Article

Clinical advances in myasthenia gravis from the 2023 American Academy of Neurology (AAN) Annual Meeting include the association between fatigue and disease severity and promising results from three ongoing trials of novel therapies, as reported by Dr Nicholas Silvestri, from the University at Buffalo, Buffalo, New York. 

Dr Silvestri begins by discussing a study of autoantibodies in patients with seronegative disease, which highlighted the potential for impaired B-cell tolerance, and goes on to examine research underscoring the association between fatigue and disease severity, as well as anxiety and depression. 

Moving on to novel therapies, Dr Silvestri reviews a combined analysis of three trials of rozanolixizumab, which demonstrated the drug's encouraging efficacy and favorable safety profile. 

Next, he turns to the ADAPT+ trial, which showed that efgartigimod continued to have an improved clinical response after patients rolled over from the initial ADAPT trial to ADAPT+, with no new safety signals apparent. 

Finally, Dr Silvestri looks at data from the postmarketing registry of eculizumab, which revealed how a significant proportion of patients were able discontinue or reduce their other medications once they started the drug. 

--

Nicholas J. Silvestri, MD, Associate Professor, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 

Nicholas J. Silvestri, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: argenx; Alexion; Immunovant; UCB 

Serve(d) as a speaker or a member of a speakers bureau for: argenx; Alexion 

Clinical advances in myasthenia gravis from the 2023 American Academy of Neurology (AAN) Annual Meeting include the association between fatigue and disease severity and promising results from three ongoing trials of novel therapies, as reported by Dr Nicholas Silvestri, from the University at Buffalo, Buffalo, New York. 

Dr Silvestri begins by discussing a study of autoantibodies in patients with seronegative disease, which highlighted the potential for impaired B-cell tolerance, and goes on to examine research underscoring the association between fatigue and disease severity, as well as anxiety and depression. 

Moving on to novel therapies, Dr Silvestri reviews a combined analysis of three trials of rozanolixizumab, which demonstrated the drug's encouraging efficacy and favorable safety profile. 

Next, he turns to the ADAPT+ trial, which showed that efgartigimod continued to have an improved clinical response after patients rolled over from the initial ADAPT trial to ADAPT+, with no new safety signals apparent. 

Finally, Dr Silvestri looks at data from the postmarketing registry of eculizumab, which revealed how a significant proportion of patients were able discontinue or reduce their other medications once they started the drug. 

--

Nicholas J. Silvestri, MD, Associate Professor, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 

Nicholas J. Silvestri, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: argenx; Alexion; Immunovant; UCB 

Serve(d) as a speaker or a member of a speakers bureau for: argenx; Alexion 

Clinical advances in myasthenia gravis from the 2023 American Academy of Neurology (AAN) Annual Meeting include the association between fatigue and disease severity and promising results from three ongoing trials of novel therapies, as reported by Dr Nicholas Silvestri, from the University at Buffalo, Buffalo, New York. 

Dr Silvestri begins by discussing a study of autoantibodies in patients with seronegative disease, which highlighted the potential for impaired B-cell tolerance, and goes on to examine research underscoring the association between fatigue and disease severity, as well as anxiety and depression. 

Moving on to novel therapies, Dr Silvestri reviews a combined analysis of three trials of rozanolixizumab, which demonstrated the drug's encouraging efficacy and favorable safety profile. 

Next, he turns to the ADAPT+ trial, which showed that efgartigimod continued to have an improved clinical response after patients rolled over from the initial ADAPT trial to ADAPT+, with no new safety signals apparent. 

Finally, Dr Silvestri looks at data from the postmarketing registry of eculizumab, which revealed how a significant proportion of patients were able discontinue or reduce their other medications once they started the drug. 

--

Nicholas J. Silvestri, MD, Associate Professor, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 

Nicholas J. Silvestri, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: argenx; Alexion; Immunovant; UCB 

Serve(d) as a speaker or a member of a speakers bureau for: argenx; Alexion 

Throughout the COVID-19 pandemic, health care professionals (HCPs), including emergency medicine physicians and hospitalists, have been continuously challenged to maintain an up-to-date clinical practice on COVID-19 therapeutics as new evidence emerged.^1,2 In the early part of the pandemic, these included not only appropriate and time-sensitive prescriptions of COVID-19 therapeutics, such as remdesivir and dexamethasone, but also judicious use of empiric antibiotics given the low prevalence for bacterial coinfection in early disease.^3-6 Alongside this, curbing the excessive laboratory testing of these patients during the pandemic was important not only to minimize costs but also to reduce potential iatrogenic harm and extended length of stay (LOS).⁷

At the beginning of the pandemic in March 2020 at the US Department of Veterans Affairs (VA) North Texas Health Care System (VANTHCS) Dallas VA Medical Center (DVAMC), we attempted to provide therapeutic guidance for physicians primarily through direct infectious disease (ID) consultation (in-person or electronic).⁸ This was secondarily supported by a pharmacist and ID physician–curated “living guidance” document on COVID-19 care accessible to all physicians through the DVAMC electronic health record (EHR) and intranet.

As the alpha variant (lineage B.1.1.7) of COVID-19 began spreading throughout North Texas in the winter of 2020, we implemented a targeted educational intervention toward the hospitalist group taking care of patients with COVID-19 with the primary goal of improving the accuracy of COVID-19 therapeutics while minimizing the consultative burden on ID clinical and pharmacy staff. This initiative consisted of (1) proactive guideline dissemination through email and text messages; (2) virtual didactics; and (3) physician reminders during the consultation process. Our ultimate aims were to improve hospitalist-led appropriate prescriptions of remdesivir and dexamethasone, reducing empiric antibiotic days of therapy in patients with COVID-19 at low risk of bacterial coinfection, and reducing laboratory orders that were not indicated for the management of these patients. Following this intervention and the resolution of the second wave, we retrospectively assessed the temporal trends of COVID-19 practices by hospitalists and associated patterns of ID consultation in the DVAMC from October 1, 2020, to March 31, 2021.

METHODS

The educational intervention was carried out at the DVAMC, a 1A high complex facility with more than 200 inpatient beds and part of the VANTHCS. During the study period, patients admitted with COVID-19 were located either on a closed floor (managed by the hospitalist team) or in a closed intensive care unit (ICU) (managed by the pulmonary/critical care team) contingent on the level of care or oxygen supplementation required. ID and other subspecialties provided consultation services as requested by hospitalists or ICU teams either electronically or in person. During the study period, 66 hospitalists were involved in the care of the patients: 59 (89.5%) permanent staff, 4 (6.0%) fee-basis physicians, and 3 (4.5%) moonlighting fellows.

Educational Initiative

We delivered educational sessions to the hospitalists, using collaboration software with video meeting capability every 1 to 2 months beginning in December 2020. An additional session focused on reducing empiric antibiotic prescriptions was also delivered to the emergency medicine department, based on feedback from the hospitalist group. The content for the educational sessions came from informal surveys of both ID trainees assigned to the consultation service and hospitalists, covering the following topics: understanding the stages of COVID-19 illness (virologic replication vs inflammatory) and rationales for therapy; assessing disease severity; indications and use of remdesivir; indications and use of dexamethasone; assessing for bacterial coinfections; when an ID consultation is required; management algorithm for COVID-19; and locating guidelines on the intranet. About 15 to 20 physicians participated in each session. In addition, slides of these didactics and updated institutional COVID-19 guidelines were disseminated to the hospitalist group via email and text messaging. We also linked the intranet institution guidelines in our communication, including a revised user-friendly flowchart (eAppendix).

Laboratory Stewardship Initiative

Laboratory stewardship initiatives were implemented by modifying suggested orders on the admission of patients with COVID-19 and directly educating hospitalist and emergency medicine physicians on evidence-based laboratory orders. At the beginning of the pandemic, a broad admission order set was established at DVAMC, based on the then limited knowledge of the course of infection with COVID-19. This order set allowed the admitting physicians to efficiently order laboratory tests for patients, especially during the demanding increase in patient volume experienced by DVAMC.

As new evidence emerged during the pandemic, many of the laboratory orders were reviewed for clinical utility during care for the patient with COVID-19 per the latest guidance. In December 2020, the admission orders for patients with COVID-19 were revised to reflect better laboratory stewardship to reduce cost and harm. The ID section revised the laboratory orders and disseminated the new order set to admitting physicians. Specifically, the admission order set removed the following laboratory tests available for selection: routine blood cultures, interleukin 6 (IL-6) level, and Legionella sputum culture. These laboratory orders were removed based on the lack of supporting evidence in persons admitted with COVID-19.⁹ In addition to modification of the admission order set, educational sessions were held with hospitalists to disseminate knowledge of the new changes and address any concerns.

Observations of Care

This study was approved by the VANTHCS Institutional Review Board (protocol code 20-047). Records were retrospectively reviewed for patients admitted to DVAMC for COVID-19 under hospitalist care (patients admitted directly to the ICU were excluded) from October 1, 2020, to March 31, 2021. Age, sex, race and ethnicity, and comorbidities were collected from the EHR. In addition clinical measures such as maximum oxygen requirement during admission (none, nasal cannula of 2-4 L/min, high flow/bilevel positive airway pressure [BiPAP] or mechanical ventilation), proven presence of coinfection (defined as the isolation of a probable pathogen in pure culture and/or clinically determined by ID specialist evaluation), and the average LOS also were collected. For laboratory stewardship data, a retrospective chart review was conducted to determine the total number of blood cultures obtained within 24 hours of admission per month during the study period. Both IL-6 levels and Legionella sputum culture data were collected as the total number of laboratory orders per month, as it was assumed that most of these orders were obtained for patients admitted with COVID-19.

Individual patient-level data were extracted to calculate monthly percentages of ID consultations for COVID-19 by the hospitalist team, adherence to institutional guidelines for dexamethasone and remdesivir prescriptions, and empiric antibiotic prescriptions for patients with COVID-19, including use of a priori adjudication criteria to determine justified vs unjustified empiric use. These criteria included asymmetric chest X-ray infiltrates concerning for bacterial pneumonia; peripheral white blood cell count > 11 K/μL; critical respiratory failure in the emergency department (ED) and being transferred to the ICU; and ID consultation recommended. Because the total number of antibiotics was not being analyzed but rather just the use of antibiotics for the justified and unjustified groups, antibiotic days were reported as the length of therapy (LOT).¹⁰ A subset analysis was performed on antibiotic prescriptions by the hospitalist group focusing on those with mild-to-moderate oxygen requirements (no high flow, noninvasive or invasive ventilatory methods) and excluding infections with a proven microbiologic entity.

Differences in demographic and clinical characteristics of patients with COVID-19 admitted from October 1, 2020, to March 31, 2021, were assessed using ANOVA, χ², and Kruskal-Wallis test. χ² was used to compare the difference in total laboratory orders for routine blood cultures, IL-6 levels, and Legionella sputum cultures between pre-intervention (October to December 2020) and postintervention (January to March 2021). These pre- and postintervention periods were determined based on the timing of revised admission orders in the EHR and initiation of focused educational sessions starting in late December 2020 and early January 2021. Linear regressions were used to examine the possible 6-month trend of the percentage of patients receiving ID consultation for appropriate dexamethasone prescriptions, appropriate remdesivir prescriptions, appropriate antibiotic coadministration, and mean number of antibiotic days per patient. Linear and logistic regression were also used to assess the trend in LOS over the 6 months while adjusting for age, race and ethnicity, sex, and coinfections. All analyses were performed using SAS 9.4. Statistical significance was defined as P < .05.

RESULTS

From October 1, 2020, to March 31, 2021, there were 565 admissions for COVID-19, which peaked in January 2021 with 163. Analysis of the patient characteristics showed no statistically significant difference for age, sex, oxygen requirements during admission, or proven presence of coinfection between the months of interest (Table 1).

The number of blood cultures obtained in the first 24 hours of admission significantly decreased from 58.1% of admissions in October 2020 to 34.8% of admissions in March 2021 (P < .01) (Table 2).

DISCUSSION

As the COVID-19 pandemic has evolved, the ability to enact up-to-date guidance is crucial to streamlining patient care, improving time to COVID-19–specific therapies, and minimizing the burden on subspecialty consultation services. At DVAMC, we initiated a targeted and deliberate educational effort directed toward hospitalist and ED groups combined with a laboratory stewardship effort over 6 months to improve the implementation of COVID-19 therapeutics, reduce empiric antibiotic use without reliance on ID consultation services, and reduce the number of unnecessary laboratory orders for admitted patients with COVID-19. During this time, we observed modest but statistically significant improvements in the accuracy of dexamethasone and remdesivir prescribing. In addition, we observed statistically significant improvement in the average LOT per patient regarding antibiotic use and overall decreased LOS. These improvements were seen in parallel with decreasing requests for ID consultation, suggesting that they were attributable in part to increasing self-confidence and efficacy in COVID-19 practices by the hospitalist group. Modification of the COVID-19 admission order set for our facility resulted in substantial decreases in orders for blood cultures, IL-6 levels, and sputum cultures for Legionella.

ID consultation, either in person or remotely, has been instrumental in assisting physicians in COVID-19 management and has been shown to reduce morbidity, mortality, and patient LOS in other infections.^11,12 However, in scenarios where ID consultation is not available or in limited supply, accessibility, familiarity, and confidence of primary practitioners to use therapeutic guidance material are integral. Frequent and accessible guidance for the management of COVID-19 has been provided by the National Institutes of Health and the Infectious Diseases Society of America.^13,14 Other mechanisms of assisting physicians in both test ordering and therapeutics include clinical decision support tools built into the EHR and the use of a smartphone digital application.¹⁵ Guidance needs to be adapted to the context of the facility, including available resources and specific restrictions and/or prohibitions on therapeutics (eg, mandatory ID consultation or approval). In our facility, while COVID-19 therapeutic living guidance documents were maintained and accessible through the intranet, proactive dissemination and redirection were important steps in enabling the use of these documents.

