treatment vs system treatment alone for OMD with a progression-free survival (PFS) benefit (16.8 vs 9.9 months; hazard ratio [HR], 0.63; P = .03) and overall survival (OS) benefit (45.3 vs 40.5 months; HR, 0.74; P = .02) with the addition of local treatment with RFA.

Since the presentations of the SABR-COMET phase 2 RCT and another study by Gomez et al at the American Society for Radiation Oncology (ASTRO) 2018 annual meeting, the paradigm for offering local RT for OMD has rapidly evolved. Both studies found PFS and OS benefits of RT for patients with OMD.^4,5 Additional RCTs have since demonstrated that for properly selected patients with OMD, aggressive local RT improved PFS and OS.^6-9 These small studies have led to larger RCTs to better understand who benefits from local consolidative treatment, particularly RT.^10,11

There is a large degree of heterogeneity in how oncologists define and approach OMD treatment. The 2020 European Society for Radiotherapy and Oncology (ESTRO) and ASTRO consensus guidelines defined the OMD state as 1 to 5 metastatic lesions for which all metastatic sites are safely treatable.¹² The purpose of this study was to evaluate perceptions and practice patterns among radiation oncologists and medical oncologists regarding the use of local RT for OMD across the Veterans Health Administration (VHA).

Methods

A 12-question survey was developed by the VHA Palliative Radiotherapy Task Force using the ESTRO-ASTRO consensus guidelines to define OMD. The survey was emailed to the VHA radiation oncology and medical oncology listservs on August 1, 2023. These listservs consist of physicians in these specialties either directly employed by the VHA or serve in its facilities as contractors. The original response closure date was August 11, 2023, but it was extended to August 18, 2023, to increase responses. No incentives were offered to respondents. Two email reminders were sent to the medical oncology listserv and 3 to the radiation oncology listserv. Descriptive statistics and X² tests were used for data analysis. The impact of specialty and presence of an on-site department of radiation oncology were reviewed. This project was approved by the VHA National Oncology Program and National Radiation Oncology Program.

Results

The survey was sent to 125 radiation oncologists and 515 medical oncologists and 106 were completed for a 16.6% response rate. There were 59 (55.7%) radiation oncologist responses and 47 (44.3%) medical oncologist responses. Most (96.2%) respondents were board-certified, and 84 (79.2%) were affiliated with an academic center. Not every respondent answered every question (Table).

All respondents (n = 105) indicated there is a potential benefit of high-dose RT for appropriately selected cases. Ninety-four oncologists (88.7%) believed that RT for OMD contributes to cure (88.1% of radiation oncologists, 89.4% of medical oncologists; P = .84) for appropriately selected cases. Some respondents who did not believe RT for OMD contributes to cure added comments about other perceived benefits, such as local disease control for palliation, delaying systemic therapy with its associated toxicities, and prolongation of disease-free survival or OS. A higher percentage of respondents with academic affiliations believed high-dose RT contributes to cure, although this difference did not reach statistical significance (Figure 1).

Fifty-five respondents (51.9%; 55.2% radiation oncologists vs 50.0% medical oncologists; P = .60) responded that local RT for OMD treatment should not be limited by primary tumor type. Of respondents who responded that OMD treatment should be limited based on the type of primary tumor, many provided comments that argued there was a benefit for non-small cell lung cancer (NSCLC), prostate adenocarcinoma (PCa), and colorectal cancer.

The definition of how many metastatic lesions qualify as OMD varied. A total of 48.6% of respondents defined OMD as ≤ 3 lesions and 42.9% answered ≤ 5 lesions. A majority of radiation oncologists (55.2%) classified ≤ 5 lesions as OMD, whereas a majority of medical oncologists (66.0%) considered ≤ 3 lesions as OMD (P = .006) (Figure 2).

Thirty-six medical oncologists (76.6%) report having an on-site department of radiation oncology (Figure 3). This subgroup was more likely to consider local RT potentially curative compared with their medical oncology peers without on-site radiation oncology (94.4% vs 72.7%; P = .04).

Case Management

The 3 clinical cases demonstrated the heterogeneity of management approaches for OMD. The first described a man aged 65 years with PCa and 2 asymptomatic pelvic bone metastases. Ninety-three respondents (90.3%) recommended RT at the primary site and 74.8% recommended RT to both the primary site and metastatic foci. Sixty-three respondents (67.7%) recommended a STAMPEDE-compatible dose, and 30 (32.3%) recommended a definitive dose.

The second clinical case was a 60-year-old man with a cT1N2M1 NSCLC, with a solitary metastatic focus to the left iliac wing. Fifty-eight respondents (54.7%) recommended upfront systemic chemotherapy and the option of local therapy to the chest and metastatic focus after initial chemotherapy; 28 respondents (26.4%) recommended upfront chemoradiation to the chest and definitive radiation to the left iliac wing metastasis.

The third clinical case described a male aged 70 years with a history of a treated base of tongue squamous cell carcinoma, with a solitary metastatic focus within the right lung. Respondents could pick multiple treatment options and 85 (81.7%) favored upfront definitive local therapy with surgery or stereotactic body radiotherapy (SBRT), rather than upfront chemotherapy, with future consideration for local treatment. About half of respondents (51.8%) recommended SBRT and 41.2% would let the patient decide between surgery or SBRT. Additionally, 39.6% included in their patient counselling that the treatment may be for curative intent.

Discussion

The use of local treatment to increased PFS, OS, or even cure treatment for OMD has become more accepted since the 2018 ASTRO meeting.^4,5 Palma et al analyzed a controlled primary malignancy of any histology and ≤ 5 metastatic lesions, with all lesions amenable to SBRT.⁴ With a median follow-up of 51 months when comparing the standard-of-care (SOC) arm and the SBRT arm, the 5-year PFS was not reached and the 5-year OS rates were 17.7% and 42.3% (P = .006), respectively. In the SBRT arm, about 1 in 5 patients survived > 5 years without a recurrence or disease progression, vs 0 patients in the control arm. There was a 29% rate of grade 2 or higher toxicity in the SBRT arm, including 3 deaths that were likely due to treatment. Subsequent trials, such as the phase 3 SABR-COMET-3 (1-3 metastases), phase 3 SABR-COMET-10 (4-10 metastases), and phase 1 ARREST (> 10 metastases) trials, have been specifically designed to minimize treatment-related toxicities.^13-15

Gomez et al analyzed patients at 3 sites with a controlled NSCLC primary tumor and ≤ 3 metastases.⁵ At a follow-up of 38.8 months, the PFS was 4.4 months in the SOC arm vs 14.2 months in the RT and/or surgery local treatment arm (P = .02). There was also an OS benefit of 17.0 vs 41.2 months (P = .02), respectively.

Several RCTs soon followed that demonstrated improved PFS and OS with local radiotherapy for OMD; however, total metastatic ablation of the foci is necessary to attain these PFS and OS benefits.^6-9 Still, an oncologic benefit has yet to be proven. The randomized NRGBR002 study phase 2/3 trial for oligometastatic breast cancer included patients with ≤ 4 extracranial metastases and controlled primary disease to metastasis-directed therapy (SBRT and/ or surgical resection) and systemic therapy vs systemic therapy alone.¹⁰ The study did not demonstrate improved PFS or OS at 3 years. However, for most breast cancers, especially with the rapid advancements in systemic therapy that have been achieved, longer follow-up may be necessary to detect a significant difference.

The prospective single-arm phase 2 SABR-5 trial retrospectively demonstrated important lessons about the timing of SBRT and systemic therapy.¹¹ This study included patients with ≤ 5 metastases of any histology, and they received SBRT to all lesions. SABR-5 retrospectively compared patients who received upfront systemic therapy followed by SBRT vs another cohort that first received SBRT and did not receive systemic therapy until there was disease progression. Patients with oligo-progression were excluded, as it demonstrated systemic drug resistance. At a median follow-up time of 34 months, delayed systemic treatment was associated with shorter PFS (23 vs 34 months, respectively; P = .001), but not worse 3-year OS (80% vs 85%, respectively; P = .66). In addition, the delayed systemic treatment arm demonstrated a reduced risk of grade 2 or higher SBRT-related toxicity (odds ratio, 0.35; P < .001).

Similarly, the STOMP phase 2 trial analyzed the role of metastasis-directed therapy (MDT) in delaying initiation of androgen deprivation therapy (ADT) in a randomized phase 2 trial.¹⁶ This study included patients with asymptomatic PCa with a biochemical recurrence after primary treatment, 1 to 3 extracranial metastatic lesions, and serum testosterone levels > 50 ng/mL. Sixty-two patients were randomized 1:1 to either MDT (SBRT or surgery) of all lesions or surveillance. The 5-year ADT-free survival was 34% for MDT vs 8% for surveillance (P = .06).

VHA Radiation Oncology

The VHA has 138 departments of medical oncology, but only 41 departments of radiation oncology. Compared with medical oncologists without an on-site radiation oncology department, those with on-site departments were more likely to believe that local RT was potentially curative (94.4% vs 72.7%, respectively; P = .04). This finding suggests that a cancer center that includes both specialties has closer collaboration, which results in greater inclination to embrace local RT for OMD, as it has demonstrated PFS and OS benefits.

The radiation and medical oncologists surveyed had statistically significant differences in response by specialty regarding the maximal number of lesions still believed to constitute OMD. Most radiation oncologists classified ≤ 5 lesions as OMD, whereas most medical oncologists classified ≤ 3 lesions as OMD. This difference is not unexpected. There is no universally agreed-upon definition of OMD, and criteria differ across studies.

While the SABR-COMET trial did include ≤ 5 metastatic lesions, it was a phase 2 RCT, making subgroup analysis difficult. Ongoing phase 3 trials that are more specific in the number of metastases, comparing 1 to 3 vs 4 to 10 metastases (SABR-COMET-3 and SABR-COMET-10, respectively).^13,14 There is even an ongoing phase 1 trial (ARREST) studying the potential benefits of treating (“restraining”) > 10 metastases, if dosimetrically feasible.¹⁵ Within the VHA, VA STARPORT is investigating MDT for recurrent or de novo hormone-sensitive metastatic PCa.¹⁷ The ongoing HALT phase 2/3 trial focuses on patients with actionable mutations to help determine management of oligo-progression in mutation-positive NSCLC.¹⁸

There was no significant difference by specialty in who responded that offering local RT for OMD treatment should not be limited by histology (55.2% of radiation oncologists and 50.0% of medical oncologists; P = .60). Oncologists could make the argument that some histologies (eg, pancreatic adenocarcinomas) have such poor prognoses that local RT would not meaningfully affect oncologic outcomes, while potentially adding toxicity, whereas others could point to improved systemic therapy regimens and the low toxicity rates with careful hypofractionation regimens. Of note, the 41-patient phase 2 EXTEND trial for pancreatic ductal adenocarcinoma suggested an oncologic benefit to MDT, with far better PFS and no grade ≥ 3 toxicities related to MDT.¹⁹ About half of respondents for each specialty believed the primary histology should affect the decision. Further clarification may emerge from phase 3 trials.

Of note, a 2023 study of 44 radiation and medical oncologists at 2 Harvard Medical School-affiliated hospitals found that for synchronous OMD, 50.0% of medical oncologists and 5.3% (P < .01) of radiation oncologists recommended systemic treatment, suggesting a greater divergence in approach than found in this study.²⁰

Limitations

The response rate of 17.0% raised a potential for selection bias, but this rate is expected for a nonincentivized medical survey. A study by the American Board of Internal Medicine with 11 surveys and 6 weekly email contacts only generated a 23.7% response rate, while another study among physicians demonstrated a 4.5% response rate for email-based contact and 11.8% for mail-based contact.^21,22 We could have asked participants questions regarding demographics and geography to ensure the survey represented a diverse sample of the medical community, although additional questions would likely suppress the response rate. Additional data collection about respondents may elucidate the rationale for differences in their responses, especially between the specialties. In a planned subsequent survey in several years, the question on the number of lesions that qualifies as OMD may be amended to reflect the context and dosimetry for the maximal number of metastases constituting OMD; the joint ESTRO-ASTRO consensus defined OMD as 1 to 5 metastatic lesions, but in which all metastatic sites must be safely treatable.¹² Also, fewer example cases could be included to simplify the survey and boost response rates. A future survey may ask about the timing of SBRT and systemic therapy, and whether SBRT can safely delay systemic therapy.

Conclusions

Survey results demonstrated significant confidence among both radiation oncologists and medical oncologists that local RT for OMD improves outcomes, which is encouraging and a reflection of the recent evidence-based paradigm shift in viewing metastatic disease as a spectrum. However, there is a difference between radiation oncologists and medical oncologists in how they define OMD, and preferred treatment of the sample cases presented revealed nuanced differences by specialty. Close collaboration with radiation oncologists influences the belief of medical oncologists in the beneficial role of RT for OMD. As more phase 3 data for OMD local treatments emerge, additional investigation is needed on how beliefs and practice patterns evolve among radiation and medical oncologists.

The treatment of metastatic solid tumors has been based historically on systemic therapies, with the goal of delaying progression and extend life as long as possible, with tolerable treatment-related adverse events. Some exceptions were made for local treatment with surgery or radiotherapy (RT), often for patients with a single metastasis. A 1939 report describes a patient with renal adenocarcinoma and a solitary lung metastasis who underwent RT to the lung lesion after nephrectomy and subsequently partial lobectomy after the metastatic lesion progressed. The authors argued that if a metastasis appears solitary and accessible, it is plausible to remove it in addition to the primary growth.¹

In 1995 Hellman and Weichselbaum proposed oligometastatic disease (OMD). They reasoned that malignancy exists along a spectrum from localized disease to widely disseminated disease, with OMD existing in between with a still-restricted tumor metastatic capacity. Appropriately selected patients with OMD may be candidates for prolonged disease-free survival or cure with the addition of local therapy to systemic therapy.²

The EORTC 4004 phase 2 randomized control trial (RCT) analyzed radiofrequency ablation (RFA) for colorectal liver metastases with systemic therapy vs systemic therapy alone for patients with ≤ 9 liver lesions.³ Systemic therapyconsisted of 5-FU/leucovorin/oxaliplatin, with bevacizumab added to the regimen 3.5 years into the study, per updated standard- of-care. This trial was the first to demonstrate the benefit of aggressive local treatment vs system treatment alone for OMD with a progression-free survival (PFS) benefit (16.8 vs 9.9 months; hazard ratio [HR], 0.63; P = .03) and overall survival (OS) benefit (45.3 vs 40.5 months; HR, 0.74; P = .02) with the addition of local treatment with RFA.