Limitations

We acknowledge several limitations to this study. Most important, the correlations we observed do not represent causation. Our analysis was not designed to ascertain the direct impact of any single or combined educational and laboratory stewardship intervention from this study, and we acknowledge that the improvements in part could be related to increased experience and confidence with COVID-19 management that occurred over time independent of our programs. Furthermore, we acknowledge that several areas of COVID-19 management did not improve over time (such as overall empiric antibiotic use from the ED) or had very modest improvements (hospitalist-initiated remdesivir use). These results underscore the complex dynamics and contextual barriers to rapidly implementing guideline-based care at VANTHCS. Potential factors include insufficient reach to all physicians, variable learner motivation, and therapeutic momentum of antibiotic use carried forward from the ED.^16,17 These factors should be considered as grounds for further study. Another limitation was the inability to track viewership and engagement of our COVID-19 guidance document. Without the use metrics, it is difficult to know the individual impact of the document regarding the changing trends in COVID-19 management we observed during the study period.

Conclusions

We report improvements in COVID-19 therapeutic prescriptions and the use of antibiotics and laboratory testing over 6 months at the DVAMC. This was correlated with a deliberate COVID-19 educational initiative that included antibiotic and laboratory stewardship interventions with simultaneous decreased reliance on ID consultation. These efforts lend support to the proof of the principle of combined educational and laboratory stewardship interventions to improve the care of COVID-19 patients, especially where ID support may not be available or is accessed remotely.

Throughout the COVID-19 pandemic, health care professionals (HCPs), including emergency medicine physicians and hospitalists, have been continuously challenged to maintain an up-to-date clinical practice on COVID-19 therapeutics as new evidence emerged.^1,2 In the early part of the pandemic, these included not only appropriate and time-sensitive prescriptions of COVID-19 therapeutics, such as remdesivir and dexamethasone, but also judicious use of empiric antibiotics given the low prevalence for bacterial coinfection in early disease.^3-6 Alongside this, curbing the excessive laboratory testing of these patients during the pandemic was important not only to minimize costs but also to reduce potential iatrogenic harm and extended length of stay (LOS).⁷

At the beginning of the pandemic in March 2020 at the US Department of Veterans Affairs (VA) North Texas Health Care System (VANTHCS) Dallas VA Medical Center (DVAMC), we attempted to provide therapeutic guidance for physicians primarily through direct infectious disease (ID) consultation (in-person or electronic).⁸ This was secondarily supported by a pharmacist and ID physician–curated “living guidance” document on COVID-19 care accessible to all physicians through the DVAMC electronic health record (EHR) and intranet.

As the alpha variant (lineage B.1.1.7) of COVID-19 began spreading throughout North Texas in the winter of 2020, we implemented a targeted educational intervention toward the hospitalist group taking care of patients with COVID-19 with the primary goal of improving the accuracy of COVID-19 therapeutics while minimizing the consultative burden on ID clinical and pharmacy staff. This initiative consisted of (1) proactive guideline dissemination through email and text messages; (2) virtual didactics; and (3) physician reminders during the consultation process. Our ultimate aims were to improve hospitalist-led appropriate prescriptions of remdesivir and dexamethasone, reducing empiric antibiotic days of therapy in patients with COVID-19 at low risk of bacterial coinfection, and reducing laboratory orders that were not indicated for the management of these patients. Following this intervention and the resolution of the second wave, we retrospectively assessed the temporal trends of COVID-19 practices by hospitalists and associated patterns of ID consultation in the DVAMC from October 1, 2020, to March 31, 2021.

METHODS

The educational intervention was carried out at the DVAMC, a 1A high complex facility with more than 200 inpatient beds and part of the VANTHCS. During the study period, patients admitted with COVID-19 were located either on a closed floor (managed by the hospitalist team) or in a closed intensive care unit (ICU) (managed by the pulmonary/critical care team) contingent on the level of care or oxygen supplementation required. ID and other subspecialties provided consultation services as requested by hospitalists or ICU teams either electronically or in person. During the study period, 66 hospitalists were involved in the care of the patients: 59 (89.5%) permanent staff, 4 (6.0%) fee-basis physicians, and 3 (4.5%) moonlighting fellows.

Educational Initiative

We delivered educational sessions to the hospitalists, using collaboration software with video meeting capability every 1 to 2 months beginning in December 2020. An additional session focused on reducing empiric antibiotic prescriptions was also delivered to the emergency medicine department, based on feedback from the hospitalist group. The content for the educational sessions came from informal surveys of both ID trainees assigned to the consultation service and hospitalists, covering the following topics: understanding the stages of COVID-19 illness (virologic replication vs inflammatory) and rationales for therapy; assessing disease severity; indications and use of remdesivir; indications and use of dexamethasone; assessing for bacterial coinfections; when an ID consultation is required; management algorithm for COVID-19; and locating guidelines on the intranet. About 15 to 20 physicians participated in each session. In addition, slides of these didactics and updated institutional COVID-19 guidelines were disseminated to the hospitalist group via email and text messaging. We also linked the intranet institution guidelines in our communication, including a revised user-friendly flowchart (eAppendix).

Laboratory Stewardship Initiative

Laboratory stewardship initiatives were implemented by modifying suggested orders on the admission of patients with COVID-19 and directly educating hospitalist and emergency medicine physicians on evidence-based laboratory orders. At the beginning of the pandemic, a broad admission order set was established at DVAMC, based on the then limited knowledge of the course of infection with COVID-19. This order set allowed the admitting physicians to efficiently order laboratory tests for patients, especially during the demanding increase in patient volume experienced by DVAMC.

As new evidence emerged during the pandemic, many of the laboratory orders were reviewed for clinical utility during care for the patient with COVID-19 per the latest guidance. In December 2020, the admission orders for patients with COVID-19 were revised to reflect better laboratory stewardship to reduce cost and harm. The ID section revised the laboratory orders and disseminated the new order set to admitting physicians. Specifically, the admission order set removed the following laboratory tests available for selection: routine blood cultures, interleukin 6 (IL-6) level, and Legionella sputum culture. These laboratory orders were removed based on the lack of supporting evidence in persons admitted with COVID-19.⁹ In addition to modification of the admission order set, educational sessions were held with hospitalists to disseminate knowledge of the new changes and address any concerns.

Observations of Care

This study was approved by the VANTHCS Institutional Review Board (protocol code 20-047). Records were retrospectively reviewed for patients admitted to DVAMC for COVID-19 under hospitalist care (patients admitted directly to the ICU were excluded) from October 1, 2020, to March 31, 2021. Age, sex, race and ethnicity, and comorbidities were collected from the EHR. In addition clinical measures such as maximum oxygen requirement during admission (none, nasal cannula of 2-4 L/min, high flow/bilevel positive airway pressure [BiPAP] or mechanical ventilation), proven presence of coinfection (defined as the isolation of a probable pathogen in pure culture and/or clinically determined by ID specialist evaluation), and the average LOS also were collected. For laboratory stewardship data, a retrospective chart review was conducted to determine the total number of blood cultures obtained within 24 hours of admission per month during the study period. Both IL-6 levels and Legionella sputum culture data were collected as the total number of laboratory orders per month, as it was assumed that most of these orders were obtained for patients admitted with COVID-19.

Individual patient-level data were extracted to calculate monthly percentages of ID consultations for COVID-19 by the hospitalist team, adherence to institutional guidelines for dexamethasone and remdesivir prescriptions, and empiric antibiotic prescriptions for patients with COVID-19, including use of a priori adjudication criteria to determine justified vs unjustified empiric use. These criteria included asymmetric chest X-ray infiltrates concerning for bacterial pneumonia; peripheral white blood cell count > 11 K/μL; critical respiratory failure in the emergency department (ED) and being transferred to the ICU; and ID consultation recommended. Because the total number of antibiotics was not being analyzed but rather just the use of antibiotics for the justified and unjustified groups, antibiotic days were reported as the length of therapy (LOT).¹⁰ A subset analysis was performed on antibiotic prescriptions by the hospitalist group focusing on those with mild-to-moderate oxygen requirements (no high flow, noninvasive or invasive ventilatory methods) and excluding infections with a proven microbiologic entity.

Differences in demographic and clinical characteristics of patients with COVID-19 admitted from October 1, 2020, to March 31, 2021, were assessed using ANOVA, χ², and Kruskal-Wallis test. χ² was used to compare the difference in total laboratory orders for routine blood cultures, IL-6 levels, and Legionella sputum cultures between pre-intervention (October to December 2020) and postintervention (January to March 2021). These pre- and postintervention periods were determined based on the timing of revised admission orders in the EHR and initiation of focused educational sessions starting in late December 2020 and early January 2021. Linear regressions were used to examine the possible 6-month trend of the percentage of patients receiving ID consultation for appropriate dexamethasone prescriptions, appropriate remdesivir prescriptions, appropriate antibiotic coadministration, and mean number of antibiotic days per patient. Linear and logistic regression were also used to assess the trend in LOS over the 6 months while adjusting for age, race and ethnicity, sex, and coinfections. All analyses were performed using SAS 9.4. Statistical significance was defined as P < .05.

RESULTS

From October 1, 2020, to March 31, 2021, there were 565 admissions for COVID-19, which peaked in January 2021 with 163. Analysis of the patient characteristics showed no statistically significant difference for age, sex, oxygen requirements during admission, or proven presence of coinfection between the months of interest (Table 1).

The number of blood cultures obtained in the first 24 hours of admission significantly decreased from 58.1% of admissions in October 2020 to 34.8% of admissions in March 2021 (P < .01) (Table 2).

DISCUSSION

As the COVID-19 pandemic has evolved, the ability to enact up-to-date guidance is crucial to streamlining patient care, improving time to COVID-19–specific therapies, and minimizing the burden on subspecialty consultation services. At DVAMC, we initiated a targeted and deliberate educational effort directed toward hospitalist and ED groups combined with a laboratory stewardship effort over 6 months to improve the implementation of COVID-19 therapeutics, reduce empiric antibiotic use without reliance on ID consultation services, and reduce the number of unnecessary laboratory orders for admitted patients with COVID-19. During this time, we observed modest but statistically significant improvements in the accuracy of dexamethasone and remdesivir prescribing. In addition, we observed statistically significant improvement in the average LOT per patient regarding antibiotic use and overall decreased LOS. These improvements were seen in parallel with decreasing requests for ID consultation, suggesting that they were attributable in part to increasing self-confidence and efficacy in COVID-19 practices by the hospitalist group. Modification of the COVID-19 admission order set for our facility resulted in substantial decreases in orders for blood cultures, IL-6 levels, and sputum cultures for Legionella.

ID consultation, either in person or remotely, has been instrumental in assisting physicians in COVID-19 management and has been shown to reduce morbidity, mortality, and patient LOS in other infections.^11,12 However, in scenarios where ID consultation is not available or in limited supply, accessibility, familiarity, and confidence of primary practitioners to use therapeutic guidance material are integral. Frequent and accessible guidance for the management of COVID-19 has been provided by the National Institutes of Health and the Infectious Diseases Society of America.^13,14 Other mechanisms of assisting physicians in both test ordering and therapeutics include clinical decision support tools built into the EHR and the use of a smartphone digital application.¹⁵ Guidance needs to be adapted to the context of the facility, including available resources and specific restrictions and/or prohibitions on therapeutics (eg, mandatory ID consultation or approval). In our facility, while COVID-19 therapeutic living guidance documents were maintained and accessible through the intranet, proactive dissemination and redirection were important steps in enabling the use of these documents.

Limitations

We acknowledge several limitations to this study. Most important, the correlations we observed do not represent causation. Our analysis was not designed to ascertain the direct impact of any single or combined educational and laboratory stewardship intervention from this study, and we acknowledge that the improvements in part could be related to increased experience and confidence with COVID-19 management that occurred over time independent of our programs. Furthermore, we acknowledge that several areas of COVID-19 management did not improve over time (such as overall empiric antibiotic use from the ED) or had very modest improvements (hospitalist-initiated remdesivir use). These results underscore the complex dynamics and contextual barriers to rapidly implementing guideline-based care at VANTHCS. Potential factors include insufficient reach to all physicians, variable learner motivation, and therapeutic momentum of antibiotic use carried forward from the ED.^16,17 These factors should be considered as grounds for further study. Another limitation was the inability to track viewership and engagement of our COVID-19 guidance document. Without the use metrics, it is difficult to know the individual impact of the document regarding the changing trends in COVID-19 management we observed during the study period.

Conclusions

We report improvements in COVID-19 therapeutic prescriptions and the use of antibiotics and laboratory testing over 6 months at the DVAMC. This was correlated with a deliberate COVID-19 educational initiative that included antibiotic and laboratory stewardship interventions with simultaneous decreased reliance on ID consultation. These efforts lend support to the proof of the principle of combined educational and laboratory stewardship interventions to improve the care of COVID-19 patients, especially where ID support may not be available or is accessed remotely.

Throughout the COVID-19 pandemic, health care professionals (HCPs), including emergency medicine physicians and hospitalists, have been continuously challenged to maintain an up-to-date clinical practice on COVID-19 therapeutics as new evidence emerged.^1,2 In the early part of the pandemic, these included not only appropriate and time-sensitive prescriptions of COVID-19 therapeutics, such as remdesivir and dexamethasone, but also judicious use of empiric antibiotics given the low prevalence for bacterial coinfection in early disease.^3-6 Alongside this, curbing the excessive laboratory testing of these patients during the pandemic was important not only to minimize costs but also to reduce potential iatrogenic harm and extended length of stay (LOS).⁷

At the beginning of the pandemic in March 2020 at the US Department of Veterans Affairs (VA) North Texas Health Care System (VANTHCS) Dallas VA Medical Center (DVAMC), we attempted to provide therapeutic guidance for physicians primarily through direct infectious disease (ID) consultation (in-person or electronic).⁸ This was secondarily supported by a pharmacist and ID physician–curated “living guidance” document on COVID-19 care accessible to all physicians through the DVAMC electronic health record (EHR) and intranet.

As the alpha variant (lineage B.1.1.7) of COVID-19 began spreading throughout North Texas in the winter of 2020, we implemented a targeted educational intervention toward the hospitalist group taking care of patients with COVID-19 with the primary goal of improving the accuracy of COVID-19 therapeutics while minimizing the consultative burden on ID clinical and pharmacy staff. This initiative consisted of (1) proactive guideline dissemination through email and text messages; (2) virtual didactics; and (3) physician reminders during the consultation process. Our ultimate aims were to improve hospitalist-led appropriate prescriptions of remdesivir and dexamethasone, reducing empiric antibiotic days of therapy in patients with COVID-19 at low risk of bacterial coinfection, and reducing laboratory orders that were not indicated for the management of these patients. Following this intervention and the resolution of the second wave, we retrospectively assessed the temporal trends of COVID-19 practices by hospitalists and associated patterns of ID consultation in the DVAMC from October 1, 2020, to March 31, 2021.

METHODS

The educational intervention was carried out at the DVAMC, a 1A high complex facility with more than 200 inpatient beds and part of the VANTHCS. During the study period, patients admitted with COVID-19 were located either on a closed floor (managed by the hospitalist team) or in a closed intensive care unit (ICU) (managed by the pulmonary/critical care team) contingent on the level of care or oxygen supplementation required. ID and other subspecialties provided consultation services as requested by hospitalists or ICU teams either electronically or in person. During the study period, 66 hospitalists were involved in the care of the patients: 59 (89.5%) permanent staff, 4 (6.0%) fee-basis physicians, and 3 (4.5%) moonlighting fellows.

Educational Initiative

We delivered educational sessions to the hospitalists, using collaboration software with video meeting capability every 1 to 2 months beginning in December 2020. An additional session focused on reducing empiric antibiotic prescriptions was also delivered to the emergency medicine department, based on feedback from the hospitalist group. The content for the educational sessions came from informal surveys of both ID trainees assigned to the consultation service and hospitalists, covering the following topics: understanding the stages of COVID-19 illness (virologic replication vs inflammatory) and rationales for therapy; assessing disease severity; indications and use of remdesivir; indications and use of dexamethasone; assessing for bacterial coinfections; when an ID consultation is required; management algorithm for COVID-19; and locating guidelines on the intranet. About 15 to 20 physicians participated in each session. In addition, slides of these didactics and updated institutional COVID-19 guidelines were disseminated to the hospitalist group via email and text messaging. We also linked the intranet institution guidelines in our communication, including a revised user-friendly flowchart (eAppendix).

Laboratory Stewardship Initiative

Laboratory stewardship initiatives were implemented by modifying suggested orders on the admission of patients with COVID-19 and directly educating hospitalist and emergency medicine physicians on evidence-based laboratory orders. At the beginning of the pandemic, a broad admission order set was established at DVAMC, based on the then limited knowledge of the course of infection with COVID-19. This order set allowed the admitting physicians to efficiently order laboratory tests for patients, especially during the demanding increase in patient volume experienced by DVAMC.

As new evidence emerged during the pandemic, many of the laboratory orders were reviewed for clinical utility during care for the patient with COVID-19 per the latest guidance. In December 2020, the admission orders for patients with COVID-19 were revised to reflect better laboratory stewardship to reduce cost and harm. The ID section revised the laboratory orders and disseminated the new order set to admitting physicians. Specifically, the admission order set removed the following laboratory tests available for selection: routine blood cultures, interleukin 6 (IL-6) level, and Legionella sputum culture. These laboratory orders were removed based on the lack of supporting evidence in persons admitted with COVID-19.⁹ In addition to modification of the admission order set, educational sessions were held with hospitalists to disseminate knowledge of the new changes and address any concerns.

Observations of Care

This study was approved by the VANTHCS Institutional Review Board (protocol code 20-047). Records were retrospectively reviewed for patients admitted to DVAMC for COVID-19 under hospitalist care (patients admitted directly to the ICU were excluded) from October 1, 2020, to March 31, 2021. Age, sex, race and ethnicity, and comorbidities were collected from the EHR. In addition clinical measures such as maximum oxygen requirement during admission (none, nasal cannula of 2-4 L/min, high flow/bilevel positive airway pressure [BiPAP] or mechanical ventilation), proven presence of coinfection (defined as the isolation of a probable pathogen in pure culture and/or clinically determined by ID specialist evaluation), and the average LOS also were collected. For laboratory stewardship data, a retrospective chart review was conducted to determine the total number of blood cultures obtained within 24 hours of admission per month during the study period. Both IL-6 levels and Legionella sputum culture data were collected as the total number of laboratory orders per month, as it was assumed that most of these orders were obtained for patients admitted with COVID-19.

Individual patient-level data were extracted to calculate monthly percentages of ID consultations for COVID-19 by the hospitalist team, adherence to institutional guidelines for dexamethasone and remdesivir prescriptions, and empiric antibiotic prescriptions for patients with COVID-19, including use of a priori adjudication criteria to determine justified vs unjustified empiric use. These criteria included asymmetric chest X-ray infiltrates concerning for bacterial pneumonia; peripheral white blood cell count > 11 K/μL; critical respiratory failure in the emergency department (ED) and being transferred to the ICU; and ID consultation recommended. Because the total number of antibiotics was not being analyzed but rather just the use of antibiotics for the justified and unjustified groups, antibiotic days were reported as the length of therapy (LOT).¹⁰ A subset analysis was performed on antibiotic prescriptions by the hospitalist group focusing on those with mild-to-moderate oxygen requirements (no high flow, noninvasive or invasive ventilatory methods) and excluding infections with a proven microbiologic entity.

Differences in demographic and clinical characteristics of patients with COVID-19 admitted from October 1, 2020, to March 31, 2021, were assessed using ANOVA, χ², and Kruskal-Wallis test. χ² was used to compare the difference in total laboratory orders for routine blood cultures, IL-6 levels, and Legionella sputum cultures between pre-intervention (October to December 2020) and postintervention (January to March 2021). These pre- and postintervention periods were determined based on the timing of revised admission orders in the EHR and initiation of focused educational sessions starting in late December 2020 and early January 2021. Linear regressions were used to examine the possible 6-month trend of the percentage of patients receiving ID consultation for appropriate dexamethasone prescriptions, appropriate remdesivir prescriptions, appropriate antibiotic coadministration, and mean number of antibiotic days per patient. Linear and logistic regression were also used to assess the trend in LOS over the 6 months while adjusting for age, race and ethnicity, sex, and coinfections. All analyses were performed using SAS 9.4. Statistical significance was defined as P < .05.

RESULTS

From October 1, 2020, to March 31, 2021, there were 565 admissions for COVID-19, which peaked in January 2021 with 163. Analysis of the patient characteristics showed no statistically significant difference for age, sex, oxygen requirements during admission, or proven presence of coinfection between the months of interest (Table 1).

The number of blood cultures obtained in the first 24 hours of admission significantly decreased from 58.1% of admissions in October 2020 to 34.8% of admissions in March 2021 (P < .01) (Table 2).

DISCUSSION

As the COVID-19 pandemic has evolved, the ability to enact up-to-date guidance is crucial to streamlining patient care, improving time to COVID-19–specific therapies, and minimizing the burden on subspecialty consultation services. At DVAMC, we initiated a targeted and deliberate educational effort directed toward hospitalist and ED groups combined with a laboratory stewardship effort over 6 months to improve the implementation of COVID-19 therapeutics, reduce empiric antibiotic use without reliance on ID consultation services, and reduce the number of unnecessary laboratory orders for admitted patients with COVID-19. During this time, we observed modest but statistically significant improvements in the accuracy of dexamethasone and remdesivir prescribing. In addition, we observed statistically significant improvement in the average LOT per patient regarding antibiotic use and overall decreased LOS. These improvements were seen in parallel with decreasing requests for ID consultation, suggesting that they were attributable in part to increasing self-confidence and efficacy in COVID-19 practices by the hospitalist group. Modification of the COVID-19 admission order set for our facility resulted in substantial decreases in orders for blood cultures, IL-6 levels, and sputum cultures for Legionella.

ID consultation, either in person or remotely, has been instrumental in assisting physicians in COVID-19 management and has been shown to reduce morbidity, mortality, and patient LOS in other infections.^11,12 However, in scenarios where ID consultation is not available or in limited supply, accessibility, familiarity, and confidence of primary practitioners to use therapeutic guidance material are integral. Frequent and accessible guidance for the management of COVID-19 has been provided by the National Institutes of Health and the Infectious Diseases Society of America.^13,14 Other mechanisms of assisting physicians in both test ordering and therapeutics include clinical decision support tools built into the EHR and the use of a smartphone digital application.¹⁵ Guidance needs to be adapted to the context of the facility, including available resources and specific restrictions and/or prohibitions on therapeutics (eg, mandatory ID consultation or approval). In our facility, while COVID-19 therapeutic living guidance documents were maintained and accessible through the intranet, proactive dissemination and redirection were important steps in enabling the use of these documents.

Limitations

We acknowledge several limitations to this study. Most important, the correlations we observed do not represent causation. Our analysis was not designed to ascertain the direct impact of any single or combined educational and laboratory stewardship intervention from this study, and we acknowledge that the improvements in part could be related to increased experience and confidence with COVID-19 management that occurred over time independent of our programs. Furthermore, we acknowledge that several areas of COVID-19 management did not improve over time (such as overall empiric antibiotic use from the ED) or had very modest improvements (hospitalist-initiated remdesivir use). These results underscore the complex dynamics and contextual barriers to rapidly implementing guideline-based care at VANTHCS. Potential factors include insufficient reach to all physicians, variable learner motivation, and therapeutic momentum of antibiotic use carried forward from the ED.^16,17 These factors should be considered as grounds for further study. Another limitation was the inability to track viewership and engagement of our COVID-19 guidance document. Without the use metrics, it is difficult to know the individual impact of the document regarding the changing trends in COVID-19 management we observed during the study period.

Conclusions

We report improvements in COVID-19 therapeutic prescriptions and the use of antibiotics and laboratory testing over 6 months at the DVAMC. This was correlated with a deliberate COVID-19 educational initiative that included antibiotic and laboratory stewardship interventions with simultaneous decreased reliance on ID consultation. These efforts lend support to the proof of the principle of combined educational and laboratory stewardship interventions to improve the care of COVID-19 patients, especially where ID support may not be available or is accessed remotely.

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

THE CASE

A 23-year-old woman sought care from her primary care physician (PCP) after being sick for 7 days. The illness started with a headache and fatigue, and by Day 6, she also had fever, chills, sore throat, nausea, a poor appetite, and intractable vomiting. The patient had no significant medical history and was socially isolating due to the COVID-19 pandemic. She had no known sick contacts or recent sexual activity and did not use any illicit drugs.

On examination, her vital signs were normal although she appeared ill and diaphoretic. A shallow tonsil ulcer and tonsillar adenopathy were present. Laboratory tests included a complete blood count (CBC), comprehensive metabolic panel, Monospot test, and Epstein-Barr virus (EBV) antibody test. Results were notable for leukocytosis with atypical lymphocytes on her CBC. Her Monospot test and EBV immunoglobulin (Ig) M antibody were positive, and her EBV IgG antibody was negative. She was given a diagnosis of infectious mononucleosis (IM) and told to get adequate rest, drink a lot of fluids, and take ibuprofen or acetaminophen for pain control.

Two days later, she returned to her PCP with scleral icterus (FIGURE 1A), increasingly tender cervical lymphadenopathy, and left-side abdominal pain. Her liver function tests (LFTs) had worsened (TABLE). An abdominal ultrasound revealed mild diffuse decreased hepatic echogenicity and prominent periportal echogenicity, likely related to diffuse hepatic parenchymal disease, as well as splenomegaly and a mildly thickened gallbladder with no gallstones. She also had severe throat discomfort, with bilateral tonsillar exudates and pharyngeal erythema (FIGURE 1B).

THE DIAGNOSIS

Based on her symptoms and the results of her physical examination, LFTs, EBV serologic assays, and abdominal ultrasound, this patient was given a diagnosis of acute EBV hepatitis.

DISCUSSION

EBV infection, which is the most common cause of IM, causes asymptomatic liver enzyme abnormalities in 80% to 90% of patients.^1-3 Although not common, patients can develop acute EBV hepatitis and require hospitalization.⁴

Be aware of potential complications. Prompt assessment of elevated liver enzymes and accurate diagnosis are key.⁵ Although acute EBV hepatitis is usually self-limiting, there can be serious gastrointestinal complications such as splenic rupture, liver failure due to acute and/or chronic EBV infection, autoimmune hepatitis, and hepatocellular carcinoma.² It’s rare for EBV hepatitis to lead to acute liver failure, but when that occurs, it can be fatal.^6-9 One case series revealed that while primary EBV infection accounts for less than 1% of adult acute liver failure cases, it has a high case fatality rate of 50%.⁹

Treatment for patients with EBV hepatitis is usually supportive and includes rest, analgesia, and avoidance of vigorous activity for 1 month to reduce the risk for splenic rupture.¹ In patients with nausea and vomiting, intravenous fluids may be necessary and can be administered at an outpatient infusion center. For individuals with severe tonsillar hypertrophy, prednisone (40-60 mg/d for 2-3 days, with subsequent tapering over 1-2 weeks) is indicated to prevent airway obstruction.¹ Acyclovir may be used to reduce EBV viral shedding; however, it has no significant clinical impact.¹

Continue to: Patients who are hemodynamially stable...

Patients who are hemodynamically stable and have appropriate access to follow-up care can be managed at home.² If follow-up cannot occur remotely within 1 week or the patient’s clinical status begins to worsen (ie, the patient’s liver enzymes or bilirubin levels dramatically increase), hospitalization is necessary.¹⁰

Through shared decision-making, our patient was treated as an outpatient based on her hemodynamic stability and her ability to closely follow up in the clinic and by phone and to access an outpatient infusion center. She was reexamined within 2 days and given ondansetron 8 mg IV with 2 L of normal saline at our outpatient infusion center. We also prescribed ibuprofen (400 mg every 6 hours as needed) for analgesia and issued the standard recommendations that she avoid contact sports (for at least 6 weeks) and excessive alcohol consumption.

On Day 11, the patient followed up with her PCP by telephone. The patient was started on oral prednisone (40 mg/d for 3 days with taper over the next week as symptoms improved) for her severe throat discomfort, exudates, difficulty swallowing, and muffled voice. By Day 14, her aminotransferase levels began to decrease (TABLE), and her symptoms steadily improved thereafter.

THE TAKEAWAY

When a patient presents with unexplained elevated liver enzymes or cholestasis, it is important to assess for signs and symptoms of EBV hepatitis. Although EBV hepatitis is typically self-limiting, it can have serious complications or be fatal. Prompt initiation of outpatient management may avoid these complications and hospitalization.