Since the presentations of the SABR-COMET phase 2 RCT and another study by Gomez et al at the American Society for Radiation Oncology (ASTRO) 2018 annual meeting, the paradigm for offering local RT for OMD has rapidly evolved. Both studies found PFS and OS benefits of RT for patients with OMD.^4,5 Additional RCTs have since demonstrated that for properly selected patients with OMD, aggressive local RT improved PFS and OS.^6-9 These small studies have led to larger RCTs to better understand who benefits from local consolidative treatment, particularly RT.^10,11

There is a large degree of heterogeneity in how oncologists define and approach OMD treatment. The 2020 European Society for Radiotherapy and Oncology (ESTRO) and ASTRO consensus guidelines defined the OMD state as 1 to 5 metastatic lesions for which all metastatic sites are safely treatable.¹² The purpose of this study was to evaluate perceptions and practice patterns among radiation oncologists and medical oncologists regarding the use of local RT for OMD across the Veterans Health Administration (VHA).

Methods

A 12-question survey was developed by the VHA Palliative Radiotherapy Task Force using the ESTRO-ASTRO consensus guidelines to define OMD. The survey was emailed to the VHA radiation oncology and medical oncology listservs on August 1, 2023. These listservs consist of physicians in these specialties either directly employed by the VHA or serve in its facilities as contractors. The original response closure date was August 11, 2023, but it was extended to August 18, 2023, to increase responses. No incentives were offered to respondents. Two email reminders were sent to the medical oncology listserv and 3 to the radiation oncology listserv. Descriptive statistics and X² tests were used for data analysis. The impact of specialty and presence of an on-site department of radiation oncology were reviewed. This project was approved by the VHA National Oncology Program and National Radiation Oncology Program.

Results

The survey was sent to 125 radiation oncologists and 515 medical oncologists and 106 were completed for a 16.6% response rate. There were 59 (55.7%) radiation oncologist responses and 47 (44.3%) medical oncologist responses. Most (96.2%) respondents were board-certified, and 84 (79.2%) were affiliated with an academic center. Not every respondent answered every question (Table).

All respondents (n = 105) indicated there is a potential benefit of high-dose RT for appropriately selected cases. Ninety-four oncologists (88.7%) believed that RT for OMD contributes to cure (88.1% of radiation oncologists, 89.4% of medical oncologists; P = .84) for appropriately selected cases. Some respondents who did not believe RT for OMD contributes to cure added comments about other perceived benefits, such as local disease control for palliation, delaying systemic therapy with its associated toxicities, and prolongation of disease-free survival or OS. A higher percentage of respondents with academic affiliations believed high-dose RT contributes to cure, although this difference did not reach statistical significance (Figure 1).

Fifty-five respondents (51.9%; 55.2% radiation oncologists vs 50.0% medical oncologists; P = .60) responded that local RT for OMD treatment should not be limited by primary tumor type. Of respondents who responded that OMD treatment should be limited based on the type of primary tumor, many provided comments that argued there was a benefit for non-small cell lung cancer (NSCLC), prostate adenocarcinoma (PCa), and colorectal cancer.

The definition of how many metastatic lesions qualify as OMD varied. A total of 48.6% of respondents defined OMD as ≤ 3 lesions and 42.9% answered ≤ 5 lesions. A majority of radiation oncologists (55.2%) classified ≤ 5 lesions as OMD, whereas a majority of medical oncologists (66.0%) considered ≤ 3 lesions as OMD (P = .006) (Figure 2).

Thirty-six medical oncologists (76.6%) report having an on-site department of radiation oncology (Figure 3). This subgroup was more likely to consider local RT potentially curative compared with their medical oncology peers without on-site radiation oncology (94.4% vs 72.7%; P = .04).

Case Management

The 3 clinical cases demonstrated the heterogeneity of management approaches for OMD. The first described a man aged 65 years with PCa and 2 asymptomatic pelvic bone metastases. Ninety-three respondents (90.3%) recommended RT at the primary site and 74.8% recommended RT to both the primary site and metastatic foci. Sixty-three respondents (67.7%) recommended a STAMPEDE-compatible dose, and 30 (32.3%) recommended a definitive dose.

The second clinical case was a 60-year-old man with a cT1N2M1 NSCLC, with a solitary metastatic focus to the left iliac wing. Fifty-eight respondents (54.7%) recommended upfront systemic chemotherapy and the option of local therapy to the chest and metastatic focus after initial chemotherapy; 28 respondents (26.4%) recommended upfront chemoradiation to the chest and definitive radiation to the left iliac wing metastasis.

The third clinical case described a male aged 70 years with a history of a treated base of tongue squamous cell carcinoma, with a solitary metastatic focus within the right lung. Respondents could pick multiple treatment options and 85 (81.7%) favored upfront definitive local therapy with surgery or stereotactic body radiotherapy (SBRT), rather than upfront chemotherapy, with future consideration for local treatment. About half of respondents (51.8%) recommended SBRT and 41.2% would let the patient decide between surgery or SBRT. Additionally, 39.6% included in their patient counselling that the treatment may be for curative intent.

Discussion

The use of local treatment to increased PFS, OS, or even cure treatment for OMD has become more accepted since the 2018 ASTRO meeting.^4,5 Palma et al analyzed a controlled primary malignancy of any histology and ≤ 5 metastatic lesions, with all lesions amenable to SBRT.⁴ With a median follow-up of 51 months when comparing the standard-of-care (SOC) arm and the SBRT arm, the 5-year PFS was not reached and the 5-year OS rates were 17.7% and 42.3% (P = .006), respectively. In the SBRT arm, about 1 in 5 patients survived > 5 years without a recurrence or disease progression, vs 0 patients in the control arm. There was a 29% rate of grade 2 or higher toxicity in the SBRT arm, including 3 deaths that were likely due to treatment. Subsequent trials, such as the phase 3 SABR-COMET-3 (1-3 metastases), phase 3 SABR-COMET-10 (4-10 metastases), and phase 1 ARREST (> 10 metastases) trials, have been specifically designed to minimize treatment-related toxicities.^13-15

Gomez et al analyzed patients at 3 sites with a controlled NSCLC primary tumor and ≤ 3 metastases.⁵ At a follow-up of 38.8 months, the PFS was 4.4 months in the SOC arm vs 14.2 months in the RT and/or surgery local treatment arm (P = .02). There was also an OS benefit of 17.0 vs 41.2 months (P = .02), respectively.

Several RCTs soon followed that demonstrated improved PFS and OS with local radiotherapy for OMD; however, total metastatic ablation of the foci is necessary to attain these PFS and OS benefits.^6-9 Still, an oncologic benefit has yet to be proven. The randomized NRGBR002 study phase 2/3 trial for oligometastatic breast cancer included patients with ≤ 4 extracranial metastases and controlled primary disease to metastasis-directed therapy (SBRT and/ or surgical resection) and systemic therapy vs systemic therapy alone.¹⁰ The study did not demonstrate improved PFS or OS at 3 years. However, for most breast cancers, especially with the rapid advancements in systemic therapy that have been achieved, longer follow-up may be necessary to detect a significant difference.

The prospective single-arm phase 2 SABR-5 trial retrospectively demonstrated important lessons about the timing of SBRT and systemic therapy.¹¹ This study included patients with ≤ 5 metastases of any histology, and they received SBRT to all lesions. SABR-5 retrospectively compared patients who received upfront systemic therapy followed by SBRT vs another cohort that first received SBRT and did not receive systemic therapy until there was disease progression. Patients with oligo-progression were excluded, as it demonstrated systemic drug resistance. At a median follow-up time of 34 months, delayed systemic treatment was associated with shorter PFS (23 vs 34 months, respectively; P = .001), but not worse 3-year OS (80% vs 85%, respectively; P = .66). In addition, the delayed systemic treatment arm demonstrated a reduced risk of grade 2 or higher SBRT-related toxicity (odds ratio, 0.35; P < .001).

Similarly, the STOMP phase 2 trial analyzed the role of metastasis-directed therapy (MDT) in delaying initiation of androgen deprivation therapy (ADT) in a randomized phase 2 trial.¹⁶ This study included patients with asymptomatic PCa with a biochemical recurrence after primary treatment, 1 to 3 extracranial metastatic lesions, and serum testosterone levels > 50 ng/mL. Sixty-two patients were randomized 1:1 to either MDT (SBRT or surgery) of all lesions or surveillance. The 5-year ADT-free survival was 34% for MDT vs 8% for surveillance (P = .06).

VHA Radiation Oncology

The VHA has 138 departments of medical oncology, but only 41 departments of radiation oncology. Compared with medical oncologists without an on-site radiation oncology department, those with on-site departments were more likely to believe that local RT was potentially curative (94.4% vs 72.7%, respectively; P = .04). This finding suggests that a cancer center that includes both specialties has closer collaboration, which results in greater inclination to embrace local RT for OMD, as it has demonstrated PFS and OS benefits.

The radiation and medical oncologists surveyed had statistically significant differences in response by specialty regarding the maximal number of lesions still believed to constitute OMD. Most radiation oncologists classified ≤ 5 lesions as OMD, whereas most medical oncologists classified ≤ 3 lesions as OMD. This difference is not unexpected. There is no universally agreed-upon definition of OMD, and criteria differ across studies.

While the SABR-COMET trial did include ≤ 5 metastatic lesions, it was a phase 2 RCT, making subgroup analysis difficult. Ongoing phase 3 trials that are more specific in the number of metastases, comparing 1 to 3 vs 4 to 10 metastases (SABR-COMET-3 and SABR-COMET-10, respectively).^13,14 There is even an ongoing phase 1 trial (ARREST) studying the potential benefits of treating (“restraining”) > 10 metastases, if dosimetrically feasible.¹⁵ Within the VHA, VA STARPORT is investigating MDT for recurrent or de novo hormone-sensitive metastatic PCa.¹⁷ The ongoing HALT phase 2/3 trial focuses on patients with actionable mutations to help determine management of oligo-progression in mutation-positive NSCLC.¹⁸

There was no significant difference by specialty in who responded that offering local RT for OMD treatment should not be limited by histology (55.2% of radiation oncologists and 50.0% of medical oncologists; P = .60). Oncologists could make the argument that some histologies (eg, pancreatic adenocarcinomas) have such poor prognoses that local RT would not meaningfully affect oncologic outcomes, while potentially adding toxicity, whereas others could point to improved systemic therapy regimens and the low toxicity rates with careful hypofractionation regimens. Of note, the 41-patient phase 2 EXTEND trial for pancreatic ductal adenocarcinoma suggested an oncologic benefit to MDT, with far better PFS and no grade ≥ 3 toxicities related to MDT.¹⁹ About half of respondents for each specialty believed the primary histology should affect the decision. Further clarification may emerge from phase 3 trials.

Of note, a 2023 study of 44 radiation and medical oncologists at 2 Harvard Medical School-affiliated hospitals found that for synchronous OMD, 50.0% of medical oncologists and 5.3% (P < .01) of radiation oncologists recommended systemic treatment, suggesting a greater divergence in approach than found in this study.²⁰

Limitations

The response rate of 17.0% raised a potential for selection bias, but this rate is expected for a nonincentivized medical survey. A study by the American Board of Internal Medicine with 11 surveys and 6 weekly email contacts only generated a 23.7% response rate, while another study among physicians demonstrated a 4.5% response rate for email-based contact and 11.8% for mail-based contact.^21,22 We could have asked participants questions regarding demographics and geography to ensure the survey represented a diverse sample of the medical community, although additional questions would likely suppress the response rate. Additional data collection about respondents may elucidate the rationale for differences in their responses, especially between the specialties. In a planned subsequent survey in several years, the question on the number of lesions that qualifies as OMD may be amended to reflect the context and dosimetry for the maximal number of metastases constituting OMD; the joint ESTRO-ASTRO consensus defined OMD as 1 to 5 metastatic lesions, but in which all metastatic sites must be safely treatable.¹² Also, fewer example cases could be included to simplify the survey and boost response rates. A future survey may ask about the timing of SBRT and systemic therapy, and whether SBRT can safely delay systemic therapy.

Conclusions

Survey results demonstrated significant confidence among both radiation oncologists and medical oncologists that local RT for OMD improves outcomes, which is encouraging and a reflection of the recent evidence-based paradigm shift in viewing metastatic disease as a spectrum. However, there is a difference between radiation oncologists and medical oncologists in how they define OMD, and preferred treatment of the sample cases presented revealed nuanced differences by specialty. Close collaboration with radiation oncologists influences the belief of medical oncologists in the beneficial role of RT for OMD. As more phase 3 data for OMD local treatments emerge, additional investigation is needed on how beliefs and practice patterns evolve among radiation and medical oncologists.

Cosmetic laser procedures as well as energy-based fat reduction and body-contouring devices are increasingly popular among individuals with skin of color (SOC). Innovations in cosmetic devices and procedures tailored for SOC have allowed for the optimization of outcomes in this patient population. In this article, SOC is defined as darker skin types, including Fitzpatrick skin types (FSTs) IV to VI and ethnic backgrounds such as LatinX, African American, Southeast Asian, Native American, Pacific Islander, Middle Eastern, Asian, and African. Indications for laser treatment include dermatosis papulosa nigrans (DPN), acne scars, skin rejuvenation, and hyperpigmentation. There currently are 6 procedures for nonsurgical fat reduction that are approved by the US Food and Drug Administration (FDA): high-frequency focused ultrasound, cryolipolysis, laser lipolysis, injection lipolysis, radiofrequency lipolysis, and magnetic resonance contouring (Supplementary Table S1).¹

In this review, our initial focus is cosmetic laser ­procedures, encompassing FDA-cleared indications along with the associated risks and benefits in SOC populations. Subsequently, we delve into the realms of energy-based fat reduction and body contouring, offering a comprehensive overview of these noninvasive therapies and addressing considerations for efficacy and safety in these patients.