CORRESPONDENCE
Lydia J. Schneider, MD, 225 East Chicago Avenue, Chicago, IL 60611; lydia.schneider315@gmail.com

THE CASE

A 23-year-old woman sought care from her primary care physician (PCP) after being sick for 7 days. The illness started with a headache and fatigue, and by Day 6, she also had fever, chills, sore throat, nausea, a poor appetite, and intractable vomiting. The patient had no significant medical history and was socially isolating due to the COVID-19 pandemic. She had no known sick contacts or recent sexual activity and did not use any illicit drugs.

On examination, her vital signs were normal although she appeared ill and diaphoretic. A shallow tonsil ulcer and tonsillar adenopathy were present. Laboratory tests included a complete blood count (CBC), comprehensive metabolic panel, Monospot test, and Epstein-Barr virus (EBV) antibody test. Results were notable for leukocytosis with atypical lymphocytes on her CBC. Her Monospot test and EBV immunoglobulin (Ig) M antibody were positive, and her EBV IgG antibody was negative. She was given a diagnosis of infectious mononucleosis (IM) and told to get adequate rest, drink a lot of fluids, and take ibuprofen or acetaminophen for pain control.

Two days later, she returned to her PCP with scleral icterus (FIGURE 1A), increasingly tender cervical lymphadenopathy, and left-side abdominal pain. Her liver function tests (LFTs) had worsened (TABLE). An abdominal ultrasound revealed mild diffuse decreased hepatic echogenicity and prominent periportal echogenicity, likely related to diffuse hepatic parenchymal disease, as well as splenomegaly and a mildly thickened gallbladder with no gallstones. She also had severe throat discomfort, with bilateral tonsillar exudates and pharyngeal erythema (FIGURE 1B).

THE DIAGNOSIS

Based on her symptoms and the results of her physical examination, LFTs, EBV serologic assays, and abdominal ultrasound, this patient was given a diagnosis of acute EBV hepatitis.

DISCUSSION

EBV infection, which is the most common cause of IM, causes asymptomatic liver enzyme abnormalities in 80% to 90% of patients.^1-3 Although not common, patients can develop acute EBV hepatitis and require hospitalization.⁴

Be aware of potential complications. Prompt assessment of elevated liver enzymes and accurate diagnosis are key.⁵ Although acute EBV hepatitis is usually self-limiting, there can be serious gastrointestinal complications such as splenic rupture, liver failure due to acute and/or chronic EBV infection, autoimmune hepatitis, and hepatocellular carcinoma.² It’s rare for EBV hepatitis to lead to acute liver failure, but when that occurs, it can be fatal.^6-9 One case series revealed that while primary EBV infection accounts for less than 1% of adult acute liver failure cases, it has a high case fatality rate of 50%.⁹

Treatment for patients with EBV hepatitis is usually supportive and includes rest, analgesia, and avoidance of vigorous activity for 1 month to reduce the risk for splenic rupture.¹ In patients with nausea and vomiting, intravenous fluids may be necessary and can be administered at an outpatient infusion center. For individuals with severe tonsillar hypertrophy, prednisone (40-60 mg/d for 2-3 days, with subsequent tapering over 1-2 weeks) is indicated to prevent airway obstruction.¹ Acyclovir may be used to reduce EBV viral shedding; however, it has no significant clinical impact.¹

Continue to: Patients who are hemodynamially stable...

Patients who are hemodynamically stable and have appropriate access to follow-up care can be managed at home.² If follow-up cannot occur remotely within 1 week or the patient’s clinical status begins to worsen (ie, the patient’s liver enzymes or bilirubin levels dramatically increase), hospitalization is necessary.¹⁰

Through shared decision-making, our patient was treated as an outpatient based on her hemodynamic stability and her ability to closely follow up in the clinic and by phone and to access an outpatient infusion center. She was reexamined within 2 days and given ondansetron 8 mg IV with 2 L of normal saline at our outpatient infusion center. We also prescribed ibuprofen (400 mg every 6 hours as needed) for analgesia and issued the standard recommendations that she avoid contact sports (for at least 6 weeks) and excessive alcohol consumption.

On Day 11, the patient followed up with her PCP by telephone. The patient was started on oral prednisone (40 mg/d for 3 days with taper over the next week as symptoms improved) for her severe throat discomfort, exudates, difficulty swallowing, and muffled voice. By Day 14, her aminotransferase levels began to decrease (TABLE), and her symptoms steadily improved thereafter.

THE TAKEAWAY

When a patient presents with unexplained elevated liver enzymes or cholestasis, it is important to assess for signs and symptoms of EBV hepatitis. Although EBV hepatitis is typically self-limiting, it can have serious complications or be fatal. Prompt initiation of outpatient management may avoid these complications and hospitalization.

CORRESPONDENCE
Lydia J. Schneider, MD, 225 East Chicago Avenue, Chicago, IL 60611; lydia.schneider315@gmail.com

THE CASE

A 23-year-old woman sought care from her primary care physician (PCP) after being sick for 7 days. The illness started with a headache and fatigue, and by Day 6, she also had fever, chills, sore throat, nausea, a poor appetite, and intractable vomiting. The patient had no significant medical history and was socially isolating due to the COVID-19 pandemic. She had no known sick contacts or recent sexual activity and did not use any illicit drugs.

On examination, her vital signs were normal although she appeared ill and diaphoretic. A shallow tonsil ulcer and tonsillar adenopathy were present. Laboratory tests included a complete blood count (CBC), comprehensive metabolic panel, Monospot test, and Epstein-Barr virus (EBV) antibody test. Results were notable for leukocytosis with atypical lymphocytes on her CBC. Her Monospot test and EBV immunoglobulin (Ig) M antibody were positive, and her EBV IgG antibody was negative. She was given a diagnosis of infectious mononucleosis (IM) and told to get adequate rest, drink a lot of fluids, and take ibuprofen or acetaminophen for pain control.

Two days later, she returned to her PCP with scleral icterus (FIGURE 1A), increasingly tender cervical lymphadenopathy, and left-side abdominal pain. Her liver function tests (LFTs) had worsened (TABLE). An abdominal ultrasound revealed mild diffuse decreased hepatic echogenicity and prominent periportal echogenicity, likely related to diffuse hepatic parenchymal disease, as well as splenomegaly and a mildly thickened gallbladder with no gallstones. She also had severe throat discomfort, with bilateral tonsillar exudates and pharyngeal erythema (FIGURE 1B).

THE DIAGNOSIS

Based on her symptoms and the results of her physical examination, LFTs, EBV serologic assays, and abdominal ultrasound, this patient was given a diagnosis of acute EBV hepatitis.

DISCUSSION

EBV infection, which is the most common cause of IM, causes asymptomatic liver enzyme abnormalities in 80% to 90% of patients.^1-3 Although not common, patients can develop acute EBV hepatitis and require hospitalization.⁴

Be aware of potential complications. Prompt assessment of elevated liver enzymes and accurate diagnosis are key.⁵ Although acute EBV hepatitis is usually self-limiting, there can be serious gastrointestinal complications such as splenic rupture, liver failure due to acute and/or chronic EBV infection, autoimmune hepatitis, and hepatocellular carcinoma.² It’s rare for EBV hepatitis to lead to acute liver failure, but when that occurs, it can be fatal.^6-9 One case series revealed that while primary EBV infection accounts for less than 1% of adult acute liver failure cases, it has a high case fatality rate of 50%.⁹

Treatment for patients with EBV hepatitis is usually supportive and includes rest, analgesia, and avoidance of vigorous activity for 1 month to reduce the risk for splenic rupture.¹ In patients with nausea and vomiting, intravenous fluids may be necessary and can be administered at an outpatient infusion center. For individuals with severe tonsillar hypertrophy, prednisone (40-60 mg/d for 2-3 days, with subsequent tapering over 1-2 weeks) is indicated to prevent airway obstruction.¹ Acyclovir may be used to reduce EBV viral shedding; however, it has no significant clinical impact.¹

Continue to: Patients who are hemodynamially stable...

Patients who are hemodynamically stable and have appropriate access to follow-up care can be managed at home.² If follow-up cannot occur remotely within 1 week or the patient’s clinical status begins to worsen (ie, the patient’s liver enzymes or bilirubin levels dramatically increase), hospitalization is necessary.¹⁰

Through shared decision-making, our patient was treated as an outpatient based on her hemodynamic stability and her ability to closely follow up in the clinic and by phone and to access an outpatient infusion center. She was reexamined within 2 days and given ondansetron 8 mg IV with 2 L of normal saline at our outpatient infusion center. We also prescribed ibuprofen (400 mg every 6 hours as needed) for analgesia and issued the standard recommendations that she avoid contact sports (for at least 6 weeks) and excessive alcohol consumption.

On Day 11, the patient followed up with her PCP by telephone. The patient was started on oral prednisone (40 mg/d for 3 days with taper over the next week as symptoms improved) for her severe throat discomfort, exudates, difficulty swallowing, and muffled voice. By Day 14, her aminotransferase levels began to decrease (TABLE), and her symptoms steadily improved thereafter.

THE TAKEAWAY

When a patient presents with unexplained elevated liver enzymes or cholestasis, it is important to assess for signs and symptoms of EBV hepatitis. Although EBV hepatitis is typically self-limiting, it can have serious complications or be fatal. Prompt initiation of outpatient management may avoid these complications and hospitalization.

CORRESPONDENCE
Lydia J. Schneider, MD, 225 East Chicago Avenue, Chicago, IL 60611; lydia.schneider315@gmail.com

Evidence summary

Multiple analyses suggest HRT worsens rather than improves cognition

A 2017 Cochrane review of 22 randomized, double-blind studies compared use of HRT (estrogen only or combination estrogen + progesterone therapies) with placebo in postmenopausal women (N = 43,637). Age ranges varied, but the average age in most studies was > 60 years. Treatment duration was at least 1 year. Various outcomes were assessed across these 22 studies, including cardiovascular disease, bone health, and cognition.¹

Cognitive outcomes were assessed with the Mini-Mental Status Exam in 5 of the trials (N = 12,789). Data were not combined due to heterogeneity. The authors found no significant difference in cognitive scores between the treatment and control groups in any of these 5 studies.¹

In the largest included study, the Women’s Health Initiative (WHI) Memory Study (N = 10,739), participants were older than 65 years. Among those receiving estrogen-only HRT, there were no statistically significant differences compared to those receiving placebo. However, healthy postmenopausal women taking combination HRT had an increased risk for “probable dementia” compared to those taking placebo (relative risk [RR] = 1.97; 95% CI, 1.16-3.33). When researchers looked exclusively at women taking HRT, the risk for dementia increased from 9 in 1000 to 18 in 1000 (95% CI, 11-30) after 4 years of HRT use. This results in a number needed to harm of 4 to 50 patients.¹

Two notable limitations of this evidence are that the average age of this population was > 60 years and 80% of the participants were White.¹

A 2021 meta-analysis of 23 RCTs (N = 13,683) studied the effect of HRT on global cognitive function as well as specific cognitive domains including memory, executive function, attention, and language. Mean patient age in the studies varied from 48 to 81 years. Nine of these studies were also included in the previously discussed Cochrane review.²

There was a statistically significant but small decrease in overall global cognition (10 trials; N = 12,115; standardized mean difference [SMD] = –0.04; 95% CI, –0.08 to –0.01) in those receiving HRT compared to placebo. This effect was slightly more pronounced among those who initiated HRT at age > 60 years (8 trials; N = 11,914; SMD = –0.05; 95% CI, –0.08 to –0.01) and among patients with HRT duration > 6 months (7 trials; N = 11,828; SMD = –0.05; 95% CI, –0.08 to –0.01). There were no significant differences in specific cognitive domains.²

In a 2017 follow-up to the WHI trial, researchers analyzed data on long-term cognitive effects in women previously treated with HRT. There were 2 cohorts: participants who initiated HRT at a younger age (50-54; N = 1376) and those who initiated HRT later in life (age 65-79; N = 2880). Cognitive outcomes were assessed using the Telephone Interview for Cognitive Status-modified, with interviews conducted annually beginning 6 to 7 years after HRT was stopped.³

The investigators found no significant change in composite cognitive function in the younger HRT-treated group compared to placebo (estrogen alone: mean deviation [MD] = 0.014; 95% CI, –0.097 to 0.126; estrogen + progesterone: MD = –0.047; 95% CI, –0.134 to 0.04), or in the group who initiated HRT at an older age (estrogen alone: MD = –0.099; 95% CI, –0.202 to 0.004; estrogen + progesterone: MD = –0.022; 95% CI, –0.099 to 0.055). The authors state that although the data did not reach significance, this study also found a trend toward decreases in global cognitive function in the older age group.³

Editor’s takeaway

Abundant, consistent evidence with long-term follow-up shows postmenopausal HRT does not reduce cognitive decline. In fact, it appears to increase cognitive decline slightly. Renewed interest in postmenopausal HRT to alleviate menopausal symptoms should balance the risks and benefits to the individual patient.

Evidence summary

Multiple analyses suggest HRT worsens rather than improves cognition

A 2017 Cochrane review of 22 randomized, double-blind studies compared use of HRT (estrogen only or combination estrogen + progesterone therapies) with placebo in postmenopausal women (N = 43,637). Age ranges varied, but the average age in most studies was > 60 years. Treatment duration was at least 1 year. Various outcomes were assessed across these 22 studies, including cardiovascular disease, bone health, and cognition.¹

Cognitive outcomes were assessed with the Mini-Mental Status Exam in 5 of the trials (N = 12,789). Data were not combined due to heterogeneity. The authors found no significant difference in cognitive scores between the treatment and control groups in any of these 5 studies.¹

In the largest included study, the Women’s Health Initiative (WHI) Memory Study (N = 10,739), participants were older than 65 years. Among those receiving estrogen-only HRT, there were no statistically significant differences compared to those receiving placebo. However, healthy postmenopausal women taking combination HRT had an increased risk for “probable dementia” compared to those taking placebo (relative risk [RR] = 1.97; 95% CI, 1.16-3.33). When researchers looked exclusively at women taking HRT, the risk for dementia increased from 9 in 1000 to 18 in 1000 (95% CI, 11-30) after 4 years of HRT use. This results in a number needed to harm of 4 to 50 patients.¹

Two notable limitations of this evidence are that the average age of this population was > 60 years and 80% of the participants were White.¹

A 2021 meta-analysis of 23 RCTs (N = 13,683) studied the effect of HRT on global cognitive function as well as specific cognitive domains including memory, executive function, attention, and language. Mean patient age in the studies varied from 48 to 81 years. Nine of these studies were also included in the previously discussed Cochrane review.²

There was a statistically significant but small decrease in overall global cognition (10 trials; N = 12,115; standardized mean difference [SMD] = –0.04; 95% CI, –0.08 to –0.01) in those receiving HRT compared to placebo. This effect was slightly more pronounced among those who initiated HRT at age > 60 years (8 trials; N = 11,914; SMD = –0.05; 95% CI, –0.08 to –0.01) and among patients with HRT duration > 6 months (7 trials; N = 11,828; SMD = –0.05; 95% CI, –0.08 to –0.01). There were no significant differences in specific cognitive domains.²

In a 2017 follow-up to the WHI trial, researchers analyzed data on long-term cognitive effects in women previously treated with HRT. There were 2 cohorts: participants who initiated HRT at a younger age (50-54; N = 1376) and those who initiated HRT later in life (age 65-79; N = 2880). Cognitive outcomes were assessed using the Telephone Interview for Cognitive Status-modified, with interviews conducted annually beginning 6 to 7 years after HRT was stopped.³

The investigators found no significant change in composite cognitive function in the younger HRT-treated group compared to placebo (estrogen alone: mean deviation [MD] = 0.014; 95% CI, –0.097 to 0.126; estrogen + progesterone: MD = –0.047; 95% CI, –0.134 to 0.04), or in the group who initiated HRT at an older age (estrogen alone: MD = –0.099; 95% CI, –0.202 to 0.004; estrogen + progesterone: MD = –0.022; 95% CI, –0.099 to 0.055). The authors state that although the data did not reach significance, this study also found a trend toward decreases in global cognitive function in the older age group.³

Editor’s takeaway

Abundant, consistent evidence with long-term follow-up shows postmenopausal HRT does not reduce cognitive decline. In fact, it appears to increase cognitive decline slightly. Renewed interest in postmenopausal HRT to alleviate menopausal symptoms should balance the risks and benefits to the individual patient.

Evidence summary

Multiple analyses suggest HRT worsens rather than improves cognition

A 2017 Cochrane review of 22 randomized, double-blind studies compared use of HRT (estrogen only or combination estrogen + progesterone therapies) with placebo in postmenopausal women (N = 43,637). Age ranges varied, but the average age in most studies was > 60 years. Treatment duration was at least 1 year. Various outcomes were assessed across these 22 studies, including cardiovascular disease, bone health, and cognition.¹

Cognitive outcomes were assessed with the Mini-Mental Status Exam in 5 of the trials (N = 12,789). Data were not combined due to heterogeneity. The authors found no significant difference in cognitive scores between the treatment and control groups in any of these 5 studies.¹

In the largest included study, the Women’s Health Initiative (WHI) Memory Study (N = 10,739), participants were older than 65 years. Among those receiving estrogen-only HRT, there were no statistically significant differences compared to those receiving placebo. However, healthy postmenopausal women taking combination HRT had an increased risk for “probable dementia” compared to those taking placebo (relative risk [RR] = 1.97; 95% CI, 1.16-3.33). When researchers looked exclusively at women taking HRT, the risk for dementia increased from 9 in 1000 to 18 in 1000 (95% CI, 11-30) after 4 years of HRT use. This results in a number needed to harm of 4 to 50 patients.¹

Two notable limitations of this evidence are that the average age of this population was > 60 years and 80% of the participants were White.¹

A 2021 meta-analysis of 23 RCTs (N = 13,683) studied the effect of HRT on global cognitive function as well as specific cognitive domains including memory, executive function, attention, and language. Mean patient age in the studies varied from 48 to 81 years. Nine of these studies were also included in the previously discussed Cochrane review.²

There was a statistically significant but small decrease in overall global cognition (10 trials; N = 12,115; standardized mean difference [SMD] = –0.04; 95% CI, –0.08 to –0.01) in those receiving HRT compared to placebo. This effect was slightly more pronounced among those who initiated HRT at age > 60 years (8 trials; N = 11,914; SMD = –0.05; 95% CI, –0.08 to –0.01) and among patients with HRT duration > 6 months (7 trials; N = 11,828; SMD = –0.05; 95% CI, –0.08 to –0.01). There were no significant differences in specific cognitive domains.²

In a 2017 follow-up to the WHI trial, researchers analyzed data on long-term cognitive effects in women previously treated with HRT. There were 2 cohorts: participants who initiated HRT at a younger age (50-54; N = 1376) and those who initiated HRT later in life (age 65-79; N = 2880). Cognitive outcomes were assessed using the Telephone Interview for Cognitive Status-modified, with interviews conducted annually beginning 6 to 7 years after HRT was stopped.³

The investigators found no significant change in composite cognitive function in the younger HRT-treated group compared to placebo (estrogen alone: mean deviation [MD] = 0.014; 95% CI, –0.097 to 0.126; estrogen + progesterone: MD = –0.047; 95% CI, –0.134 to 0.04), or in the group who initiated HRT at an older age (estrogen alone: MD = –0.099; 95% CI, –0.202 to 0.004; estrogen + progesterone: MD = –0.022; 95% CI, –0.099 to 0.055). The authors state that although the data did not reach significance, this study also found a trend toward decreases in global cognitive function in the older age group.³

Editor’s takeaway

Abundant, consistent evidence with long-term follow-up shows postmenopausal HRT does not reduce cognitive decline. In fact, it appears to increase cognitive decline slightly. Renewed interest in postmenopausal HRT to alleviate menopausal symptoms should balance the risks and benefits to the individual patient.

Recently, my family had a conversation about the volume of news reports on overdose deaths from the illicit use of opioid drugs—a phenomenon that is complex and stems from many factors. We decided, as a family, that we could have a small impact on the problem. How? By carrying naloxone with us and administering it if we encounter a person with potential opioid overdose. Our decision was made possible by the recent US Food and Drug Administration (FDA) approval of naloxone nasal spray for over-the-counter use.¹ At a cost of about $50 for 2 nasal sprays, we decided it would be a reasonable price to pay to potentially save a life.

The CDC encourages clinicians to find a balance of the potential benefits and harms and to avoid inflexibility.

Prescribing opioids in clinical practice is a different side of the problem. The Centers for Disease Control and Prevention (CDC) reports that prescription opioids account for about one-quarter of opioid overdose deaths.² This is not trivial, and much effort has gone into addressing how clinicians can do better by their patients. There are training programs and risk-mitigation strategies for opioid prescribing. States have developed prescribing registries to identify patients who receive controlled substances from multiple prescribers, at higher-than-recommended doses, and too early in the pain management process. These efforts have reduced the number of opioid prescriptions and rates of high-dose prescribing (> 90 morphine milligram equivalents). However, that hasn’t translated into a reduction in the number of deaths.²

The article by Posen et al³ in this issue further reminded me how trends in health care, including opioid prescribing, are like a pendulum—swinging from one extreme to the other before eventually centering. I recall conversations with colleagues about how often we undertreated pain—and then later, how relieved we were when new approaches to pain management, using newer opiates, emerged and were reported to be much safer, even for long-term use. We now know the rest of that story: more prescriptions, higher doses, longer duration, addiction, death, and deception by manufacturers.

In our efforts to prevent addiction and decrease opioid deaths, we tried to get patients off opioids completely, thereby increasing demand for addiction therapy, including medication-assisted recovery. This also drove many of our patients to seek opioids from nefarious suppliers, resulting in even more deaths from fentanyl-laced drugs.

At least one positive has arisen from the “no more opioids” movement: We have re-evaluated their true effect on managing pain. Initially, we were told opioids were safe and highly effective—and, having few tools to help our patients, we were ­Pollyanna-ish in accepting this. But many recent studies have demonstrated that using opioids for pain is no more effective than using other analgesics.^4-9 In addition to overdose deaths and addiction, these studies show significantly higher rates of opioid discontinuation due to adverse effects.

We certainly can manage most patients’ pain effectively with other approaches. For some, though—patients whose pain is not adequately controlled and/or interferes with their ability to function, and those who are terminally ill—opioid nihilism has had unintended consequences. Recognizing these issues, the CDC updated its guideline for prescribing opioids in 2022.¹⁰ Four areas were addressed: whether to initiate opioids; opioid selection and dosing; duration of therapy and need for follow-up; and assessing risk and addressing potential harms of opioid use. The CDC encourages clinicians to find a balance of the potential benefits and harms and to avoid inflexibility. Finally, the CDC encourages clinicians to identify and treat patients with opioid use disorders.

Clearly, opioid overuse and overdose result from complex medical, economic, and societal factors. Individual clinicians are well equipped to manage things “in their own backyards.” However, what we do can be perceived as a bandage for a much larger problem. Our public health system has the potential for greater impact, but the “cure” will require multimodal solutions addressing many facets of society and government.¹¹ At the very least, we should keep some naloxone close by and vote for political candidates who see broader solutions for addressing this life-and-death crisis.

Recently, my family had a conversation about the volume of news reports on overdose deaths from the illicit use of opioid drugs—a phenomenon that is complex and stems from many factors. We decided, as a family, that we could have a small impact on the problem. How? By carrying naloxone with us and administering it if we encounter a person with potential opioid overdose. Our decision was made possible by the recent US Food and Drug Administration (FDA) approval of naloxone nasal spray for over-the-counter use.¹ At a cost of about $50 for 2 nasal sprays, we decided it would be a reasonable price to pay to potentially save a life.

The CDC encourages clinicians to find a balance of the potential benefits and harms and to avoid inflexibility.

Prescribing opioids in clinical practice is a different side of the problem. The Centers for Disease Control and Prevention (CDC) reports that prescription opioids account for about one-quarter of opioid overdose deaths.² This is not trivial, and much effort has gone into addressing how clinicians can do better by their patients. There are training programs and risk-mitigation strategies for opioid prescribing. States have developed prescribing registries to identify patients who receive controlled substances from multiple prescribers, at higher-than-recommended doses, and too early in the pain management process. These efforts have reduced the number of opioid prescriptions and rates of high-dose prescribing (> 90 morphine milligram equivalents). However, that hasn’t translated into a reduction in the number of deaths.²

The article by Posen et al³ in this issue further reminded me how trends in health care, including opioid prescribing, are like a pendulum—swinging from one extreme to the other before eventually centering. I recall conversations with colleagues about how often we undertreated pain—and then later, how relieved we were when new approaches to pain management, using newer opiates, emerged and were reported to be much safer, even for long-term use. We now know the rest of that story: more prescriptions, higher doses, longer duration, addiction, death, and deception by manufacturers.

In our efforts to prevent addiction and decrease opioid deaths, we tried to get patients off opioids completely, thereby increasing demand for addiction therapy, including medication-assisted recovery. This also drove many of our patients to seek opioids from nefarious suppliers, resulting in even more deaths from fentanyl-laced drugs.

At least one positive has arisen from the “no more opioids” movement: We have re-evaluated their true effect on managing pain. Initially, we were told opioids were safe and highly effective—and, having few tools to help our patients, we were ­Pollyanna-ish in accepting this. But many recent studies have demonstrated that using opioids for pain is no more effective than using other analgesics.^4-9 In addition to overdose deaths and addiction, these studies show significantly higher rates of opioid discontinuation due to adverse effects.

We certainly can manage most patients’ pain effectively with other approaches. For some, though—patients whose pain is not adequately controlled and/or interferes with their ability to function, and those who are terminally ill—opioid nihilism has had unintended consequences. Recognizing these issues, the CDC updated its guideline for prescribing opioids in 2022.¹⁰ Four areas were addressed: whether to initiate opioids; opioid selection and dosing; duration of therapy and need for follow-up; and assessing risk and addressing potential harms of opioid use. The CDC encourages clinicians to find a balance of the potential benefits and harms and to avoid inflexibility. Finally, the CDC encourages clinicians to identify and treat patients with opioid use disorders.

Clearly, opioid overuse and overdose result from complex medical, economic, and societal factors. Individual clinicians are well equipped to manage things “in their own backyards.” However, what we do can be perceived as a bandage for a much larger problem. Our public health system has the potential for greater impact, but the “cure” will require multimodal solutions addressing many facets of society and government.¹¹ At the very least, we should keep some naloxone close by and vote for political candidates who see broader solutions for addressing this life-and-death crisis.

Recently, my family had a conversation about the volume of news reports on overdose deaths from the illicit use of opioid drugs—a phenomenon that is complex and stems from many factors. We decided, as a family, that we could have a small impact on the problem. How? By carrying naloxone with us and administering it if we encounter a person with potential opioid overdose. Our decision was made possible by the recent US Food and Drug Administration (FDA) approval of naloxone nasal spray for over-the-counter use.¹ At a cost of about $50 for 2 nasal sprays, we decided it would be a reasonable price to pay to potentially save a life.

The CDC encourages clinicians to find a balance of the potential benefits and harms and to avoid inflexibility.

Prescribing opioids in clinical practice is a different side of the problem. The Centers for Disease Control and Prevention (CDC) reports that prescription opioids account for about one-quarter of opioid overdose deaths.² This is not trivial, and much effort has gone into addressing how clinicians can do better by their patients. There are training programs and risk-mitigation strategies for opioid prescribing. States have developed prescribing registries to identify patients who receive controlled substances from multiple prescribers, at higher-than-recommended doses, and too early in the pain management process. These efforts have reduced the number of opioid prescriptions and rates of high-dose prescribing (> 90 morphine milligram equivalents). However, that hasn’t translated into a reduction in the number of deaths.²

The article by Posen et al³ in this issue further reminded me how trends in health care, including opioid prescribing, are like a pendulum—swinging from one extreme to the other before eventually centering. I recall conversations with colleagues about how often we undertreated pain—and then later, how relieved we were when new approaches to pain management, using newer opiates, emerged and were reported to be much safer, even for long-term use. We now know the rest of that story: more prescriptions, higher doses, longer duration, addiction, death, and deception by manufacturers.

In our efforts to prevent addiction and decrease opioid deaths, we tried to get patients off opioids completely, thereby increasing demand for addiction therapy, including medication-assisted recovery. This also drove many of our patients to seek opioids from nefarious suppliers, resulting in even more deaths from fentanyl-laced drugs.