Dermatosis Papulosa Nigra

In patients with SOC, scissor excision, curettage, or electrodesiccation are the mainstay treatments for removal of DPN (Figure 1). Curettage and electrodesiccation can cause temporary postinflammatory hyperpigmentation (PIH) in these populations, while cryotherapy is not a preferred method in patients with SOC due to the possibility of cryotherapy-induced depigmentation. In a 14-patient split-face study comparing the 532-nm potassium titanyl phosphate (KTP) laser vs electrodesiccation in FSTs IV to VI, the KTP-treated side showed an improvement rate of 96%, while the electrodesiccation side showed an improvement rate of 79%. There was a statistically significant favorable experience for KTP with regard to pain tolerability (P=.002).² Complete resolution of lesions may be seen after 3 to 4 sessions at 4-week intervals. Additionally, the 1064-nm Nd:YAG laser was assessed for treatment of DPN in 2 patients, with 70% to 90% of lesions resolved after a single treatment with no complications.³

Most dermatologists still rely on curettage and electrodesiccation instead of laser therapy to remove DPNs in patients with SOC. The use of the Nd:YAG laser is promising yet expensive for the provider both to purchase and maintain. Electrodesiccation has been used by dermatology practices for decades and can be used without permanent discoloration. To minimize the risk for PIH, we recommend application of a healing ointment such as petroleum jelly or aloe vera gel to the treated lesions as well as lightening agents for PIH and daily use of sunscreen. Overall, providers do not need to purchase an expensive laser device for DPN removal.

Acne Scars

The invention of fractional technology in the early 2000s and its favorable safety profile have changed how dermatologists treat scarring in patients with SOC.^4,5 In fact, nonablative fractional (NAF) resurfacing is a preferred treatment modality for management of acne scars in patients with SOC.⁶ In one study of the 1550-nm erbium-doped fiber laser for treatment of acne scars (3 treatments at intervals of 2-3 weeks) in 10 Japanese patients, clinical improvement was seen in all patients and no severe adverse effects were reported.⁷ In another study, 27 Korean patients with FSTs IV and V were treated with an NAF resurfacing device for acne scars. Excellent results were reported in 30% (8/27) of patients, substantial improvement in 59% (16/27), and moderate improvement in 11% (3/27).⁸ To evaluate outcomes in patients treated with NAF resurfacing, a retrospective review of 961 treatments showed a hyperpigmentation rate of 11.6% in those with FST IV and 33% in FST V.⁹

In one study of the short-pulsed nonablative Nd:YAG laser, 9 patients with FSTs I to V and 2 patients with FSTs IV to V underwent 8 treatments at 2-week intervals. Three blinded observers found a 29% improvement in the Global Acne Scar Severity score, while 89% (8/9) of patients self-reported subjective improvement in their acne scars.¹⁰

The 755-nm picosecond laser and diffractive lens array also have been shown to reduce the appearance of acne scars in patients with SOC, as shown via serial photography in a retrospective study of 56 patients with FSTs IV to VI. Transient hyperpigmentation, erythema, and edema were reported.¹¹

Nonablative laser therapy is preferred for skin rejuvenation in patients with SOC due to a reduced risk for postprocedural hyperpigmentation.¹¹ Ablative resurfacing (eg, CO₂ laser) poses major risks for postprocedural hyperpigmentation, hypopigmentation, and scar formation and therefore should be avoided in these populations.^12,13 A study involving 30 Asian patients (FSTs III-IV) demonstrated that the 1550-nm fractional laser was well tolerated, though higher treatment densities and fluences may lead to temporary adverse effects such as increased redness, swelling, and pain (P<.01).¹⁴ Furthermore, greater density was shown to cause higher levels of redness, hyperpigmentation, and swelling in comparison to higher fluence settings. Of note, patient satisfaction was markedly higher in patients who underwent treatment with higher fluence settings but not in patients with higher densities (P<.05). Postprocedural hyperpigmentation was noted in 6.7% (2/30) of patients studied.¹⁴ In another study, 8 patients with FSTs II to V were treated with either the 1064-nm long-pulsed Nd:YAG laser or the grid fractional monopolar radiofrequency laser.¹⁵ All participants experienced a significant decrease in mean wrinkle count using the Lemperle wrinkle assessment (P<.05). A significant decrease in mean wrinkle assessment score from 3.5 to 3.17 in clinical assessment and a decrease from 3.165 to 2.33 for photographic assessment was noted in patients treated with the grid laser (P<.05). A similar decrease in mean wrinkle assessment score was observed in the Nd:YAG group, with a mean decrease of 3.665 to 2.83 after 2 months for clinical assessment and 3.5 to 2.67 for photographic assessment. Among all patients in the study, 68% (6/8) experienced erythema, 25% (2/8) had a burning sensation, and 25% (2/8) experienced urticaria immediately postprocedure.¹⁵

Nonablative fractional resurfacing is preferred for the management of acne scars in patients with SOC. Adverse effects such as hyperpigmentation typically are transient, and the risk may be minimized with strict photoprotective practices following the procedure. Furthermore, avoidance of topicals containing exfoliants or α-hydroxy acids applied to the treated area following the procedure also may mitigate the risk for postprocedural hyperpigmentation.¹⁶ If hyperpigmentation does occur, use of topical melanogenesis inhibitors such as hydroquinone, kojic acid, or azelaic acid has shown some utility in practice.

Skin Rejuvenation

Nonablative fractional lasers (NAFLs) continue to be popular for treatment of photoaging. One study including 10 Asian patients (FSTs III-V) assessed the 1440-nm diode-based fractional laser for facial rejuvenation.¹⁷ After 4 sessions at 2-week intervals, 80% (8/10) of patients reported decreased skin roughness after both the second and third treatments, while 90% (9/10) had improved texture 1 month after the final procedure. Adverse effects included moderate facial edema and one case of transient hyperpigmentation.¹⁷ Another study reported a significant reduction in pore score (P<.002), with patients noting an overall improvement in skin appearance with minimal erythema, dryness, and flaking following 6 sessions at 2-week intervals using the 1440-nm diode-based fractional laser.¹⁸

The 1550-nm diode fractional laser significantly improved skin pigmentation (P<.001) and texture (P<.001) in 10 patients with FSTs II to IV following 5 sessions at 2- to 3-week intervals, with self-resolving erythema and edema posttreatment (Supplementary Table S2).¹⁹ Overall, NAFLs for the treatment of photoaging are effective with minimal adverse effects (eg, facial edema), which can be reduced with application of cold compression to the face and elevation of the head following treatment as well as the use of additional pillows during overnight sleep.

Laser Treatment for Hyperpigmentation Disorders

Melasma—The FDA recently approved fractional photothermolysis for the treatment of melasma; however, due to the risk for hyperpigmentation given its pathogenesis linked to hyperactive melanocytes, this laser is not considered a first-line therapy for melasma.²⁰ In a split-face, randomized study, 22 patients with FSTs III to V who were diagnosed with either dermal or mixed-type melasma were treated with a low-fluence Q-switched Nd:YAG laser combined with hydroquinone 2% vs hydroquinone 2% alone (Supplementary Table S3).²¹ Each patient was treated weekly for 5 consecutive weeks. The laser-treated side was found to reach an average of 92.5% improvement compared with 19.7% on the hydroquinone-only side. Three of the 22 (13.6%) patients developed mottled hypopigmentation after 5 laser treatments, and 8 (36.4%) developed confetti-type hypopigmentation. Four (18.2%) patients developed rebound hyperpigmentation, and all 22 patients experienced recurrence of melasma by 12 weeks posttreatment.²¹

First-line treatment for melasma involves the application of topical lightening agents such as hydroquinone, azelaic acid, kojic acid, retinoids, or mild topical steroids. Combining laser technology with topical medications can enhance treatment outcomes, particularly yielding positive results for patients with persistent pigmentation concerns. Notably, utilization of 650-microsecond technology with the 1064-nm Nd:YAG laser is considered superior in clinical practice, especially for patients with FSTs IV through VI.

Postinflammatory Hyperpigmentation—A retrospective evaluation of 61 patients with FSTs IV to VI with PIH treated with a 1927-nm NAFL showed a mean improvement of 43.24%, as assessed by 2 dermatologists.²² Additionally, the Nd:YAG 1064-nm 650-microsecond pulse duration laser is an emerging treatment that delivers high and low fluences between 4 J/cm² and 255 J/cm² within a single 650-microsecond pulse duration.²³ The short-pulse duration avoids overheating the skin, mitigating procedural discomfort and the risk for adverse effects commonly seen with the previous generation of low-pulsed lasers. In addition to PIH, this laser has been successfully used to treat pseudofolliculitis barbae.²⁴

Solar Lentigos—In a split-face study treating solar lentigos in Asian patients, 4 treatments with a low-pulsed KTP 532-nm laser were administered with and without a second treatment with a low-pulsed 1064-nm Nd:YAG laser.²⁵ Scoring of a modified pigment severity index and measurement of the melanin index showed that skin treated with the low-pulsed 532-nm laser alone and in combination with the low-pulsed 1064-nm Nd:YAG laser resulted in improvement at 3 months’ follow-up. However, there was no difference between the 2 sides of the face, leading the researchers to conclude that the low-pulsed 532-nm laser appears to be safe and effective for treatment of solar lentigos in Asian patients and does not require the addition of the low-pulsed 1064-nm laser.²⁵  

To avoid hyperpigmentation in patients with SOC, strict photoprotection to the treated areas should be advised. Proper cooling of the laser-treated area is required to minimize PIH, as cooling decreases tissue damage and excessive thermal injury. Test spots should be considered prior to initiation of the full laser treatment. Hydroquinone in a 4% concentration applied daily for 2 weeks preprocedure commonly is employed to reduce the risk for postprocedural hyperpigmentation in clinical practice.^26,27

Skin Tightening and Body Contouring

In general, skin-tightening and body-contouring devices are among the most sought-after procedures. Studies performed in patients with SOC are limited. Herein, we provide background on why these devices are favorable for patients with SOC and our experiences in using them. A summary of these devices can be found in Supplementary Table S4.

Radiofrequency Skin Tightening—Radiofrequency devices are utilized for skin tightening as well as mild fat reduction; they commonly are used on the abdomen, thighs, buttocks, and face.²⁸ People with SOC are more responsive to radiofrequency skin-tightening therapy due to higher baseline collagen content and dermal thickness, more sebaceous activity and skin elasticity, and more melanin content which offers protective thermal buffering.^29,30 As the radiofrequency device emits heat, penetrating deep into the dermis, it generates collagen remodeling and synthesis within 4 to 6 months posttreatment.

Nonsurgical Fat Reduction

Procedures for nonsurgical fat reduction are favorable due to minimal recovery time, manageable cost, and an in-office procedure setting. As noted previously, there are 6 FDA-indicated interventions for nonsurgical fat reduction: ultrasonography, cryolipolysis, laser lipolysis, injection lipolysis, radiofrequency lipolysis, and magnetic resonance contouring.³¹

Ultrasonography—Ultrasound devices designed for body contouring are used for skin tightening and mild fat reduction through the use of acoustic energy.³² These devices can be divided into 2 categories: high frequency and low frequency, with the high-frequency devices being the most popular. High-frequency ultrasound energy produces heat at target sites, which induces necrosis of adipocytes and stimulates collagen remodeling within the tissue matrix.³³ Tissue temperatures above 56°C stimulate adipocyte necrosis while sparing nearby nerves and vessels.²⁸ Because of the short duration of the procedure, the risk for epidermal damage is minimal. Contrary to high-frequency ultrasonography, focus-pulsed ultrasonography employs low-frequency waves to induce the mechanical disruption of adipocytes, which is generally better tolerated due to its nonthermal mechanism. The latter may be advantageous in patients with SOC due to a reduced risk for thermal injury to the epidermis. Multiple treatments often are needed at 3- to 4-week intervals, resulting in gradual improvement observed over 2 to 6 months. One study of microfocused ultrasonography in 25 Asian patients for treatment of face and neck laxity reported that skin laxity was improved or much improved in 84% (21/25) of patients following treatment.³⁴ Adverse effects were reported as mild and transient, resolving within 90 days.³⁴ Ultrasound devices also were shown to improve wrinkles, texture, and overall appearance of the skin in a 71-year-old African American woman 4 months following treatment (Figure 2). These photographs highlight the clinical utility of a microfocused ultrasound skin-tightening treatment in African American patients.

Cryolipolysis—Cryolipolysis is a noninvasive body contouring procedure that employs controlled cooling to induce subcutaneous panniculitis. Through cold-induced apoptosis of adipocytes, this procedure selectively reduces adipose tissue in localized areas such as the flank, abdomen, thighs, buttocks, back, submental area, and upper arms. The temperature used in cryolipolysis is approximately –10°C.³⁵ The lethal temperature for melanocytes is –4 °C, below which melanocyte apoptosis may be induced, resulting in depigmentation. Given the prolonged contact of the skin with a cryolipolysis device for up to 60 minutes during a body-contouring procedure, there is a risk for resultant depigmentation in darker skin types. Controlled studies are needed to fully evaluate the safety and efficacy of cryolipolysis in patients with SOC. One retrospective study of cryolipolysis applied to the abdomen and upper arm of 4122 Asian patients reported a significant (P<.05) reduction in the circumference of the abdomen and the upper-arm areas. No long-term adverse effects were reported.³⁶

Laser Lipolysis—The 1060-nm diode laser for body contouring selectively destroys adipose tissue, resulting in body contouring via thermally induced inflammation. Hyperthermic exposure for 15 minutes selectively elevates adipocyte temperature between 42°C to 47°C, which triggers apoptosis and the eventual clearance of destroyed cells from the interstitial space.³⁷ The selectivity of the 1060-nm wavelength coupled with the device’s contact cooling system preserves the overlying skin and adnexa during the procedure,³⁷ which would minimize epidermal damage that may induce dyspigmentation in patients with SOC. No notable adverse effects or dyspigmentation have been reported using this device.

Injection Lipolysis—Deoxycholic acid is an injectable adipocytolytic for the reduction of submental fat. It nonselectively lyses muscle and other adjacent nonfatty tissue. One study of 50 Indian patients demonstrated a substantial reduction of submental fat in 90% (45/50).³⁸ For each treatment, 5 mL of 30 mg/mL deoxycholic acid was injected. Serial sessions were conducted at 2-month intervals, and most (64% [32/50]) patients required 3 sessions to see a treatment effect. Adverse effects included transient swelling, lumpiness, and tenderness. A phase 2a investigation of the novel injectable small-molecule drug CBL-514 in 43 Asian and White participants found a significant improvement in the reduction in abdominal fat volume (P<.00001) and thickness (P<.0001) relative to baseline at higher doses (unit dose, 2.0 mg/cm² and 1.6 mg/cm²).³⁹ In addition to the adverse effects mentioned previously, pruritus, repeated urticaria, body rash, and fever also were reported.³⁹  

Radiofrequency Lipolysis—Radiofrequency is used for adipolysis through heat-induced apoptosis. To achieve this effect, adipose tissue must sustain a temperature of 42 °C to 45 °C for at least 15 minutes.⁴⁰ In one study, 4 treatments performed at 7-day intervals resulted in a statistically significant reduction in circumference to the treated areas of the inner and outer thighs without any reported adverse effects (P<0.001).⁴¹ Of note, there was 1 cm of distance between the applicator and the skin. The absence of direct contact with the skin is likely to reduce the risk for postprocedural complications in patients with SOC.

Magnetic Resonance Contouring—Magnetic resonance contouring with high-intensity focused electromagnetic technology is an emerging treatment modality for noninvasive body contouring. One distinguishing characteristic from other currently available noninvasive fat-­reduction therapies is that magnetic resonance may improve strength, tone, and muscle thickness.⁴² This modality is FDA approved for contouring of the buttocks and abdomen and employs electromagnetic energy to stimulate approximately 20,000 muscle contractions within a time frame of 30 minutes. Though the mechanisms causing benefits to muscular and adipose tissue have not been elucidated, current findings suggest that the contractions stimulate substantial lipolysis of adipocytes, resulting in the release of large amounts of free fatty acids that cause damage to nearby adipose tissue.⁴³ Multiple treatments are required over time to maintain effect. No major adverse effects have been reported. The likely mechanism of action of magnetic resonance contouring does not appear to pose an increased risk to patients with SOC.

Final Thoughts

One of the major roadblocks in distilling indications along with associated risks and benefits for nonsurgical cosmetic practices for patients with SOC is a void in the primary literature involving these populations. Clinical experience serves to address this deficit in combination with a thorough review of the literature. The 1064-nm Nd:YAG laser has shown clinical utility in the treatment of DPN, melanoma, and acne scars, but it poses financial constraints to the provider in comparison to modalities used for many years. Notably, NAF resurfacing is preferred for the management of acne scars in patients with SOC and continues to gain popularity for the treatment of photoaging. Regarding skin-tightening and body-contouring devices, studies performed in patients with SOC are limited and affected by factors such as small sample sizes, underrepresentation of FSTs IV through VI, short follow-up durations, and a lack of standardized outcome measures. Additionally, few studies assess pigmentary adverse effects or stratify results by skin type, which is critical given the higher risk for PIH in SOC. Ultrasound devices showed clinical utility in improvement of skin laxity, texture, and overall improvement. Patients with SOC respond well to skin-tightening devices due to the increased collagen synthesis. Regarding emerging devices for reduction of adipocytes, deoxycholic acid when injected showed notable improvement in fat reduction but also had adverse effects. As additional studies on cosmetic procedures in SOC emerge, an expansion of treatment options could be offered to this demographic group with confidence, provided proper treatment and follow-up protocols are in place.

Cosmetic laser procedures as well as energy-based fat reduction and body-contouring devices are increasingly popular among individuals with skin of color (SOC). Innovations in cosmetic devices and procedures tailored for SOC have allowed for the optimization of outcomes in this patient population. In this article, SOC is defined as darker skin types, including Fitzpatrick skin types (FSTs) IV to VI and ethnic backgrounds such as LatinX, African American, Southeast Asian, Native American, Pacific Islander, Middle Eastern, Asian, and African. Indications for laser treatment include dermatosis papulosa nigrans (DPN), acne scars, skin rejuvenation, and hyperpigmentation. There currently are 6 procedures for nonsurgical fat reduction that are approved by the US Food and Drug Administration (FDA): high-frequency focused ultrasound, cryolipolysis, laser lipolysis, injection lipolysis, radiofrequency lipolysis, and magnetic resonance contouring (Supplementary Table S1).¹

In this review, our initial focus is cosmetic laser ­procedures, encompassing FDA-cleared indications along with the associated risks and benefits in SOC populations. Subsequently, we delve into the realms of energy-based fat reduction and body contouring, offering a comprehensive overview of these noninvasive therapies and addressing considerations for efficacy and safety in these patients.

Dermatosis Papulosa Nigra

In patients with SOC, scissor excision, curettage, or electrodesiccation are the mainstay treatments for removal of DPN (Figure 1). Curettage and electrodesiccation can cause temporary postinflammatory hyperpigmentation (PIH) in these populations, while cryotherapy is not a preferred method in patients with SOC due to the possibility of cryotherapy-induced depigmentation. In a 14-patient split-face study comparing the 532-nm potassium titanyl phosphate (KTP) laser vs electrodesiccation in FSTs IV to VI, the KTP-treated side showed an improvement rate of 96%, while the electrodesiccation side showed an improvement rate of 79%. There was a statistically significant favorable experience for KTP with regard to pain tolerability (P=.002).² Complete resolution of lesions may be seen after 3 to 4 sessions at 4-week intervals. Additionally, the 1064-nm Nd:YAG laser was assessed for treatment of DPN in 2 patients, with 70% to 90% of lesions resolved after a single treatment with no complications.³

Most dermatologists still rely on curettage and electrodesiccation instead of laser therapy to remove DPNs in patients with SOC. The use of the Nd:YAG laser is promising yet expensive for the provider both to purchase and maintain. Electrodesiccation has been used by dermatology practices for decades and can be used without permanent discoloration. To minimize the risk for PIH, we recommend application of a healing ointment such as petroleum jelly or aloe vera gel to the treated lesions as well as lightening agents for PIH and daily use of sunscreen. Overall, providers do not need to purchase an expensive laser device for DPN removal.

Acne Scars

The invention of fractional technology in the early 2000s and its favorable safety profile have changed how dermatologists treat scarring in patients with SOC.^4,5 In fact, nonablative fractional (NAF) resurfacing is a preferred treatment modality for management of acne scars in patients with SOC.⁶ In one study of the 1550-nm erbium-doped fiber laser for treatment of acne scars (3 treatments at intervals of 2-3 weeks) in 10 Japanese patients, clinical improvement was seen in all patients and no severe adverse effects were reported.⁷ In another study, 27 Korean patients with FSTs IV and V were treated with an NAF resurfacing device for acne scars. Excellent results were reported in 30% (8/27) of patients, substantial improvement in 59% (16/27), and moderate improvement in 11% (3/27).⁸ To evaluate outcomes in patients treated with NAF resurfacing, a retrospective review of 961 treatments showed a hyperpigmentation rate of 11.6% in those with FST IV and 33% in FST V.⁹

In one study of the short-pulsed nonablative Nd:YAG laser, 9 patients with FSTs I to V and 2 patients with FSTs IV to V underwent 8 treatments at 2-week intervals. Three blinded observers found a 29% improvement in the Global Acne Scar Severity score, while 89% (8/9) of patients self-reported subjective improvement in their acne scars.¹⁰

The 755-nm picosecond laser and diffractive lens array also have been shown to reduce the appearance of acne scars in patients with SOC, as shown via serial photography in a retrospective study of 56 patients with FSTs IV to VI. Transient hyperpigmentation, erythema, and edema were reported.¹¹

Nonablative laser therapy is preferred for skin rejuvenation in patients with SOC due to a reduced risk for postprocedural hyperpigmentation.¹¹ Ablative resurfacing (eg, CO₂ laser) poses major risks for postprocedural hyperpigmentation, hypopigmentation, and scar formation and therefore should be avoided in these populations.^12,13 A study involving 30 Asian patients (FSTs III-IV) demonstrated that the 1550-nm fractional laser was well tolerated, though higher treatment densities and fluences may lead to temporary adverse effects such as increased redness, swelling, and pain (P<.01).¹⁴ Furthermore, greater density was shown to cause higher levels of redness, hyperpigmentation, and swelling in comparison to higher fluence settings. Of note, patient satisfaction was markedly higher in patients who underwent treatment with higher fluence settings but not in patients with higher densities (P<.05). Postprocedural hyperpigmentation was noted in 6.7% (2/30) of patients studied.¹⁴ In another study, 8 patients with FSTs II to V were treated with either the 1064-nm long-pulsed Nd:YAG laser or the grid fractional monopolar radiofrequency laser.¹⁵ All participants experienced a significant decrease in mean wrinkle count using the Lemperle wrinkle assessment (P<.05). A significant decrease in mean wrinkle assessment score from 3.5 to 3.17 in clinical assessment and a decrease from 3.165 to 2.33 for photographic assessment was noted in patients treated with the grid laser (P<.05). A similar decrease in mean wrinkle assessment score was observed in the Nd:YAG group, with a mean decrease of 3.665 to 2.83 after 2 months for clinical assessment and 3.5 to 2.67 for photographic assessment. Among all patients in the study, 68% (6/8) experienced erythema, 25% (2/8) had a burning sensation, and 25% (2/8) experienced urticaria immediately postprocedure.¹⁵

Nonablative fractional resurfacing is preferred for the management of acne scars in patients with SOC. Adverse effects such as hyperpigmentation typically are transient, and the risk may be minimized with strict photoprotective practices following the procedure. Furthermore, avoidance of topicals containing exfoliants or α-hydroxy acids applied to the treated area following the procedure also may mitigate the risk for postprocedural hyperpigmentation.¹⁶ If hyperpigmentation does occur, use of topical melanogenesis inhibitors such as hydroquinone, kojic acid, or azelaic acid has shown some utility in practice.

Skin Rejuvenation

Nonablative fractional lasers (NAFLs) continue to be popular for treatment of photoaging. One study including 10 Asian patients (FSTs III-V) assessed the 1440-nm diode-based fractional laser for facial rejuvenation.¹⁷ After 4 sessions at 2-week intervals, 80% (8/10) of patients reported decreased skin roughness after both the second and third treatments, while 90% (9/10) had improved texture 1 month after the final procedure. Adverse effects included moderate facial edema and one case of transient hyperpigmentation.¹⁷ Another study reported a significant reduction in pore score (P<.002), with patients noting an overall improvement in skin appearance with minimal erythema, dryness, and flaking following 6 sessions at 2-week intervals using the 1440-nm diode-based fractional laser.¹⁸

The 1550-nm diode fractional laser significantly improved skin pigmentation (P<.001) and texture (P<.001) in 10 patients with FSTs II to IV following 5 sessions at 2- to 3-week intervals, with self-resolving erythema and edema posttreatment (Supplementary Table S2).¹⁹ Overall, NAFLs for the treatment of photoaging are effective with minimal adverse effects (eg, facial edema), which can be reduced with application of cold compression to the face and elevation of the head following treatment as well as the use of additional pillows during overnight sleep.

Laser Treatment for Hyperpigmentation Disorders

Melasma—The FDA recently approved fractional photothermolysis for the treatment of melasma; however, due to the risk for hyperpigmentation given its pathogenesis linked to hyperactive melanocytes, this laser is not considered a first-line therapy for melasma.²⁰ In a split-face, randomized study, 22 patients with FSTs III to V who were diagnosed with either dermal or mixed-type melasma were treated with a low-fluence Q-switched Nd:YAG laser combined with hydroquinone 2% vs hydroquinone 2% alone (Supplementary Table S3).²¹ Each patient was treated weekly for 5 consecutive weeks. The laser-treated side was found to reach an average of 92.5% improvement compared with 19.7% on the hydroquinone-only side. Three of the 22 (13.6%) patients developed mottled hypopigmentation after 5 laser treatments, and 8 (36.4%) developed confetti-type hypopigmentation. Four (18.2%) patients developed rebound hyperpigmentation, and all 22 patients experienced recurrence of melasma by 12 weeks posttreatment.²¹

First-line treatment for melasma involves the application of topical lightening agents such as hydroquinone, azelaic acid, kojic acid, retinoids, or mild topical steroids. Combining laser technology with topical medications can enhance treatment outcomes, particularly yielding positive results for patients with persistent pigmentation concerns. Notably, utilization of 650-microsecond technology with the 1064-nm Nd:YAG laser is considered superior in clinical practice, especially for patients with FSTs IV through VI.

Postinflammatory Hyperpigmentation—A retrospective evaluation of 61 patients with FSTs IV to VI with PIH treated with a 1927-nm NAFL showed a mean improvement of 43.24%, as assessed by 2 dermatologists.²² Additionally, the Nd:YAG 1064-nm 650-microsecond pulse duration laser is an emerging treatment that delivers high and low fluences between 4 J/cm² and 255 J/cm² within a single 650-microsecond pulse duration.²³ The short-pulse duration avoids overheating the skin, mitigating procedural discomfort and the risk for adverse effects commonly seen with the previous generation of low-pulsed lasers. In addition to PIH, this laser has been successfully used to treat pseudofolliculitis barbae.²⁴

Solar Lentigos—In a split-face study treating solar lentigos in Asian patients, 4 treatments with a low-pulsed KTP 532-nm laser were administered with and without a second treatment with a low-pulsed 1064-nm Nd:YAG laser.²⁵ Scoring of a modified pigment severity index and measurement of the melanin index showed that skin treated with the low-pulsed 532-nm laser alone and in combination with the low-pulsed 1064-nm Nd:YAG laser resulted in improvement at 3 months’ follow-up. However, there was no difference between the 2 sides of the face, leading the researchers to conclude that the low-pulsed 532-nm laser appears to be safe and effective for treatment of solar lentigos in Asian patients and does not require the addition of the low-pulsed 1064-nm laser.²⁵  

To avoid hyperpigmentation in patients with SOC, strict photoprotection to the treated areas should be advised. Proper cooling of the laser-treated area is required to minimize PIH, as cooling decreases tissue damage and excessive thermal injury. Test spots should be considered prior to initiation of the full laser treatment. Hydroquinone in a 4% concentration applied daily for 2 weeks preprocedure commonly is employed to reduce the risk for postprocedural hyperpigmentation in clinical practice.^26,27

Skin Tightening and Body Contouring

In general, skin-tightening and body-contouring devices are among the most sought-after procedures. Studies performed in patients with SOC are limited. Herein, we provide background on why these devices are favorable for patients with SOC and our experiences in using them. A summary of these devices can be found in Supplementary Table S4.