At least one positive has arisen from the “no more opioids” movement: We have re-evaluated their true effect on managing pain. Initially, we were told opioids were safe and highly effective—and, having few tools to help our patients, we were ­Pollyanna-ish in accepting this. But many recent studies have demonstrated that using opioids for pain is no more effective than using other analgesics.^4-9 In addition to overdose deaths and addiction, these studies show significantly higher rates of opioid discontinuation due to adverse effects.

We certainly can manage most patients’ pain effectively with other approaches. For some, though—patients whose pain is not adequately controlled and/or interferes with their ability to function, and those who are terminally ill—opioid nihilism has had unintended consequences. Recognizing these issues, the CDC updated its guideline for prescribing opioids in 2022.¹⁰ Four areas were addressed: whether to initiate opioids; opioid selection and dosing; duration of therapy and need for follow-up; and assessing risk and addressing potential harms of opioid use. The CDC encourages clinicians to find a balance of the potential benefits and harms and to avoid inflexibility. Finally, the CDC encourages clinicians to identify and treat patients with opioid use disorders.

Clearly, opioid overuse and overdose result from complex medical, economic, and societal factors. Individual clinicians are well equipped to manage things “in their own backyards.” However, what we do can be perceived as a bandage for a much larger problem. Our public health system has the potential for greater impact, but the “cure” will require multimodal solutions addressing many facets of society and government.¹¹ At the very least, we should keep some naloxone close by and vote for political candidates who see broader solutions for addressing this life-and-death crisis.

Subclinical hypothyroidism (SCH) is a biochemical state in which the thyroid-stimulating hormone (TSH) is elevated while the free thyroxine (T4) level is normal. Overt hypothyroidism is not diagnosed until the free T4 level is decreased, regardless of the degree of TSH elevation.

The overall prevalence of SCH in iodine-rich areas is 4% to 10%, with a risk for progression to overt hypothyroidism of between 2% and 6% annually.¹ The prevalence of SCH varies depending on the TSH reference range used.¹ The normal reference range for TSH varies depending on the laboratory and/or the reference population surveyed, with the range likely widening with increasing age.

SCH is most common among women, the elderly, and White individuals.² The discovery of SCH is often incidental, given that usually it is detected by laboratory findings alone without associated symptoms of overt hypothyroidism.³

The not-so-significant role of symptoms in subclinical hypothyroidism

Symptoms associated with overt hypothyroidism include constipation, dry skin, fatigue, slow thinking, poor memory, muscle cramps, weakness, and cold intolerance. In SCH, these symptoms are inconsistent, with around 1 in 3 patients having no symptoms at all.⁴

One study reported that roughly 18% of euthyroid individuals, 22% of SCH patients, and 26% of those with overt hypothyroidism reported 4 or more symptoms classically thought to be related to hypothyroidism.⁴ A large Danish cohort study found that hypothyroid symptoms were no more common in patients with SCH than in euthyroid individuals in the general population.⁵ These studies question the validity of attributing symptoms to SCH.

Adverse health associations

Observational data suggest that SCH is associated with an increased risk for dyslipidemia, coronary heart disease, heart failure, and cardiovascular mortality, particularly in those with TSH levels ≥ 10 mIU/L.^6,7 Such associations were not found for most adults with TSH levels between 5 and 10 mIU/L.⁸ There are also potential associations of SCH with obesity, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.^9,10 Despite thyroid studies being commonly ordered as part of a mental health evaluation, SCH has not been statistically associated with depressive symptoms.^11,12

Caveats with laboratory testing

There are several issues to consider when performing a laboratory assessment of thyroid function. TSH levels fluctuate considerably during the day, as TSH secretion has a circadian rhythm. TSH values are 50% higher at night and in the early morning than during the rest of the day.¹³ TSH values also may rise in response to current illness or stress. Due to this biologic variability, repeat testing to confirm TSH levels is recommended if an initial test result is abnormal.¹⁴

Continue to: An exact reference range...

Supplements containing biotin should be withheld for several days before assessing thyroid function.

An exact reference range for TSH is not widely agreed upon—although most laboratories regard 4.0 to 5.0 mIU/L as the high-end cutoff for normal. Also, “normal” TSH levels appear to differ by age. Accordingly, some experts have recommended an age-based reference range for TSH levels,¹⁵ although this is not implemented widely by laboratories. A TSH level of 6.0 mIU/L (or even higher) may be more appropriate for adults older than 65 years.¹

Biotin supplementation has been shown to cause spurious thyroid testing results (TSH, T3, T4) depending on the type of assay used. Therefore, supplements containing biotin should be withheld for several days before assessing thyroid function.¹⁶Patients with SCH are often categorized as having TSH levels between 4.5 and 10 mIU/L (around 90% of patients) or levels ≥ 10 mIU/L.^8,17 If followed for 5 years, approximately 60% of patients with SCH and TSH levels between 4 and 10 mIU/L will normalize without intervention.¹⁸ Normalization is less common in patients with a TSH level greater than 10 mIU/L.¹⁸

The risk for progression to overt hypothyroidism also appears to be higher for those with certain risk factors. These include higher baseline TSH levels, presence of thyroid peroxidase antibodies (TPOAbs), or history of neck irradiation or radioactive iodine uptake.¹ Other risk factors for eventual thyroid dysfunction include female sex, older age, goiter, and high iodine intake.¹³

Evidence for treatment varies

Guidelines for the treatment of SCH (TABLE 1^8,14,19,20) are founded on the condition’s risk for progression to overt hypothyroidism and its association with health consequences such as cardiovascular disease. Guidelines of the American Thyroid Association (ATA) and European Thyroid Association (ETA), and those of the United Kingdom–based National Institute for Health and Care Excellence (NICE), prioritize treatment for individuals with a TSH level > 10 mIU/L^a and for those with TSH values < 10 mIU/L but still elevated and apparent symptoms of hypothyroidism.^14,19,20 The strength of evidence behind this guidance is challenged by a lack of data from prospective randomized controlled trials (RCTs) demonstrating health benefits following treatment of SCH. The British Medical Journal (BMJ) Guideline cites this lack of evidence and recommends against treating SCH at any TSH level, regardless of symptoms.⁸

There are few large RCTs of treatment outcomes for SCH. A 2017 RCT (the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism, or TRUST, trial) of 737 adults older than 65 years with SCH evaluated the ability of levothyroxine to normalize TSH values compared with placebo. At 1 year, there was no difference in hypothyroid symptoms or tiredness scale scores with levothyroxine treatment compared with placebo.²¹ This finding was consistent even in the subgroup with a higher baseline symptom burden.²²

Continue to: Two small RCTs evaluated...

Two small RCTs evaluated treatment of SCH with depressive symptoms and cognitive function, neither finding benefit compared with placebo.^12,23 A 2018 systematic review and meta-analysis of 21 studies and 2192 adults did not show a benefit to quality of life or thyroid-specific symptoms in those treated for SCH compared with controls.²⁴

RCT support also is lacking for a reduction in cardiovascular mortality following treatment for SCH. A large population-level retrospective cohort from Denmark showed no difference in cardiovascular mortality or myocardial infarction in those treated for SCH compared with controls.²⁵ Pooled results from 2 RCTs (for patients older than 65 years, and those older than 80 years) showed no change in risk for cardiovascular outcomes in older adults treated for SCH.²⁶ Older adults treated for SCH in the TRUST trial showed no improvements in systolic or diastolic­ function on echocardiography.^27­ Two trials showed no difference in carotid intima-media thickness with treatment of SCH compared with placebo.^28,29

While most of the RCT data come from older adults, a retrospective cohort study in the United Kingdom of younger (ages 40-70 years; n = 3093) and older (age > 70 years; n = 1642) patients showed a reduction in cardiovascular mortality among treated patients who were younger (hazard ratio [HR] = 0.61; 4.2% vs. 6.6%) but not those who were older (HR = 0.99; 12.7% vs. 10.7%).³⁰ There is also evidence that thyroid size in those with goiter can be reduced with treatment of SCH.³¹

A measured approach to treating subclinical hypothyroidism

Consider several factors when deciding whether to treat SCH. For instance, RCT data suggest a lack of treatment benefit in relieving depression, improving cognition, or reducing general hypothyroid symptoms. Treatment of SCH in older adults does not appear to improve cardiovascular outcomes. The question of whether long-term treatment of SCH in younger patients reduces cardiovascular morbidity or mortality lacks answers from RCTs. Before diagnosing SCH or starting treatment, always confirm SCH with repeat testing in 2 to 3 months, as a high percentage of those with untreated SCH will have normal thyroid function on repeat testing.

Before diagnosing subclinical hypothyroidism (SCH) or starting treatment, always confirm SCH with repeat testing in 2 to 3 months.

In the event you and your patient elect to treat SCH, guidelines and trials generally support a low initial daily dose of 25 to 50 mcg of levothyroxine (T4), followed with dose changes­ every 4 to 8 weeks and a goal of normalizing TSH to within the lower half of the reference range (0.4-2.5 mIU/L).¹⁴ This is generally similar to published treatment goals for primary hypothyroidism and is based on studies suggesting the lower half of the reference range is normal for young, healthy, euthyroid individuals.³² Though full replacement doses (1.6-1.8 mcg/kg of ideal body weight) can be started for those who are elderly or who have ischemic heart disease or angina, this approach should be avoided in favor of low-dose initial therapy.³³ Thyroid supplements are best absorbed when taken apart from food, calcium, or iron supplements. The ATA suggests taking thyroid medication 60 minutes before breakfast or at bedtime (3 or more hours after the evening meal).³³

Continue to: Screening guidelines differ

 

 

Screening guidelines differ

Lacking population-level screening data from RCTs, most organizations do not recommend screening for thyroid dysfunction or they note insufficient evidence to make a screening recommendation (TABLE 2^17,19,20,34). In their most recent recommendation statement on the subject in 2015, the US Preventive Services Task Force (USPSTF) concluded the current evidence was insufficient to recommend for or against thyroid dysfunction screening in nonpregnant, asymptomatic adults.¹⁷ This differs from the ATA and the American Association of Clinical Endocrinology (AACE; formerly known as the American Association of Clinical Endocrinologists), which both recommend targeted screening for thyroid dysfunction based on symptoms or risk factors.²⁰

What about subclinical hypothyroidism in pregnancy?

Overt hypothyroidism is associated with adverse events during pregnancy and with subsequent neurodevelopmental complications in children, although the effects of SCH during pregnancy remain less certain. Concerns have been raised over the potential association of SCH with pregnancy loss, placental abruption, premature rupture of membranes, and neonatal death.³⁵ Historically, the prevalence of SCH during pregnancy has ranged from 2% to 2.5%, but using lower trimester-based TSH reference ranges, the prevalence of SCH in pregnancy may be as high as 15%.³⁵

Guided by a large RCT that failed to find benefit (pregnancy outcomes, neurodevelopmental outcomes in children) following treatment of SCH in pregnancy,³⁶ the American College of Obstetricians and Gynecologists (ACOG) recommends against routine screening for thyroid disease in pregnancy.³⁴ The ATA notes insufficient evidence to rec-ommend universal screening for thyroid dysfunction in pregnancy but recommends targeted screening of those with risk factors.³⁷ Data are conflicting on the benefit of treating known or recently detected SCH on pregnancy outcomes including pregnancy loss.^35,38 As such, the American Society of Reproductive Medicine and the ATA both generally recommend treatment of SCH in pregnant patients, particularly when the TSH is ≥ 4.0 mIU/L and TPOAbs are present.^37,39

^a The ATA, ETA, and NICE have slightly different recommendations when a TSH level = 10 mIU/L. ETA and NICE recommend prioritizing treatment for individuals with this level, while ATA recommends treatment when individual factors are also considered.

ACKNOWLEDGEMENT
The authors thank Family Medicine Medical Librarian Gwen Wilson, MLS, AHIP, for her assistance with literature searches.

CORRESPONDENCE
Nicholas LeFevre, MD, Family and Community Medicine, University of Missouri–Columbia School of Medicine, One Hospital Drive, M224 Medical Science Building, Columbia, MO 65212; nlefevre@health.missouri.edu

Subclinical hypothyroidism (SCH) is a biochemical state in which the thyroid-stimulating hormone (TSH) is elevated while the free thyroxine (T4) level is normal. Overt hypothyroidism is not diagnosed until the free T4 level is decreased, regardless of the degree of TSH elevation.

The overall prevalence of SCH in iodine-rich areas is 4% to 10%, with a risk for progression to overt hypothyroidism of between 2% and 6% annually.¹ The prevalence of SCH varies depending on the TSH reference range used.¹ The normal reference range for TSH varies depending on the laboratory and/or the reference population surveyed, with the range likely widening with increasing age.

SCH is most common among women, the elderly, and White individuals.² The discovery of SCH is often incidental, given that usually it is detected by laboratory findings alone without associated symptoms of overt hypothyroidism.³

The not-so-significant role of symptoms in subclinical hypothyroidism

Symptoms associated with overt hypothyroidism include constipation, dry skin, fatigue, slow thinking, poor memory, muscle cramps, weakness, and cold intolerance. In SCH, these symptoms are inconsistent, with around 1 in 3 patients having no symptoms at all.⁴

One study reported that roughly 18% of euthyroid individuals, 22% of SCH patients, and 26% of those with overt hypothyroidism reported 4 or more symptoms classically thought to be related to hypothyroidism.⁴ A large Danish cohort study found that hypothyroid symptoms were no more common in patients with SCH than in euthyroid individuals in the general population.⁵ These studies question the validity of attributing symptoms to SCH.

Adverse health associations

Observational data suggest that SCH is associated with an increased risk for dyslipidemia, coronary heart disease, heart failure, and cardiovascular mortality, particularly in those with TSH levels ≥ 10 mIU/L.^6,7 Such associations were not found for most adults with TSH levels between 5 and 10 mIU/L.⁸ There are also potential associations of SCH with obesity, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.^9,10 Despite thyroid studies being commonly ordered as part of a mental health evaluation, SCH has not been statistically associated with depressive symptoms.^11,12

Caveats with laboratory testing

There are several issues to consider when performing a laboratory assessment of thyroid function. TSH levels fluctuate considerably during the day, as TSH secretion has a circadian rhythm. TSH values are 50% higher at night and in the early morning than during the rest of the day.¹³ TSH values also may rise in response to current illness or stress. Due to this biologic variability, repeat testing to confirm TSH levels is recommended if an initial test result is abnormal.¹⁴

Continue to: An exact reference range...