Radiofrequency Skin Tightening—Radiofrequency devices are utilized for skin tightening as well as mild fat reduction; they commonly are used on the abdomen, thighs, buttocks, and face.²⁸ People with SOC are more responsive to radiofrequency skin-tightening therapy due to higher baseline collagen content and dermal thickness, more sebaceous activity and skin elasticity, and more melanin content which offers protective thermal buffering.^29,30 As the radiofrequency device emits heat, penetrating deep into the dermis, it generates collagen remodeling and synthesis within 4 to 6 months posttreatment.

Nonsurgical Fat Reduction

Procedures for nonsurgical fat reduction are favorable due to minimal recovery time, manageable cost, and an in-office procedure setting. As noted previously, there are 6 FDA-indicated interventions for nonsurgical fat reduction: ultrasonography, cryolipolysis, laser lipolysis, injection lipolysis, radiofrequency lipolysis, and magnetic resonance contouring.³¹

Ultrasonography—Ultrasound devices designed for body contouring are used for skin tightening and mild fat reduction through the use of acoustic energy.³² These devices can be divided into 2 categories: high frequency and low frequency, with the high-frequency devices being the most popular. High-frequency ultrasound energy produces heat at target sites, which induces necrosis of adipocytes and stimulates collagen remodeling within the tissue matrix.³³ Tissue temperatures above 56°C stimulate adipocyte necrosis while sparing nearby nerves and vessels.²⁸ Because of the short duration of the procedure, the risk for epidermal damage is minimal. Contrary to high-frequency ultrasonography, focus-pulsed ultrasonography employs low-frequency waves to induce the mechanical disruption of adipocytes, which is generally better tolerated due to its nonthermal mechanism. The latter may be advantageous in patients with SOC due to a reduced risk for thermal injury to the epidermis. Multiple treatments often are needed at 3- to 4-week intervals, resulting in gradual improvement observed over 2 to 6 months. One study of microfocused ultrasonography in 25 Asian patients for treatment of face and neck laxity reported that skin laxity was improved or much improved in 84% (21/25) of patients following treatment.³⁴ Adverse effects were reported as mild and transient, resolving within 90 days.³⁴ Ultrasound devices also were shown to improve wrinkles, texture, and overall appearance of the skin in a 71-year-old African American woman 4 months following treatment (Figure 2). These photographs highlight the clinical utility of a microfocused ultrasound skin-tightening treatment in African American patients.

Cryolipolysis—Cryolipolysis is a noninvasive body contouring procedure that employs controlled cooling to induce subcutaneous panniculitis. Through cold-induced apoptosis of adipocytes, this procedure selectively reduces adipose tissue in localized areas such as the flank, abdomen, thighs, buttocks, back, submental area, and upper arms. The temperature used in cryolipolysis is approximately –10°C.³⁵ The lethal temperature for melanocytes is –4 °C, below which melanocyte apoptosis may be induced, resulting in depigmentation. Given the prolonged contact of the skin with a cryolipolysis device for up to 60 minutes during a body-contouring procedure, there is a risk for resultant depigmentation in darker skin types. Controlled studies are needed to fully evaluate the safety and efficacy of cryolipolysis in patients with SOC. One retrospective study of cryolipolysis applied to the abdomen and upper arm of 4122 Asian patients reported a significant (P<.05) reduction in the circumference of the abdomen and the upper-arm areas. No long-term adverse effects were reported.³⁶

Laser Lipolysis—The 1060-nm diode laser for body contouring selectively destroys adipose tissue, resulting in body contouring via thermally induced inflammation. Hyperthermic exposure for 15 minutes selectively elevates adipocyte temperature between 42°C to 47°C, which triggers apoptosis and the eventual clearance of destroyed cells from the interstitial space.³⁷ The selectivity of the 1060-nm wavelength coupled with the device’s contact cooling system preserves the overlying skin and adnexa during the procedure,³⁷ which would minimize epidermal damage that may induce dyspigmentation in patients with SOC. No notable adverse effects or dyspigmentation have been reported using this device.

Injection Lipolysis—Deoxycholic acid is an injectable adipocytolytic for the reduction of submental fat. It nonselectively lyses muscle and other adjacent nonfatty tissue. One study of 50 Indian patients demonstrated a substantial reduction of submental fat in 90% (45/50).³⁸ For each treatment, 5 mL of 30 mg/mL deoxycholic acid was injected. Serial sessions were conducted at 2-month intervals, and most (64% [32/50]) patients required 3 sessions to see a treatment effect. Adverse effects included transient swelling, lumpiness, and tenderness. A phase 2a investigation of the novel injectable small-molecule drug CBL-514 in 43 Asian and White participants found a significant improvement in the reduction in abdominal fat volume (P<.00001) and thickness (P<.0001) relative to baseline at higher doses (unit dose, 2.0 mg/cm² and 1.6 mg/cm²).³⁹ In addition to the adverse effects mentioned previously, pruritus, repeated urticaria, body rash, and fever also were reported.³⁹  

Radiofrequency Lipolysis—Radiofrequency is used for adipolysis through heat-induced apoptosis. To achieve this effect, adipose tissue must sustain a temperature of 42 °C to 45 °C for at least 15 minutes.⁴⁰ In one study, 4 treatments performed at 7-day intervals resulted in a statistically significant reduction in circumference to the treated areas of the inner and outer thighs without any reported adverse effects (P<0.001).⁴¹ Of note, there was 1 cm of distance between the applicator and the skin. The absence of direct contact with the skin is likely to reduce the risk for postprocedural complications in patients with SOC.

Magnetic Resonance Contouring—Magnetic resonance contouring with high-intensity focused electromagnetic technology is an emerging treatment modality for noninvasive body contouring. One distinguishing characteristic from other currently available noninvasive fat-­reduction therapies is that magnetic resonance may improve strength, tone, and muscle thickness.⁴² This modality is FDA approved for contouring of the buttocks and abdomen and employs electromagnetic energy to stimulate approximately 20,000 muscle contractions within a time frame of 30 minutes. Though the mechanisms causing benefits to muscular and adipose tissue have not been elucidated, current findings suggest that the contractions stimulate substantial lipolysis of adipocytes, resulting in the release of large amounts of free fatty acids that cause damage to nearby adipose tissue.⁴³ Multiple treatments are required over time to maintain effect. No major adverse effects have been reported. The likely mechanism of action of magnetic resonance contouring does not appear to pose an increased risk to patients with SOC.

Final Thoughts

One of the major roadblocks in distilling indications along with associated risks and benefits for nonsurgical cosmetic practices for patients with SOC is a void in the primary literature involving these populations. Clinical experience serves to address this deficit in combination with a thorough review of the literature. The 1064-nm Nd:YAG laser has shown clinical utility in the treatment of DPN, melanoma, and acne scars, but it poses financial constraints to the provider in comparison to modalities used for many years. Notably, NAF resurfacing is preferred for the management of acne scars in patients with SOC and continues to gain popularity for the treatment of photoaging. Regarding skin-tightening and body-contouring devices, studies performed in patients with SOC are limited and affected by factors such as small sample sizes, underrepresentation of FSTs IV through VI, short follow-up durations, and a lack of standardized outcome measures. Additionally, few studies assess pigmentary adverse effects or stratify results by skin type, which is critical given the higher risk for PIH in SOC. Ultrasound devices showed clinical utility in improvement of skin laxity, texture, and overall improvement. Patients with SOC respond well to skin-tightening devices due to the increased collagen synthesis. Regarding emerging devices for reduction of adipocytes, deoxycholic acid when injected showed notable improvement in fat reduction but also had adverse effects. As additional studies on cosmetic procedures in SOC emerge, an expansion of treatment options could be offered to this demographic group with confidence, provided proper treatment and follow-up protocols are in place.

Cosmetic laser procedures as well as energy-based fat reduction and body-contouring devices are increasingly popular among individuals with skin of color (SOC). Innovations in cosmetic devices and procedures tailored for SOC have allowed for the optimization of outcomes in this patient population. In this article, SOC is defined as darker skin types, including Fitzpatrick skin types (FSTs) IV to VI and ethnic backgrounds such as LatinX, African American, Southeast Asian, Native American, Pacific Islander, Middle Eastern, Asian, and African. Indications for laser treatment include dermatosis papulosa nigrans (DPN), acne scars, skin rejuvenation, and hyperpigmentation. There currently are 6 procedures for nonsurgical fat reduction that are approved by the US Food and Drug Administration (FDA): high-frequency focused ultrasound, cryolipolysis, laser lipolysis, injection lipolysis, radiofrequency lipolysis, and magnetic resonance contouring (Supplementary Table S1).¹

In this review, our initial focus is cosmetic laser ­procedures, encompassing FDA-cleared indications along with the associated risks and benefits in SOC populations. Subsequently, we delve into the realms of energy-based fat reduction and body contouring, offering a comprehensive overview of these noninvasive therapies and addressing considerations for efficacy and safety in these patients.

Dermatosis Papulosa Nigra

In patients with SOC, scissor excision, curettage, or electrodesiccation are the mainstay treatments for removal of DPN (Figure 1). Curettage and electrodesiccation can cause temporary postinflammatory hyperpigmentation (PIH) in these populations, while cryotherapy is not a preferred method in patients with SOC due to the possibility of cryotherapy-induced depigmentation. In a 14-patient split-face study comparing the 532-nm potassium titanyl phosphate (KTP) laser vs electrodesiccation in FSTs IV to VI, the KTP-treated side showed an improvement rate of 96%, while the electrodesiccation side showed an improvement rate of 79%. There was a statistically significant favorable experience for KTP with regard to pain tolerability (P=.002).² Complete resolution of lesions may be seen after 3 to 4 sessions at 4-week intervals. Additionally, the 1064-nm Nd:YAG laser was assessed for treatment of DPN in 2 patients, with 70% to 90% of lesions resolved after a single treatment with no complications.³

Most dermatologists still rely on curettage and electrodesiccation instead of laser therapy to remove DPNs in patients with SOC. The use of the Nd:YAG laser is promising yet expensive for the provider both to purchase and maintain. Electrodesiccation has been used by dermatology practices for decades and can be used without permanent discoloration. To minimize the risk for PIH, we recommend application of a healing ointment such as petroleum jelly or aloe vera gel to the treated lesions as well as lightening agents for PIH and daily use of sunscreen. Overall, providers do not need to purchase an expensive laser device for DPN removal.

Acne Scars

The invention of fractional technology in the early 2000s and its favorable safety profile have changed how dermatologists treat scarring in patients with SOC.^4,5 In fact, nonablative fractional (NAF) resurfacing is a preferred treatment modality for management of acne scars in patients with SOC.⁶ In one study of the 1550-nm erbium-doped fiber laser for treatment of acne scars (3 treatments at intervals of 2-3 weeks) in 10 Japanese patients, clinical improvement was seen in all patients and no severe adverse effects were reported.⁷ In another study, 27 Korean patients with FSTs IV and V were treated with an NAF resurfacing device for acne scars. Excellent results were reported in 30% (8/27) of patients, substantial improvement in 59% (16/27), and moderate improvement in 11% (3/27).⁸ To evaluate outcomes in patients treated with NAF resurfacing, a retrospective review of 961 treatments showed a hyperpigmentation rate of 11.6% in those with FST IV and 33% in FST V.⁹

In one study of the short-pulsed nonablative Nd:YAG laser, 9 patients with FSTs I to V and 2 patients with FSTs IV to V underwent 8 treatments at 2-week intervals. Three blinded observers found a 29% improvement in the Global Acne Scar Severity score, while 89% (8/9) of patients self-reported subjective improvement in their acne scars.¹⁰

The 755-nm picosecond laser and diffractive lens array also have been shown to reduce the appearance of acne scars in patients with SOC, as shown via serial photography in a retrospective study of 56 patients with FSTs IV to VI. Transient hyperpigmentation, erythema, and edema were reported.¹¹

Nonablative laser therapy is preferred for skin rejuvenation in patients with SOC due to a reduced risk for postprocedural hyperpigmentation.¹¹ Ablative resurfacing (eg, CO₂ laser) poses major risks for postprocedural hyperpigmentation, hypopigmentation, and scar formation and therefore should be avoided in these populations.^12,13 A study involving 30 Asian patients (FSTs III-IV) demonstrated that the 1550-nm fractional laser was well tolerated, though higher treatment densities and fluences may lead to temporary adverse effects such as increased redness, swelling, and pain (P<.01).¹⁴ Furthermore, greater density was shown to cause higher levels of redness, hyperpigmentation, and swelling in comparison to higher fluence settings. Of note, patient satisfaction was markedly higher in patients who underwent treatment with higher fluence settings but not in patients with higher densities (P<.05). Postprocedural hyperpigmentation was noted in 6.7% (2/30) of patients studied.¹⁴ In another study, 8 patients with FSTs II to V were treated with either the 1064-nm long-pulsed Nd:YAG laser or the grid fractional monopolar radiofrequency laser.¹⁵ All participants experienced a significant decrease in mean wrinkle count using the Lemperle wrinkle assessment (P<.05). A significant decrease in mean wrinkle assessment score from 3.5 to 3.17 in clinical assessment and a decrease from 3.165 to 2.33 for photographic assessment was noted in patients treated with the grid laser (P<.05). A similar decrease in mean wrinkle assessment score was observed in the Nd:YAG group, with a mean decrease of 3.665 to 2.83 after 2 months for clinical assessment and 3.5 to 2.67 for photographic assessment. Among all patients in the study, 68% (6/8) experienced erythema, 25% (2/8) had a burning sensation, and 25% (2/8) experienced urticaria immediately postprocedure.¹⁵

Nonablative fractional resurfacing is preferred for the management of acne scars in patients with SOC. Adverse effects such as hyperpigmentation typically are transient, and the risk may be minimized with strict photoprotective practices following the procedure. Furthermore, avoidance of topicals containing exfoliants or α-hydroxy acids applied to the treated area following the procedure also may mitigate the risk for postprocedural hyperpigmentation.¹⁶ If hyperpigmentation does occur, use of topical melanogenesis inhibitors such as hydroquinone, kojic acid, or azelaic acid has shown some utility in practice.

Skin Rejuvenation

Nonablative fractional lasers (NAFLs) continue to be popular for treatment of photoaging. One study including 10 Asian patients (FSTs III-V) assessed the 1440-nm diode-based fractional laser for facial rejuvenation.¹⁷ After 4 sessions at 2-week intervals, 80% (8/10) of patients reported decreased skin roughness after both the second and third treatments, while 90% (9/10) had improved texture 1 month after the final procedure. Adverse effects included moderate facial edema and one case of transient hyperpigmentation.¹⁷ Another study reported a significant reduction in pore score (P<.002), with patients noting an overall improvement in skin appearance with minimal erythema, dryness, and flaking following 6 sessions at 2-week intervals using the 1440-nm diode-based fractional laser.¹⁸

The 1550-nm diode fractional laser significantly improved skin pigmentation (P<.001) and texture (P<.001) in 10 patients with FSTs II to IV following 5 sessions at 2- to 3-week intervals, with self-resolving erythema and edema posttreatment (Supplementary Table S2).¹⁹ Overall, NAFLs for the treatment of photoaging are effective with minimal adverse effects (eg, facial edema), which can be reduced with application of cold compression to the face and elevation of the head following treatment as well as the use of additional pillows during overnight sleep.

Laser Treatment for Hyperpigmentation Disorders

Melasma—The FDA recently approved fractional photothermolysis for the treatment of melasma; however, due to the risk for hyperpigmentation given its pathogenesis linked to hyperactive melanocytes, this laser is not considered a first-line therapy for melasma.²⁰ In a split-face, randomized study, 22 patients with FSTs III to V who were diagnosed with either dermal or mixed-type melasma were treated with a low-fluence Q-switched Nd:YAG laser combined with hydroquinone 2% vs hydroquinone 2% alone (Supplementary Table S3).²¹ Each patient was treated weekly for 5 consecutive weeks. The laser-treated side was found to reach an average of 92.5% improvement compared with 19.7% on the hydroquinone-only side. Three of the 22 (13.6%) patients developed mottled hypopigmentation after 5 laser treatments, and 8 (36.4%) developed confetti-type hypopigmentation. Four (18.2%) patients developed rebound hyperpigmentation, and all 22 patients experienced recurrence of melasma by 12 weeks posttreatment.²¹

First-line treatment for melasma involves the application of topical lightening agents such as hydroquinone, azelaic acid, kojic acid, retinoids, or mild topical steroids. Combining laser technology with topical medications can enhance treatment outcomes, particularly yielding positive results for patients with persistent pigmentation concerns. Notably, utilization of 650-microsecond technology with the 1064-nm Nd:YAG laser is considered superior in clinical practice, especially for patients with FSTs IV through VI.

Postinflammatory Hyperpigmentation—A retrospective evaluation of 61 patients with FSTs IV to VI with PIH treated with a 1927-nm NAFL showed a mean improvement of 43.24%, as assessed by 2 dermatologists.²² Additionally, the Nd:YAG 1064-nm 650-microsecond pulse duration laser is an emerging treatment that delivers high and low fluences between 4 J/cm² and 255 J/cm² within a single 650-microsecond pulse duration.²³ The short-pulse duration avoids overheating the skin, mitigating procedural discomfort and the risk for adverse effects commonly seen with the previous generation of low-pulsed lasers. In addition to PIH, this laser has been successfully used to treat pseudofolliculitis barbae.²⁴

Solar Lentigos—In a split-face study treating solar lentigos in Asian patients, 4 treatments with a low-pulsed KTP 532-nm laser were administered with and without a second treatment with a low-pulsed 1064-nm Nd:YAG laser.²⁵ Scoring of a modified pigment severity index and measurement of the melanin index showed that skin treated with the low-pulsed 532-nm laser alone and in combination with the low-pulsed 1064-nm Nd:YAG laser resulted in improvement at 3 months’ follow-up. However, there was no difference between the 2 sides of the face, leading the researchers to conclude that the low-pulsed 532-nm laser appears to be safe and effective for treatment of solar lentigos in Asian patients and does not require the addition of the low-pulsed 1064-nm laser.²⁵  

To avoid hyperpigmentation in patients with SOC, strict photoprotection to the treated areas should be advised. Proper cooling of the laser-treated area is required to minimize PIH, as cooling decreases tissue damage and excessive thermal injury. Test spots should be considered prior to initiation of the full laser treatment. Hydroquinone in a 4% concentration applied daily for 2 weeks preprocedure commonly is employed to reduce the risk for postprocedural hyperpigmentation in clinical practice.^26,27

Skin Tightening and Body Contouring

In general, skin-tightening and body-contouring devices are among the most sought-after procedures. Studies performed in patients with SOC are limited. Herein, we provide background on why these devices are favorable for patients with SOC and our experiences in using them. A summary of these devices can be found in Supplementary Table S4.

Radiofrequency Skin Tightening—Radiofrequency devices are utilized for skin tightening as well as mild fat reduction; they commonly are used on the abdomen, thighs, buttocks, and face.²⁸ People with SOC are more responsive to radiofrequency skin-tightening therapy due to higher baseline collagen content and dermal thickness, more sebaceous activity and skin elasticity, and more melanin content which offers protective thermal buffering.^29,30 As the radiofrequency device emits heat, penetrating deep into the dermis, it generates collagen remodeling and synthesis within 4 to 6 months posttreatment.

Nonsurgical Fat Reduction

Procedures for nonsurgical fat reduction are favorable due to minimal recovery time, manageable cost, and an in-office procedure setting. As noted previously, there are 6 FDA-indicated interventions for nonsurgical fat reduction: ultrasonography, cryolipolysis, laser lipolysis, injection lipolysis, radiofrequency lipolysis, and magnetic resonance contouring.³¹

Ultrasonography—Ultrasound devices designed for body contouring are used for skin tightening and mild fat reduction through the use of acoustic energy.³² These devices can be divided into 2 categories: high frequency and low frequency, with the high-frequency devices being the most popular. High-frequency ultrasound energy produces heat at target sites, which induces necrosis of adipocytes and stimulates collagen remodeling within the tissue matrix.³³ Tissue temperatures above 56°C stimulate adipocyte necrosis while sparing nearby nerves and vessels.²⁸ Because of the short duration of the procedure, the risk for epidermal damage is minimal. Contrary to high-frequency ultrasonography, focus-pulsed ultrasonography employs low-frequency waves to induce the mechanical disruption of adipocytes, which is generally better tolerated due to its nonthermal mechanism. The latter may be advantageous in patients with SOC due to a reduced risk for thermal injury to the epidermis. Multiple treatments often are needed at 3- to 4-week intervals, resulting in gradual improvement observed over 2 to 6 months. One study of microfocused ultrasonography in 25 Asian patients for treatment of face and neck laxity reported that skin laxity was improved or much improved in 84% (21/25) of patients following treatment.³⁴ Adverse effects were reported as mild and transient, resolving within 90 days.³⁴ Ultrasound devices also were shown to improve wrinkles, texture, and overall appearance of the skin in a 71-year-old African American woman 4 months following treatment (Figure 2). These photographs highlight the clinical utility of a microfocused ultrasound skin-tightening treatment in African American patients.

Cryolipolysis—Cryolipolysis is a noninvasive body contouring procedure that employs controlled cooling to induce subcutaneous panniculitis. Through cold-induced apoptosis of adipocytes, this procedure selectively reduces adipose tissue in localized areas such as the flank, abdomen, thighs, buttocks, back, submental area, and upper arms. The temperature used in cryolipolysis is approximately –10°C.³⁵ The lethal temperature for melanocytes is –4 °C, below which melanocyte apoptosis may be induced, resulting in depigmentation. Given the prolonged contact of the skin with a cryolipolysis device for up to 60 minutes during a body-contouring procedure, there is a risk for resultant depigmentation in darker skin types. Controlled studies are needed to fully evaluate the safety and efficacy of cryolipolysis in patients with SOC. One retrospective study of cryolipolysis applied to the abdomen and upper arm of 4122 Asian patients reported a significant (P<.05) reduction in the circumference of the abdomen and the upper-arm areas. No long-term adverse effects were reported.³⁶

Laser Lipolysis—The 1060-nm diode laser for body contouring selectively destroys adipose tissue, resulting in body contouring via thermally induced inflammation. Hyperthermic exposure for 15 minutes selectively elevates adipocyte temperature between 42°C to 47°C, which triggers apoptosis and the eventual clearance of destroyed cells from the interstitial space.³⁷ The selectivity of the 1060-nm wavelength coupled with the device’s contact cooling system preserves the overlying skin and adnexa during the procedure,³⁷ which would minimize epidermal damage that may induce dyspigmentation in patients with SOC. No notable adverse effects or dyspigmentation have been reported using this device.

Injection Lipolysis—Deoxycholic acid is an injectable adipocytolytic for the reduction of submental fat. It nonselectively lyses muscle and other adjacent nonfatty tissue. One study of 50 Indian patients demonstrated a substantial reduction of submental fat in 90% (45/50).³⁸ For each treatment, 5 mL of 30 mg/mL deoxycholic acid was injected. Serial sessions were conducted at 2-month intervals, and most (64% [32/50]) patients required 3 sessions to see a treatment effect. Adverse effects included transient swelling, lumpiness, and tenderness. A phase 2a investigation of the novel injectable small-molecule drug CBL-514 in 43 Asian and White participants found a significant improvement in the reduction in abdominal fat volume (P<.00001) and thickness (P<.0001) relative to baseline at higher doses (unit dose, 2.0 mg/cm² and 1.6 mg/cm²).³⁹ In addition to the adverse effects mentioned previously, pruritus, repeated urticaria, body rash, and fever also were reported.³⁹  

Radiofrequency Lipolysis—Radiofrequency is used for adipolysis through heat-induced apoptosis. To achieve this effect, adipose tissue must sustain a temperature of 42 °C to 45 °C for at least 15 minutes.⁴⁰ In one study, 4 treatments performed at 7-day intervals resulted in a statistically significant reduction in circumference to the treated areas of the inner and outer thighs without any reported adverse effects (P<0.001).⁴¹ Of note, there was 1 cm of distance between the applicator and the skin. The absence of direct contact with the skin is likely to reduce the risk for postprocedural complications in patients with SOC.

Magnetic Resonance Contouring—Magnetic resonance contouring with high-intensity focused electromagnetic technology is an emerging treatment modality for noninvasive body contouring. One distinguishing characteristic from other currently available noninvasive fat-­reduction therapies is that magnetic resonance may improve strength, tone, and muscle thickness.⁴² This modality is FDA approved for contouring of the buttocks and abdomen and employs electromagnetic energy to stimulate approximately 20,000 muscle contractions within a time frame of 30 minutes. Though the mechanisms causing benefits to muscular and adipose tissue have not been elucidated, current findings suggest that the contractions stimulate substantial lipolysis of adipocytes, resulting in the release of large amounts of free fatty acids that cause damage to nearby adipose tissue.⁴³ Multiple treatments are required over time to maintain effect. No major adverse effects have been reported. The likely mechanism of action of magnetic resonance contouring does not appear to pose an increased risk to patients with SOC.

Final Thoughts

One of the major roadblocks in distilling indications along with associated risks and benefits for nonsurgical cosmetic practices for patients with SOC is a void in the primary literature involving these populations. Clinical experience serves to address this deficit in combination with a thorough review of the literature. The 1064-nm Nd:YAG laser has shown clinical utility in the treatment of DPN, melanoma, and acne scars, but it poses financial constraints to the provider in comparison to modalities used for many years. Notably, NAF resurfacing is preferred for the management of acne scars in patients with SOC and continues to gain popularity for the treatment of photoaging. Regarding skin-tightening and body-contouring devices, studies performed in patients with SOC are limited and affected by factors such as small sample sizes, underrepresentation of FSTs IV through VI, short follow-up durations, and a lack of standardized outcome measures. Additionally, few studies assess pigmentary adverse effects or stratify results by skin type, which is critical given the higher risk for PIH in SOC. Ultrasound devices showed clinical utility in improvement of skin laxity, texture, and overall improvement. Patients with SOC respond well to skin-tightening devices due to the increased collagen synthesis. Regarding emerging devices for reduction of adipocytes, deoxycholic acid when injected showed notable improvement in fat reduction but also had adverse effects. As additional studies on cosmetic procedures in SOC emerge, an expansion of treatment options could be offered to this demographic group with confidence, provided proper treatment and follow-up protocols are in place.

Personal electronic devices have become more common as consumer-driven health and entertainment practices continue to increase in popularity. A wide variety of devices including smartphones, headphones and earbuds, fitness watches, and continuous glucose monitors (CGMs) allow consumers to collect data and personalize their daily activities and health practices. The global market for fitness tracking devices alone was valued at $62.03 billion in 2024 and is projected to grow to $290.85 billion by 2032.¹ Accordingly, the growing demand for continuous data tracking has led to new and prolonged skin contact with these devices, which have become emerging sources of allergic contact dermatitis (ACD). In this article, we provide a summary of the potential allergenicity of personal electronic devices with a focus on wearable devices, including clinical manifestations, reported allergens, and patch testing and management considerations (Table^2-28).

Earbuds and Headphones

Wireless earbuds and headphones are used for listening to media and may contain microphones for voice calls. Earbuds are inserted into the ears while headphones are worn over the ears with a connecting band across the scalp. These devices frequently are worn during physical activity and thus in the setting of moist sweaty environments and mechanical friction on the skin. Depending on the style of the earbuds or headphones, associated ACD may manifest as acute or chronic pruritic eczema involving the inner and/or outer ears and potentially the periauricular areas or scalp.² In a reported case of earbud ACD, the patient first presented to an otolaryngologist before being referred to a dermatologist for further evaluation and patch testing.⁹ Clinicians may be unfamiliar with these devices as a source of ACD or may potentially overlook inner ear canal manifestations, which may delay diagnosis.