Supplements containing biotin should be withheld for several days before assessing thyroid function.

An exact reference range for TSH is not widely agreed upon—although most laboratories regard 4.0 to 5.0 mIU/L as the high-end cutoff for normal. Also, “normal” TSH levels appear to differ by age. Accordingly, some experts have recommended an age-based reference range for TSH levels,¹⁵ although this is not implemented widely by laboratories. A TSH level of 6.0 mIU/L (or even higher) may be more appropriate for adults older than 65 years.¹

Biotin supplementation has been shown to cause spurious thyroid testing results (TSH, T3, T4) depending on the type of assay used. Therefore, supplements containing biotin should be withheld for several days before assessing thyroid function.¹⁶Patients with SCH are often categorized as having TSH levels between 4.5 and 10 mIU/L (around 90% of patients) or levels ≥ 10 mIU/L.^8,17 If followed for 5 years, approximately 60% of patients with SCH and TSH levels between 4 and 10 mIU/L will normalize without intervention.¹⁸ Normalization is less common in patients with a TSH level greater than 10 mIU/L.¹⁸

The risk for progression to overt hypothyroidism also appears to be higher for those with certain risk factors. These include higher baseline TSH levels, presence of thyroid peroxidase antibodies (TPOAbs), or history of neck irradiation or radioactive iodine uptake.¹ Other risk factors for eventual thyroid dysfunction include female sex, older age, goiter, and high iodine intake.¹³

Evidence for treatment varies

Guidelines for the treatment of SCH (TABLE 1^8,14,19,20) are founded on the condition’s risk for progression to overt hypothyroidism and its association with health consequences such as cardiovascular disease. Guidelines of the American Thyroid Association (ATA) and European Thyroid Association (ETA), and those of the United Kingdom–based National Institute for Health and Care Excellence (NICE), prioritize treatment for individuals with a TSH level > 10 mIU/L^a and for those with TSH values < 10 mIU/L but still elevated and apparent symptoms of hypothyroidism.^14,19,20 The strength of evidence behind this guidance is challenged by a lack of data from prospective randomized controlled trials (RCTs) demonstrating health benefits following treatment of SCH. The British Medical Journal (BMJ) Guideline cites this lack of evidence and recommends against treating SCH at any TSH level, regardless of symptoms.⁸

There are few large RCTs of treatment outcomes for SCH. A 2017 RCT (the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism, or TRUST, trial) of 737 adults older than 65 years with SCH evaluated the ability of levothyroxine to normalize TSH values compared with placebo. At 1 year, there was no difference in hypothyroid symptoms or tiredness scale scores with levothyroxine treatment compared with placebo.²¹ This finding was consistent even in the subgroup with a higher baseline symptom burden.²²

Continue to: Two small RCTs evaluated...

Two small RCTs evaluated treatment of SCH with depressive symptoms and cognitive function, neither finding benefit compared with placebo.^12,23 A 2018 systematic review and meta-analysis of 21 studies and 2192 adults did not show a benefit to quality of life or thyroid-specific symptoms in those treated for SCH compared with controls.²⁴

RCT support also is lacking for a reduction in cardiovascular mortality following treatment for SCH. A large population-level retrospective cohort from Denmark showed no difference in cardiovascular mortality or myocardial infarction in those treated for SCH compared with controls.²⁵ Pooled results from 2 RCTs (for patients older than 65 years, and those older than 80 years) showed no change in risk for cardiovascular outcomes in older adults treated for SCH.²⁶ Older adults treated for SCH in the TRUST trial showed no improvements in systolic or diastolic­ function on echocardiography.^27­ Two trials showed no difference in carotid intima-media thickness with treatment of SCH compared with placebo.^28,29

While most of the RCT data come from older adults, a retrospective cohort study in the United Kingdom of younger (ages 40-70 years; n = 3093) and older (age > 70 years; n = 1642) patients showed a reduction in cardiovascular mortality among treated patients who were younger (hazard ratio [HR] = 0.61; 4.2% vs. 6.6%) but not those who were older (HR = 0.99; 12.7% vs. 10.7%).³⁰ There is also evidence that thyroid size in those with goiter can be reduced with treatment of SCH.³¹

A measured approach to treating subclinical hypothyroidism

Consider several factors when deciding whether to treat SCH. For instance, RCT data suggest a lack of treatment benefit in relieving depression, improving cognition, or reducing general hypothyroid symptoms. Treatment of SCH in older adults does not appear to improve cardiovascular outcomes. The question of whether long-term treatment of SCH in younger patients reduces cardiovascular morbidity or mortality lacks answers from RCTs. Before diagnosing SCH or starting treatment, always confirm SCH with repeat testing in 2 to 3 months, as a high percentage of those with untreated SCH will have normal thyroid function on repeat testing.

Before diagnosing subclinical hypothyroidism (SCH) or starting treatment, always confirm SCH with repeat testing in 2 to 3 months.

In the event you and your patient elect to treat SCH, guidelines and trials generally support a low initial daily dose of 25 to 50 mcg of levothyroxine (T4), followed with dose changes­ every 4 to 8 weeks and a goal of normalizing TSH to within the lower half of the reference range (0.4-2.5 mIU/L).¹⁴ This is generally similar to published treatment goals for primary hypothyroidism and is based on studies suggesting the lower half of the reference range is normal for young, healthy, euthyroid individuals.³² Though full replacement doses (1.6-1.8 mcg/kg of ideal body weight) can be started for those who are elderly or who have ischemic heart disease or angina, this approach should be avoided in favor of low-dose initial therapy.³³ Thyroid supplements are best absorbed when taken apart from food, calcium, or iron supplements. The ATA suggests taking thyroid medication 60 minutes before breakfast or at bedtime (3 or more hours after the evening meal).³³

Continue to: Screening guidelines differ

 

 

Screening guidelines differ

Lacking population-level screening data from RCTs, most organizations do not recommend screening for thyroid dysfunction or they note insufficient evidence to make a screening recommendation (TABLE 2^17,19,20,34). In their most recent recommendation statement on the subject in 2015, the US Preventive Services Task Force (USPSTF) concluded the current evidence was insufficient to recommend for or against thyroid dysfunction screening in nonpregnant, asymptomatic adults.¹⁷ This differs from the ATA and the American Association of Clinical Endocrinology (AACE; formerly known as the American Association of Clinical Endocrinologists), which both recommend targeted screening for thyroid dysfunction based on symptoms or risk factors.²⁰

What about subclinical hypothyroidism in pregnancy?

Overt hypothyroidism is associated with adverse events during pregnancy and with subsequent neurodevelopmental complications in children, although the effects of SCH during pregnancy remain less certain. Concerns have been raised over the potential association of SCH with pregnancy loss, placental abruption, premature rupture of membranes, and neonatal death.³⁵ Historically, the prevalence of SCH during pregnancy has ranged from 2% to 2.5%, but using lower trimester-based TSH reference ranges, the prevalence of SCH in pregnancy may be as high as 15%.³⁵

Guided by a large RCT that failed to find benefit (pregnancy outcomes, neurodevelopmental outcomes in children) following treatment of SCH in pregnancy,³⁶ the American College of Obstetricians and Gynecologists (ACOG) recommends against routine screening for thyroid disease in pregnancy.³⁴ The ATA notes insufficient evidence to rec-ommend universal screening for thyroid dysfunction in pregnancy but recommends targeted screening of those with risk factors.³⁷ Data are conflicting on the benefit of treating known or recently detected SCH on pregnancy outcomes including pregnancy loss.^35,38 As such, the American Society of Reproductive Medicine and the ATA both generally recommend treatment of SCH in pregnant patients, particularly when the TSH is ≥ 4.0 mIU/L and TPOAbs are present.^37,39

^a The ATA, ETA, and NICE have slightly different recommendations when a TSH level = 10 mIU/L. ETA and NICE recommend prioritizing treatment for individuals with this level, while ATA recommends treatment when individual factors are also considered.

ACKNOWLEDGEMENT
The authors thank Family Medicine Medical Librarian Gwen Wilson, MLS, AHIP, for her assistance with literature searches.

CORRESPONDENCE
Nicholas LeFevre, MD, Family and Community Medicine, University of Missouri–Columbia School of Medicine, One Hospital Drive, M224 Medical Science Building, Columbia, MO 65212; nlefevre@health.missouri.edu

Subclinical hypothyroidism (SCH) is a biochemical state in which the thyroid-stimulating hormone (TSH) is elevated while the free thyroxine (T4) level is normal. Overt hypothyroidism is not diagnosed until the free T4 level is decreased, regardless of the degree of TSH elevation.

The overall prevalence of SCH in iodine-rich areas is 4% to 10%, with a risk for progression to overt hypothyroidism of between 2% and 6% annually.¹ The prevalence of SCH varies depending on the TSH reference range used.¹ The normal reference range for TSH varies depending on the laboratory and/or the reference population surveyed, with the range likely widening with increasing age.

SCH is most common among women, the elderly, and White individuals.² The discovery of SCH is often incidental, given that usually it is detected by laboratory findings alone without associated symptoms of overt hypothyroidism.³

The not-so-significant role of symptoms in subclinical hypothyroidism

Symptoms associated with overt hypothyroidism include constipation, dry skin, fatigue, slow thinking, poor memory, muscle cramps, weakness, and cold intolerance. In SCH, these symptoms are inconsistent, with around 1 in 3 patients having no symptoms at all.⁴

One study reported that roughly 18% of euthyroid individuals, 22% of SCH patients, and 26% of those with overt hypothyroidism reported 4 or more symptoms classically thought to be related to hypothyroidism.⁴ A large Danish cohort study found that hypothyroid symptoms were no more common in patients with SCH than in euthyroid individuals in the general population.⁵ These studies question the validity of attributing symptoms to SCH.

Adverse health associations

Observational data suggest that SCH is associated with an increased risk for dyslipidemia, coronary heart disease, heart failure, and cardiovascular mortality, particularly in those with TSH levels ≥ 10 mIU/L.^6,7 Such associations were not found for most adults with TSH levels between 5 and 10 mIU/L.⁸ There are also potential associations of SCH with obesity, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.^9,10 Despite thyroid studies being commonly ordered as part of a mental health evaluation, SCH has not been statistically associated with depressive symptoms.^11,12

Caveats with laboratory testing

There are several issues to consider when performing a laboratory assessment of thyroid function. TSH levels fluctuate considerably during the day, as TSH secretion has a circadian rhythm. TSH values are 50% higher at night and in the early morning than during the rest of the day.¹³ TSH values also may rise in response to current illness or stress. Due to this biologic variability, repeat testing to confirm TSH levels is recommended if an initial test result is abnormal.¹⁴

Continue to: An exact reference range...

Supplements containing biotin should be withheld for several days before assessing thyroid function.

An exact reference range for TSH is not widely agreed upon—although most laboratories regard 4.0 to 5.0 mIU/L as the high-end cutoff for normal. Also, “normal” TSH levels appear to differ by age. Accordingly, some experts have recommended an age-based reference range for TSH levels,¹⁵ although this is not implemented widely by laboratories. A TSH level of 6.0 mIU/L (or even higher) may be more appropriate for adults older than 65 years.¹

Biotin supplementation has been shown to cause spurious thyroid testing results (TSH, T3, T4) depending on the type of assay used. Therefore, supplements containing biotin should be withheld for several days before assessing thyroid function.¹⁶Patients with SCH are often categorized as having TSH levels between 4.5 and 10 mIU/L (around 90% of patients) or levels ≥ 10 mIU/L.^8,17 If followed for 5 years, approximately 60% of patients with SCH and TSH levels between 4 and 10 mIU/L will normalize without intervention.¹⁸ Normalization is less common in patients with a TSH level greater than 10 mIU/L.¹⁸

The risk for progression to overt hypothyroidism also appears to be higher for those with certain risk factors. These include higher baseline TSH levels, presence of thyroid peroxidase antibodies (TPOAbs), or history of neck irradiation or radioactive iodine uptake.¹ Other risk factors for eventual thyroid dysfunction include female sex, older age, goiter, and high iodine intake.¹³

Evidence for treatment varies

Guidelines for the treatment of SCH (TABLE 1^8,14,19,20) are founded on the condition’s risk for progression to overt hypothyroidism and its association with health consequences such as cardiovascular disease. Guidelines of the American Thyroid Association (ATA) and European Thyroid Association (ETA), and those of the United Kingdom–based National Institute for Health and Care Excellence (NICE), prioritize treatment for individuals with a TSH level > 10 mIU/L^a and for those with TSH values < 10 mIU/L but still elevated and apparent symptoms of hypothyroidism.^14,19,20 The strength of evidence behind this guidance is challenged by a lack of data from prospective randomized controlled trials (RCTs) demonstrating health benefits following treatment of SCH. The British Medical Journal (BMJ) Guideline cites this lack of evidence and recommends against treating SCH at any TSH level, regardless of symptoms.⁸

There are few large RCTs of treatment outcomes for SCH. A 2017 RCT (the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism, or TRUST, trial) of 737 adults older than 65 years with SCH evaluated the ability of levothyroxine to normalize TSH values compared with placebo. At 1 year, there was no difference in hypothyroid symptoms or tiredness scale scores with levothyroxine treatment compared with placebo.²¹ This finding was consistent even in the subgroup with a higher baseline symptom burden.²²

Continue to: Two small RCTs evaluated...