Allergens reported in earbuds include (meth)acrylates,^4-6 nickel, gold,⁸ and silicone.⁹ Apple AirPods and Samsung Galaxy Buds disclose the presence of acrylates and nickel.^5,6 Cases also have been reported of ACD to gold earbud microphones⁸ and unknown allergens within silicone tips.^4,9 Acrylates, named the 2012 Allergen of the Year by the American Contact Dermatitis Society,²⁹ are used in a wide variety of consumer products as adhesives and coatings and are among the most frequently suspected headphone allergens.⁴ While fully polymerized acrylates theoretically are nonallergenic, residual acrylic monomers are potent allergens that may be found in in these products due to incomplete curing or polymer breakdown.²⁹ It remains unclear whether earbud allergen concentrations are sufficient to induce sensitization or merely elicit ACD in previously sensitized users.²⁹ Among patients with earbud ACD, the finding of inconsistent patch test reactions/cross-reactions led to the hypothesis that these headphones may contain an unidentified proprietary (meth)acrylate.⁴

Headphones, often utilized by runners and gymgoers for their comfort and fit, also have gained recent attention for their unique allergen profiles. In 2024, a case series described primary sensitization to octylisothiazolinone causing severe headphone-related ACD.³ This preservative, which is in the same family as methylchloroisothiazolinone/methylisothiazolinone, is used as a biocide in the leather or faux leather that encases the foam padding of headphones.³ Another case report highlighted ACD caused by methylisothiazolinone, methylchloroisothiazolinone, and octylisothiazolinone present in various components of a pair of headphones.² These cases are notable, as European legislation limiting the use of methylchloroisothiazolinone/methylisothiazolinone in personal care products does not apply to inclusion of isothiazolinones in other product categories, such as detergents, paints, glues, and personal electronic devices.

Mobile Phones

Mobile phones are a staple in modern society, used for a multitude of tasks including communication, internet browsing, entertainment, and activity tracking. In the early 2000s, mobile phone ACD primarily manifested on the lateral face, ears, and periauricular regions,¹² as well as the thighs from carriage in pants pockets. Early cases of mobile phone ACD were attributed to metals including chromium¹⁶ and nickel.¹⁴ At that time, lengthy and frequent phone calls with the device against the ear were thought to increase exposure to metal allergens.³⁰ More recently, as the utility of these devices has evolved, ACD has been reported to manifest on the fingers and hands associated with contact with cell phone cases, accessories, and screen protectors (Figure). In one report, a 17-year-old boy with chronic eczema of the palms was diagnosed with ACD to the rubber-related chemicals paraphenylenediamine and N-cyclohexyl-N-phenyl-4-phenylenediamine, confirmed via chemical analysis to be present in a phone case the patient used during daily gaming.¹⁷ Similarly, another case of palmar ACD resulted from thiuram rubber accelerators in a phone case.¹⁸ Most recently, a Japanese patient with a history of skin reactions to costume jewelry developed ACD involving the proximal middle finger due to exposure to nickel in a ring-grip phone case.¹¹ While the European Union has enacted regulations regarding maximum nickel leaching in products that come into direct and prolonged contact with the skin, such regulations have not been implemented in Japan or the United States.¹¹ International e-commerce makes these grips widely available, even in regions where strict metal regulations are in place. As screen time increases, it is important to consider all phone-related exposures including components of the case, screen protector, and main device body.

Watches

Smart watches and fitness bands are widely available to consumers and serve a variety of health and lifestyle functions. Features include fitness tracking, notification management, mobile payment, electrocardiography, navigation, and sleep and oxygen sensors. Multiple companies have produced hand- and wrist-based sensors for detailed wellness tracking within these categories. Allergic contact dermatitis to smart watches and wristbands manifests as eczematous lesions on the wrist (dorsal,^21,22 volar,²⁰ or circumferential involvement^23,24).

(Meth)acrylates used to adhere screen protectors, house lithium ion batteries, and bind metal to plastic have been reported to cause ACD in smart watch users.^22,25 In addition, there are at least 2 published reports of ACD to nickel in Apple Watches.^21,31 Apple, having sold more than 229 million watches worldwide, has acknowledged the presence of trace acrylates and nickel in their watches (the latter falling below European Registration, Evaluation, Authorization, and Restriction of Chemicals limits).³² Hosoki et al²⁰ identified ACD resulting from chromium exposure in the clasp of an Apple Watch band, which remains unreported by the manufacturer as a potential allergen.

Continuous Glucose Monitors

Continuous glucose monitoring systems provide users with dynamic information on their glycemic status and are associated with lower glycated hemoglobin and reduced episodes of hypoglycemia in patients with diabetes.³³ Recently, growing interest in personalized health monitoring and performance optimization has expanded CGM use to individuals without diabetes; there are 2 over-the-counter CGM options currently available in the United States.³⁴

Allergic contact dermatitis to CGMs in patients with diabetes is well characterized, manifesting as pruritic acute or chronic dermatitis at the sensor site.²⁷ To date, we are unaware of published cases of ACD associated with use of CGM in individuals without diabetes; however, wearing a CGM during athletic activities and sweating could potentially increase adhesive degradation and/or penetration of allergens in the skin.⁶

Isobornyl acrylate, named the 2020 Allergen of the Year,³⁵ is the most well-known contact allergen in glucose sensors.^36,33 Initially suspected as a component of the CGM skin adhesive, isobornyl acrylate was found to leach from the device body onto the skin in users of one CGM device.³⁶ Other reported allergens in CGM devices include colophony and related rosin derivatives, ethyl cyanoacrylate, and several chemicals that are not available as commercial patch test substances.²⁷ Understanding these potential allergens is important for patch testing considerations as CGM use increases in individuals without diabetes.

Final Thoughts

Allergic contact dermatitis to personal electronic devices including wearables, sensors, and fitness trackers is an emerging problem that should be considered in cases of dermatitis of the wrists, hands, face, ears, or in any area that comes into contact with such devices. Although in-depth studies are lacking, certain wearable devices appear to introduce continuous, low-level allergen exposure that may be below the sensitization threshold but still is capable of eliciting ACD in previously sensitized users.^21,26 Furthermore, increased allergen exposure is facilitated by prolonged skin contact, mechanical friction, and sweat.

Comprehensive patch testing often is necessary to diagnose cases of ACD to personal electronic devices.³³ The thin-layer rapid use epicutaneous (T.R.U.E.) test does not include (meth)acrylates, which repeatedly have come up as culprit allergens.³⁷ Isobornyl acrylate, a key allergen related to CGMs, is absent from standard patch test series.²⁶ Nickel remains a common culprit in these devices despite adherence to European regulations.²¹ Since there is no obligation for manufacturers to declare all possible ingredients, chemical analysis can be useful in identifying potential allergens and directing the patch test strategy, but this is not feasible in general clinical practice outside the research setting.²

Following patch testing, patient education is essential to managing personal electronic device—induced ACD. Informed patients should switch to products that do not contain their triggers—although this may be more easily said than done, since incomplete ingredient disclosure from manufacturers may necessitate a frustrating and expensive trial-and-error approach. As wearable technology proliferates, device composition and potential contact allergen transparency must be prioritized by manufacturers and regulatory bodies. Until then, clinicians should stay on their toes regarding new and emerging clinical presentations and contact allergens in hopes of improving patient outcomes.

Personal electronic devices have become more common as consumer-driven health and entertainment practices continue to increase in popularity. A wide variety of devices including smartphones, headphones and earbuds, fitness watches, and continuous glucose monitors (CGMs) allow consumers to collect data and personalize their daily activities and health practices. The global market for fitness tracking devices alone was valued at $62.03 billion in 2024 and is projected to grow to $290.85 billion by 2032.¹ Accordingly, the growing demand for continuous data tracking has led to new and prolonged skin contact with these devices, which have become emerging sources of allergic contact dermatitis (ACD). In this article, we provide a summary of the potential allergenicity of personal electronic devices with a focus on wearable devices, including clinical manifestations, reported allergens, and patch testing and management considerations (Table^2-28).

Earbuds and Headphones

Wireless earbuds and headphones are used for listening to media and may contain microphones for voice calls. Earbuds are inserted into the ears while headphones are worn over the ears with a connecting band across the scalp. These devices frequently are worn during physical activity and thus in the setting of moist sweaty environments and mechanical friction on the skin. Depending on the style of the earbuds or headphones, associated ACD may manifest as acute or chronic pruritic eczema involving the inner and/or outer ears and potentially the periauricular areas or scalp.² In a reported case of earbud ACD, the patient first presented to an otolaryngologist before being referred to a dermatologist for further evaluation and patch testing.⁹ Clinicians may be unfamiliar with these devices as a source of ACD or may potentially overlook inner ear canal manifestations, which may delay diagnosis.

Allergens reported in earbuds include (meth)acrylates,^4-6 nickel, gold,⁸ and silicone.⁹ Apple AirPods and Samsung Galaxy Buds disclose the presence of acrylates and nickel.^5,6 Cases also have been reported of ACD to gold earbud microphones⁸ and unknown allergens within silicone tips.^4,9 Acrylates, named the 2012 Allergen of the Year by the American Contact Dermatitis Society,²⁹ are used in a wide variety of consumer products as adhesives and coatings and are among the most frequently suspected headphone allergens.⁴ While fully polymerized acrylates theoretically are nonallergenic, residual acrylic monomers are potent allergens that may be found in in these products due to incomplete curing or polymer breakdown.²⁹ It remains unclear whether earbud allergen concentrations are sufficient to induce sensitization or merely elicit ACD in previously sensitized users.²⁹ Among patients with earbud ACD, the finding of inconsistent patch test reactions/cross-reactions led to the hypothesis that these headphones may contain an unidentified proprietary (meth)acrylate.⁴

Headphones, often utilized by runners and gymgoers for their comfort and fit, also have gained recent attention for their unique allergen profiles. In 2024, a case series described primary sensitization to octylisothiazolinone causing severe headphone-related ACD.³ This preservative, which is in the same family as methylchloroisothiazolinone/methylisothiazolinone, is used as a biocide in the leather or faux leather that encases the foam padding of headphones.³ Another case report highlighted ACD caused by methylisothiazolinone, methylchloroisothiazolinone, and octylisothiazolinone present in various components of a pair of headphones.² These cases are notable, as European legislation limiting the use of methylchloroisothiazolinone/methylisothiazolinone in personal care products does not apply to inclusion of isothiazolinones in other product categories, such as detergents, paints, glues, and personal electronic devices.

Mobile Phones

Mobile phones are a staple in modern society, used for a multitude of tasks including communication, internet browsing, entertainment, and activity tracking. In the early 2000s, mobile phone ACD primarily manifested on the lateral face, ears, and periauricular regions,¹² as well as the thighs from carriage in pants pockets. Early cases of mobile phone ACD were attributed to metals including chromium¹⁶ and nickel.¹⁴ At that time, lengthy and frequent phone calls with the device against the ear were thought to increase exposure to metal allergens.³⁰ More recently, as the utility of these devices has evolved, ACD has been reported to manifest on the fingers and hands associated with contact with cell phone cases, accessories, and screen protectors (Figure). In one report, a 17-year-old boy with chronic eczema of the palms was diagnosed with ACD to the rubber-related chemicals paraphenylenediamine and N-cyclohexyl-N-phenyl-4-phenylenediamine, confirmed via chemical analysis to be present in a phone case the patient used during daily gaming.¹⁷ Similarly, another case of palmar ACD resulted from thiuram rubber accelerators in a phone case.¹⁸ Most recently, a Japanese patient with a history of skin reactions to costume jewelry developed ACD involving the proximal middle finger due to exposure to nickel in a ring-grip phone case.¹¹ While the European Union has enacted regulations regarding maximum nickel leaching in products that come into direct and prolonged contact with the skin, such regulations have not been implemented in Japan or the United States.¹¹ International e-commerce makes these grips widely available, even in regions where strict metal regulations are in place. As screen time increases, it is important to consider all phone-related exposures including components of the case, screen protector, and main device body.

Watches

Smart watches and fitness bands are widely available to consumers and serve a variety of health and lifestyle functions. Features include fitness tracking, notification management, mobile payment, electrocardiography, navigation, and sleep and oxygen sensors. Multiple companies have produced hand- and wrist-based sensors for detailed wellness tracking within these categories. Allergic contact dermatitis to smart watches and wristbands manifests as eczematous lesions on the wrist (dorsal,^21,22 volar,²⁰ or circumferential involvement^23,24).

(Meth)acrylates used to adhere screen protectors, house lithium ion batteries, and bind metal to plastic have been reported to cause ACD in smart watch users.^22,25 In addition, there are at least 2 published reports of ACD to nickel in Apple Watches.^21,31 Apple, having sold more than 229 million watches worldwide, has acknowledged the presence of trace acrylates and nickel in their watches (the latter falling below European Registration, Evaluation, Authorization, and Restriction of Chemicals limits).³² Hosoki et al²⁰ identified ACD resulting from chromium exposure in the clasp of an Apple Watch band, which remains unreported by the manufacturer as a potential allergen.

Continuous Glucose Monitors

Continuous glucose monitoring systems provide users with dynamic information on their glycemic status and are associated with lower glycated hemoglobin and reduced episodes of hypoglycemia in patients with diabetes.³³ Recently, growing interest in personalized health monitoring and performance optimization has expanded CGM use to individuals without diabetes; there are 2 over-the-counter CGM options currently available in the United States.³⁴

Allergic contact dermatitis to CGMs in patients with diabetes is well characterized, manifesting as pruritic acute or chronic dermatitis at the sensor site.²⁷ To date, we are unaware of published cases of ACD associated with use of CGM in individuals without diabetes; however, wearing a CGM during athletic activities and sweating could potentially increase adhesive degradation and/or penetration of allergens in the skin.⁶

Isobornyl acrylate, named the 2020 Allergen of the Year,³⁵ is the most well-known contact allergen in glucose sensors.^36,33 Initially suspected as a component of the CGM skin adhesive, isobornyl acrylate was found to leach from the device body onto the skin in users of one CGM device.³⁶ Other reported allergens in CGM devices include colophony and related rosin derivatives, ethyl cyanoacrylate, and several chemicals that are not available as commercial patch test substances.²⁷ Understanding these potential allergens is important for patch testing considerations as CGM use increases in individuals without diabetes.

Final Thoughts

Allergic contact dermatitis to personal electronic devices including wearables, sensors, and fitness trackers is an emerging problem that should be considered in cases of dermatitis of the wrists, hands, face, ears, or in any area that comes into contact with such devices. Although in-depth studies are lacking, certain wearable devices appear to introduce continuous, low-level allergen exposure that may be below the sensitization threshold but still is capable of eliciting ACD in previously sensitized users.^21,26 Furthermore, increased allergen exposure is facilitated by prolonged skin contact, mechanical friction, and sweat.

Comprehensive patch testing often is necessary to diagnose cases of ACD to personal electronic devices.³³ The thin-layer rapid use epicutaneous (T.R.U.E.) test does not include (meth)acrylates, which repeatedly have come up as culprit allergens.³⁷ Isobornyl acrylate, a key allergen related to CGMs, is absent from standard patch test series.²⁶ Nickel remains a common culprit in these devices despite adherence to European regulations.²¹ Since there is no obligation for manufacturers to declare all possible ingredients, chemical analysis can be useful in identifying potential allergens and directing the patch test strategy, but this is not feasible in general clinical practice outside the research setting.²

Following patch testing, patient education is essential to managing personal electronic device—induced ACD. Informed patients should switch to products that do not contain their triggers—although this may be more easily said than done, since incomplete ingredient disclosure from manufacturers may necessitate a frustrating and expensive trial-and-error approach. As wearable technology proliferates, device composition and potential contact allergen transparency must be prioritized by manufacturers and regulatory bodies. Until then, clinicians should stay on their toes regarding new and emerging clinical presentations and contact allergens in hopes of improving patient outcomes.

Personal electronic devices have become more common as consumer-driven health and entertainment practices continue to increase in popularity. A wide variety of devices including smartphones, headphones and earbuds, fitness watches, and continuous glucose monitors (CGMs) allow consumers to collect data and personalize their daily activities and health practices. The global market for fitness tracking devices alone was valued at $62.03 billion in 2024 and is projected to grow to $290.85 billion by 2032.¹ Accordingly, the growing demand for continuous data tracking has led to new and prolonged skin contact with these devices, which have become emerging sources of allergic contact dermatitis (ACD). In this article, we provide a summary of the potential allergenicity of personal electronic devices with a focus on wearable devices, including clinical manifestations, reported allergens, and patch testing and management considerations (Table^2-28).

Earbuds and Headphones

Wireless earbuds and headphones are used for listening to media and may contain microphones for voice calls. Earbuds are inserted into the ears while headphones are worn over the ears with a connecting band across the scalp. These devices frequently are worn during physical activity and thus in the setting of moist sweaty environments and mechanical friction on the skin. Depending on the style of the earbuds or headphones, associated ACD may manifest as acute or chronic pruritic eczema involving the inner and/or outer ears and potentially the periauricular areas or scalp.² In a reported case of earbud ACD, the patient first presented to an otolaryngologist before being referred to a dermatologist for further evaluation and patch testing.⁹ Clinicians may be unfamiliar with these devices as a source of ACD or may potentially overlook inner ear canal manifestations, which may delay diagnosis.

Allergens reported in earbuds include (meth)acrylates,^4-6 nickel, gold,⁸ and silicone.⁹ Apple AirPods and Samsung Galaxy Buds disclose the presence of acrylates and nickel.^5,6 Cases also have been reported of ACD to gold earbud microphones⁸ and unknown allergens within silicone tips.^4,9 Acrylates, named the 2012 Allergen of the Year by the American Contact Dermatitis Society,²⁹ are used in a wide variety of consumer products as adhesives and coatings and are among the most frequently suspected headphone allergens.⁴ While fully polymerized acrylates theoretically are nonallergenic, residual acrylic monomers are potent allergens that may be found in in these products due to incomplete curing or polymer breakdown.²⁹ It remains unclear whether earbud allergen concentrations are sufficient to induce sensitization or merely elicit ACD in previously sensitized users.²⁹ Among patients with earbud ACD, the finding of inconsistent patch test reactions/cross-reactions led to the hypothesis that these headphones may contain an unidentified proprietary (meth)acrylate.⁴

Headphones, often utilized by runners and gymgoers for their comfort and fit, also have gained recent attention for their unique allergen profiles. In 2024, a case series described primary sensitization to octylisothiazolinone causing severe headphone-related ACD.³ This preservative, which is in the same family as methylchloroisothiazolinone/methylisothiazolinone, is used as a biocide in the leather or faux leather that encases the foam padding of headphones.³ Another case report highlighted ACD caused by methylisothiazolinone, methylchloroisothiazolinone, and octylisothiazolinone present in various components of a pair of headphones.² These cases are notable, as European legislation limiting the use of methylchloroisothiazolinone/methylisothiazolinone in personal care products does not apply to inclusion of isothiazolinones in other product categories, such as detergents, paints, glues, and personal electronic devices.

Mobile Phones

Mobile phones are a staple in modern society, used for a multitude of tasks including communication, internet browsing, entertainment, and activity tracking. In the early 2000s, mobile phone ACD primarily manifested on the lateral face, ears, and periauricular regions,¹² as well as the thighs from carriage in pants pockets. Early cases of mobile phone ACD were attributed to metals including chromium¹⁶ and nickel.¹⁴ At that time, lengthy and frequent phone calls with the device against the ear were thought to increase exposure to metal allergens.³⁰ More recently, as the utility of these devices has evolved, ACD has been reported to manifest on the fingers and hands associated with contact with cell phone cases, accessories, and screen protectors (Figure). In one report, a 17-year-old boy with chronic eczema of the palms was diagnosed with ACD to the rubber-related chemicals paraphenylenediamine and N-cyclohexyl-N-phenyl-4-phenylenediamine, confirmed via chemical analysis to be present in a phone case the patient used during daily gaming.¹⁷ Similarly, another case of palmar ACD resulted from thiuram rubber accelerators in a phone case.¹⁸ Most recently, a Japanese patient with a history of skin reactions to costume jewelry developed ACD involving the proximal middle finger due to exposure to nickel in a ring-grip phone case.¹¹ While the European Union has enacted regulations regarding maximum nickel leaching in products that come into direct and prolonged contact with the skin, such regulations have not been implemented in Japan or the United States.¹¹ International e-commerce makes these grips widely available, even in regions where strict metal regulations are in place. As screen time increases, it is important to consider all phone-related exposures including components of the case, screen protector, and main device body.

Watches

Smart watches and fitness bands are widely available to consumers and serve a variety of health and lifestyle functions. Features include fitness tracking, notification management, mobile payment, electrocardiography, navigation, and sleep and oxygen sensors. Multiple companies have produced hand- and wrist-based sensors for detailed wellness tracking within these categories. Allergic contact dermatitis to smart watches and wristbands manifests as eczematous lesions on the wrist (dorsal,^21,22 volar,²⁰ or circumferential involvement^23,24).

(Meth)acrylates used to adhere screen protectors, house lithium ion batteries, and bind metal to plastic have been reported to cause ACD in smart watch users.^22,25 In addition, there are at least 2 published reports of ACD to nickel in Apple Watches.^21,31 Apple, having sold more than 229 million watches worldwide, has acknowledged the presence of trace acrylates and nickel in their watches (the latter falling below European Registration, Evaluation, Authorization, and Restriction of Chemicals limits).³² Hosoki et al²⁰ identified ACD resulting from chromium exposure in the clasp of an Apple Watch band, which remains unreported by the manufacturer as a potential allergen.

Continuous Glucose Monitors

Continuous glucose monitoring systems provide users with dynamic information on their glycemic status and are associated with lower glycated hemoglobin and reduced episodes of hypoglycemia in patients with diabetes.³³ Recently, growing interest in personalized health monitoring and performance optimization has expanded CGM use to individuals without diabetes; there are 2 over-the-counter CGM options currently available in the United States.³⁴

Allergic contact dermatitis to CGMs in patients with diabetes is well characterized, manifesting as pruritic acute or chronic dermatitis at the sensor site.²⁷ To date, we are unaware of published cases of ACD associated with use of CGM in individuals without diabetes; however, wearing a CGM during athletic activities and sweating could potentially increase adhesive degradation and/or penetration of allergens in the skin.⁶

Isobornyl acrylate, named the 2020 Allergen of the Year,³⁵ is the most well-known contact allergen in glucose sensors.^36,33 Initially suspected as a component of the CGM skin adhesive, isobornyl acrylate was found to leach from the device body onto the skin in users of one CGM device.³⁶ Other reported allergens in CGM devices include colophony and related rosin derivatives, ethyl cyanoacrylate, and several chemicals that are not available as commercial patch test substances.²⁷ Understanding these potential allergens is important for patch testing considerations as CGM use increases in individuals without diabetes.

Final Thoughts

Allergic contact dermatitis to personal electronic devices including wearables, sensors, and fitness trackers is an emerging problem that should be considered in cases of dermatitis of the wrists, hands, face, ears, or in any area that comes into contact with such devices. Although in-depth studies are lacking, certain wearable devices appear to introduce continuous, low-level allergen exposure that may be below the sensitization threshold but still is capable of eliciting ACD in previously sensitized users.^21,26 Furthermore, increased allergen exposure is facilitated by prolonged skin contact, mechanical friction, and sweat.

Comprehensive patch testing often is necessary to diagnose cases of ACD to personal electronic devices.³³ The thin-layer rapid use epicutaneous (T.R.U.E.) test does not include (meth)acrylates, which repeatedly have come up as culprit allergens.³⁷ Isobornyl acrylate, a key allergen related to CGMs, is absent from standard patch test series.²⁶ Nickel remains a common culprit in these devices despite adherence to European regulations.²¹ Since there is no obligation for manufacturers to declare all possible ingredients, chemical analysis can be useful in identifying potential allergens and directing the patch test strategy, but this is not feasible in general clinical practice outside the research setting.²

Following patch testing, patient education is essential to managing personal electronic device—induced ACD. Informed patients should switch to products that do not contain their triggers—although this may be more easily said than done, since incomplete ingredient disclosure from manufacturers may necessitate a frustrating and expensive trial-and-error approach. As wearable technology proliferates, device composition and potential contact allergen transparency must be prioritized by manufacturers and regulatory bodies. Until then, clinicians should stay on their toes regarding new and emerging clinical presentations and contact allergens in hopes of improving patient outcomes.

Practice Gap

Many dermatology practices utilize pens and markers to label biopsy specimen containers, but the ink may have variable susceptibility to fading and smearing when exposed to moisture before processing. Specimen containers often are placed in plastic bags for transport. If formalin accidentally spills into the bag during this time, the labels may be exposed to moisture for hours, overnight, or even over a weekend. Effective labeling with formalin-resistant ink is crucial for maintaining the clarity of anatomic location and planning treatment, especially when multiple samples are obtained.

The Technique

We tested 12 pens and markers commonly used when labeling specimen containers to determine their susceptibility to fading due to accidental formalin exposure (Figure). Various inks were allowed to dry on sample specimen labels for 5 minutes before a thin layer of 10% buffered formalin was evenly distributed over the dried ink. Photographs of the labels were taken at baseline as well as 15 minutes, 1 hour, 3 hours, and 24 hours after formalin exposure.

Fading was observed in both the skin marker and gel panes after 15 minutes and peaked after 1 hour. Gel pens were most susceptible to fading on exposure to formalin, and the level of fading varied by ink color, with certain colors disappearing almost entirely (Figure). The solvent-resistant marker had a robust defense to formalin, as did both ballpoint pens.

Practice Implications

Given our findings, dermatology practices should avoid using gel pens to label specimen containers. Solvent-resistant markers performed as expected; however, ballpoint pens appeared to withstand formalin exposure to a similar degree and often are more readily available. Labeling biopsy specimens with an appropriate ink ensures that each sample is clearly identified with the appropriate anatomic location and any other relevant patient information.

Practice Gap

Many dermatology practices utilize pens and markers to label biopsy specimen containers, but the ink may have variable susceptibility to fading and smearing when exposed to moisture before processing. Specimen containers often are placed in plastic bags for transport. If formalin accidentally spills into the bag during this time, the labels may be exposed to moisture for hours, overnight, or even over a weekend. Effective labeling with formalin-resistant ink is crucial for maintaining the clarity of anatomic location and planning treatment, especially when multiple samples are obtained.

The Technique

We tested 12 pens and markers commonly used when labeling specimen containers to determine their susceptibility to fading due to accidental formalin exposure (Figure). Various inks were allowed to dry on sample specimen labels for 5 minutes before a thin layer of 10% buffered formalin was evenly distributed over the dried ink. Photographs of the labels were taken at baseline as well as 15 minutes, 1 hour, 3 hours, and 24 hours after formalin exposure.

Fading was observed in both the skin marker and gel panes after 15 minutes and peaked after 1 hour. Gel pens were most susceptible to fading on exposure to formalin, and the level of fading varied by ink color, with certain colors disappearing almost entirely (Figure). The solvent-resistant marker had a robust defense to formalin, as did both ballpoint pens.

Practice Implications

Given our findings, dermatology practices should avoid using gel pens to label specimen containers. Solvent-resistant markers performed as expected; however, ballpoint pens appeared to withstand formalin exposure to a similar degree and often are more readily available. Labeling biopsy specimens with an appropriate ink ensures that each sample is clearly identified with the appropriate anatomic location and any other relevant patient information.

Practice Gap

Many dermatology practices utilize pens and markers to label biopsy specimen containers, but the ink may have variable susceptibility to fading and smearing when exposed to moisture before processing. Specimen containers often are placed in plastic bags for transport. If formalin accidentally spills into the bag during this time, the labels may be exposed to moisture for hours, overnight, or even over a weekend. Effective labeling with formalin-resistant ink is crucial for maintaining the clarity of anatomic location and planning treatment, especially when multiple samples are obtained.

The Technique

We tested 12 pens and markers commonly used when labeling specimen containers to determine their susceptibility to fading due to accidental formalin exposure (Figure). Various inks were allowed to dry on sample specimen labels for 5 minutes before a thin layer of 10% buffered formalin was evenly distributed over the dried ink. Photographs of the labels were taken at baseline as well as 15 minutes, 1 hour, 3 hours, and 24 hours after formalin exposure.

Fading was observed in both the skin marker and gel panes after 15 minutes and peaked after 1 hour. Gel pens were most susceptible to fading on exposure to formalin, and the level of fading varied by ink color, with certain colors disappearing almost entirely (Figure). The solvent-resistant marker had a robust defense to formalin, as did both ballpoint pens.

Practice Implications

Given our findings, dermatology practices should avoid using gel pens to label specimen containers. Solvent-resistant markers performed as expected; however, ballpoint pens appeared to withstand formalin exposure to a similar degree and often are more readily available. Labeling biopsy specimens with an appropriate ink ensures that each sample is clearly identified with the appropriate anatomic location and any other relevant patient information.