Two small RCTs evaluated treatment of SCH with depressive symptoms and cognitive function, neither finding benefit compared with placebo.^12,23 A 2018 systematic review and meta-analysis of 21 studies and 2192 adults did not show a benefit to quality of life or thyroid-specific symptoms in those treated for SCH compared with controls.²⁴

RCT support also is lacking for a reduction in cardiovascular mortality following treatment for SCH. A large population-level retrospective cohort from Denmark showed no difference in cardiovascular mortality or myocardial infarction in those treated for SCH compared with controls.²⁵ Pooled results from 2 RCTs (for patients older than 65 years, and those older than 80 years) showed no change in risk for cardiovascular outcomes in older adults treated for SCH.²⁶ Older adults treated for SCH in the TRUST trial showed no improvements in systolic or diastolic­ function on echocardiography.^27­ Two trials showed no difference in carotid intima-media thickness with treatment of SCH compared with placebo.^28,29

While most of the RCT data come from older adults, a retrospective cohort study in the United Kingdom of younger (ages 40-70 years; n = 3093) and older (age > 70 years; n = 1642) patients showed a reduction in cardiovascular mortality among treated patients who were younger (hazard ratio [HR] = 0.61; 4.2% vs. 6.6%) but not those who were older (HR = 0.99; 12.7% vs. 10.7%).³⁰ There is also evidence that thyroid size in those with goiter can be reduced with treatment of SCH.³¹

A measured approach to treating subclinical hypothyroidism

Consider several factors when deciding whether to treat SCH. For instance, RCT data suggest a lack of treatment benefit in relieving depression, improving cognition, or reducing general hypothyroid symptoms. Treatment of SCH in older adults does not appear to improve cardiovascular outcomes. The question of whether long-term treatment of SCH in younger patients reduces cardiovascular morbidity or mortality lacks answers from RCTs. Before diagnosing SCH or starting treatment, always confirm SCH with repeat testing in 2 to 3 months, as a high percentage of those with untreated SCH will have normal thyroid function on repeat testing.

Before diagnosing subclinical hypothyroidism (SCH) or starting treatment, always confirm SCH with repeat testing in 2 to 3 months.

In the event you and your patient elect to treat SCH, guidelines and trials generally support a low initial daily dose of 25 to 50 mcg of levothyroxine (T4), followed with dose changes­ every 4 to 8 weeks and a goal of normalizing TSH to within the lower half of the reference range (0.4-2.5 mIU/L).¹⁴ This is generally similar to published treatment goals for primary hypothyroidism and is based on studies suggesting the lower half of the reference range is normal for young, healthy, euthyroid individuals.³² Though full replacement doses (1.6-1.8 mcg/kg of ideal body weight) can be started for those who are elderly or who have ischemic heart disease or angina, this approach should be avoided in favor of low-dose initial therapy.³³ Thyroid supplements are best absorbed when taken apart from food, calcium, or iron supplements. The ATA suggests taking thyroid medication 60 minutes before breakfast or at bedtime (3 or more hours after the evening meal).³³

Continue to: Screening guidelines differ

 

 

Screening guidelines differ

Lacking population-level screening data from RCTs, most organizations do not recommend screening for thyroid dysfunction or they note insufficient evidence to make a screening recommendation (TABLE 2^17,19,20,34). In their most recent recommendation statement on the subject in 2015, the US Preventive Services Task Force (USPSTF) concluded the current evidence was insufficient to recommend for or against thyroid dysfunction screening in nonpregnant, asymptomatic adults.¹⁷ This differs from the ATA and the American Association of Clinical Endocrinology (AACE; formerly known as the American Association of Clinical Endocrinologists), which both recommend targeted screening for thyroid dysfunction based on symptoms or risk factors.²⁰

What about subclinical hypothyroidism in pregnancy?

Overt hypothyroidism is associated with adverse events during pregnancy and with subsequent neurodevelopmental complications in children, although the effects of SCH during pregnancy remain less certain. Concerns have been raised over the potential association of SCH with pregnancy loss, placental abruption, premature rupture of membranes, and neonatal death.³⁵ Historically, the prevalence of SCH during pregnancy has ranged from 2% to 2.5%, but using lower trimester-based TSH reference ranges, the prevalence of SCH in pregnancy may be as high as 15%.³⁵

Guided by a large RCT that failed to find benefit (pregnancy outcomes, neurodevelopmental outcomes in children) following treatment of SCH in pregnancy,³⁶ the American College of Obstetricians and Gynecologists (ACOG) recommends against routine screening for thyroid disease in pregnancy.³⁴ The ATA notes insufficient evidence to rec-ommend universal screening for thyroid dysfunction in pregnancy but recommends targeted screening of those with risk factors.³⁷ Data are conflicting on the benefit of treating known or recently detected SCH on pregnancy outcomes including pregnancy loss.^35,38 As such, the American Society of Reproductive Medicine and the ATA both generally recommend treatment of SCH in pregnant patients, particularly when the TSH is ≥ 4.0 mIU/L and TPOAbs are present.^37,39

^a The ATA, ETA, and NICE have slightly different recommendations when a TSH level = 10 mIU/L. ETA and NICE recommend prioritizing treatment for individuals with this level, while ATA recommends treatment when individual factors are also considered.

ACKNOWLEDGEMENT
The authors thank Family Medicine Medical Librarian Gwen Wilson, MLS, AHIP, for her assistance with literature searches.

CORRESPONDENCE
Nicholas LeFevre, MD, Family and Community Medicine, University of Missouri–Columbia School of Medicine, One Hospital Drive, M224 Medical Science Building, Columbia, MO 65212; nlefevre@health.missouri.edu

Meet Dr. A and Dr. M

Dr. A is a 50-year-old family physician who provides prenatal care in a busy practice. She sees patients in eight 4-hour clinic sessions per week and is on inpatient call 1 week out of every 2 months. Dr. A has become disillusioned with her practice. She typically works until 7 pm and arrives home exhausted, with little energy to interact with her family. She spends hours in the evenings and on weekends completing charts and answering phone calls. Dr. A is concerned because she recently gained weight and lacks an established fitness routine. The COVID-19 pandemic made life more difficult as she dealt with the risk of getting infected and the changing recommendations for treatment and prevention. After 20 years of practice, Dr. A wonders whether she should leave clinical medicine.

Dr. M is a single, 32-year-old family physician working at an academic medical center. Dr. M is unhappy in his job, is trying to grow his practice, and views himself as having little impact or autonomy. He finds himself lost while navigating the electronic health record (EHR) and struggles to be efficient in the clinic. Dr. M has multiple administrative responsibilities that require him to work evenings and weekends. Debt from medical school loans also motivates him to moonlight several weekends per month. Over the past few months, Dr. M has become frustrated and discouraged, making his depression more difficult to manage. He feels drained by the time he arrives home, where he lives alone. He has stopped exercising, socializing with friends, and dating. Dr. M often wonders if he is in the wrong profession.

Defining burnout, stress, and wellness

Dr. A and Dr. M are experiencing symptoms of burnout, common to physicians and other health care professionals. Recent studies showed an increase in burnout during the COVID-19 pandemic.^1,2 In a survey using the Maslach Burnout Inventory (MBI), approximately 44% of physicians reported at least one symptom of burnout.³ After adjusting for age, gender, relationship status, and hours worked per week, physicians were found to be at greater risk for burnout than nonphysician workers.³ The latest Medscape physician burnout survey found an increase in burnout among US physicians from 42% in 2021 to 47% in 2022 during the COVID-19 pandemic.¹ Rates of burnout were even higher among family physicians and other frontline (eg, emergency, infectious disease, and critical care) physicians.¹

Burnout has 3 key dimensions: (1) overwhelming exhaustion; (2) feelings of cynicism and detachment from the job; and (3) a sense of ineffectiveness and lack of accomplishment.⁴ The MBI is considered the standard tool for research in the field of burnout and has been repeatedly assessed for reliability and validity.⁴ The original MBI includes such items as: “I feel emotionally drained from my work,” “I feel like I’m working too hard on my job,” and “I worry that this job is hardening me emotionally.”⁵

According to the World Health Organization, burnout is an occupational phenomenon associated with chronic work-related stress that is not successfully managed.⁶ This definition emphasizes work stress as the cause of burnout, thus highlighting the importance of addressing the work environment.⁷ Physician burnout can affect physician health and wellness and the quality of patient care.^8-13 Because of the cost of burnout to individuals and the health care system, it is important to understand stressors that can lead to physician burnout.

Stress has been described as “physical, mental, or emotional strain or tension … when a person perceives that demands exceed the personal and social resources the individual is able to mobilize.”¹⁴ Work-related sources of stress affecting practicing physicians include long workdays, multiple bureaucratic tasks, lack of autonomy/control, and complex patients.^1,15

The COVID-19 pandemic is a stressor that increased physicians’ exposure to patient suffering and deaths and physicians’ vulnerability to disease at work.¹⁶ Physicians taking care of patients with COVID-19 risk infection and the possibility of infecting others.Online health records are another source of stress for many physicians.^17,18 Access to online health records on personal devices can blur the line between work and home. For each hour of direct patient contact, a physician spends an additional 2 hours interacting with an EHR.¹⁹ Among family physicians and other primary care physicians, increased EHR interaction outside clinic hours has been associated with decreased workplace satisfaction and increased rates of burnout.^11,19,20 Time spent on non-patient-facing clinical tasks, such as peer-to-peer reviews and billing queries, contributes more to burnout than clinic time alone.¹⁷

Continue to: These and other organizational factors...

A physician burnout survey found an increase in burnout among US physicians from 42% in 2021 to 47% in 2022 during the COVID-19 pandemic.

These and other organizational factors contribute to the stress experienced by physicians. Many describe themselves as feeling consumed by their work. At the beginning of the COVID-19 pandemic, physicians (and the rest of the health care team) had to quickly­ learn how to conduct virtual office visits. Clerical responsibilities increased as patients relied more on patient portals and telephone calls to receive care.

Who is predisposed to burnout? Although burnout is a work-related syndrome, studies have shown an increase in burnout associated with individual (ie, personal) factors. For example, female physicians have been shown to have higher rates of burnout compared with male physicians.^1,3 The stress of balancing the demands of the profession can begin during medical school and residency, with younger physicians having nearly­ twice the risk for stress-related symptoms when compared with older colleagues.^15,20-23 Having a child younger than 21 years old, and other personal factors related to balancing family and life demands, increases the likelihood of burnout.^11,21,22

Physicians with certain personality types and predispositions are at increased risk for burnout.^23-25 For example, neuroticism on the Big Five Personality Inventory (one of the most well-known of the psychology inventories) is associated with an increased risk for burnout. Neuroticism may manifest as sadness or related emotional dysregulation (eg, irritability, anxiety).²⁶ Other traits measured by the Big Five Personality Inventory include extraversion, agreeableness, conscientiousness, and openness to experience.²⁶

Physicians who were depressed were more likely to experience burnout symptoms (87.5%); however, only 26.2% of physicians experiencing burnout were diagnosed as having depression.

A history of depression is also associated with an increased risk for burnout.²⁷ Although depression and burnout are separate conditions, a 2016 study found significant overlap between the two.²⁷ Physicians in this study who were depressed were more likely to experience burnout symptoms (87.5%); however, only 26.2% of physicians experiencing burnout were diagnosed as having depression.²⁷ Rates of depression are higher among physicians when compared with nonphysicians, yet physicians are less likely to seek help due to fear of stigma and potential licensing concerns.^28,29 Because of this, when physicians experience depressive symptoms, they may respond by working harder rather than seeking professional counseling or emotional support. They might believe that “asking for help is a sign of weakness,” thus sacrificing their wellness.

Wellness encompasses a sense of thriving characterized by thoughts and feelings of contentment, joy, and fulfillment—and the absence of severe distress.³⁰ Wellness is a multifaceted condition that includes physical, psychological, and social aspects of an individual’s personal and professional life. Individuals experience a sense of wellness when they nurture their physical selves, minds, and relationships. People experience a sense of wellness when they balance their schedules, eat well, and maintain physical activity. Making time to enjoy family and friends also contributes to wellness.

Continue to: The culture of medicine often rewards...

The culture of medicine often rewards physician attitudes and behaviors that detract from wellness.³¹ Physicians internalize the culture of medicine that promotes perfectionism and downplays personal vulnerability.³² Physicians are reluctant to protect and preserve their wellness, believing self-sacrifice makes them good doctors. Physicians may spend countless hours counseling patients on the importance of wellness, but then work when ill or neglect their personal health needs and self-care—potentially decreasing their resilience and increasing the risk for burnout.³¹

Two paths to managing stress and preventing burnout

Patel and colleagues distinguish between 2 burnout intervention categories: (1) those that focus on individual physicians and (2) those that focus on the organizational environment.³³ We find these distinctions useful and offer strategies for enhancing individual physician wellness (TABLE 1^34-41). Similar to West and colleagues,¹¹ we offer strategies for addressing organizational sources of stress (TABLE 2^42-48). The following text describes these burnout intervention categories, emphasizing increasing self-care and changes that enable physicians to adapt effectively.

The recommendations outlined in this article are based on published stress and burnout literature, as well as the experiences of the authors. However, the number of randomized controlled studies of interventions aimed at reducing physician stress and burnout is limited. In addition, strategies proposed to reduce burnout in other professions may not address the unique stressors physicians encounter. Hence, our recommendations are limited. We have included interventions that seem optimal for individual physicians and the organizations that employ them.

Individual strategies target physical, psychological, and social wellness

Physician wellness strategies are divided into 3 categories: physical, psychological, and social wellness. Most strategies to improve physical wellness are widely known, evidence based, and recommended to patients by physicians.^34-36 For example, most physicians advise their patients to eat healthy balanced meals, avoid unhealthy foods and beverages, maintain a healthy body weight, get daily exercise and adequate sleep, avoid excessive alcohol use, and abstain from tobacco use. However, discrepancies between physicians’ advice to patients and their own behaviors are common. Simply stated, physicians are well advised to follow their own advice regarding physical self-care.

CBT and mindfulness are key to psychological wellness. Recommendations for enhancing psychological wellness are primarily derived from cognitive behavioral therapy (CBT) and mindfulness principles and practices.^37,38 CBT has been called the “gold standard” of psychotherapy, based on the breadth of research demonstrating that “no other form of psychotherapy has been shown to be systematically superior to CBT.”³⁹

Continue to: CBT is based on the premise...

CBT is based on the premise that individuals’ thoughts and beliefs largely determine how they feel (emotions) and act (behaviors). Certain thoughts lead to positive feelings and effective behaviors, while others lead to negative feelings and less effective behaviors. For example, when a physician has self-critical or helpless thoughts (eg, “I’m just no good at managing my life”), they are more likely to feel unhappy and abandon problem-solving. In contrast, when a physician has self-affirming or hopeful thoughts (eg, “This is difficult, but I have the personal resources to succeed”), they are more likely to feel confident and act to solve problems.

Physicians vacillate between these thoughts and beliefs, and their emotions and behaviors follow accordingly. When hyper-focused on “the hassles of medicine,” physicians feel defeated, depressed, and anxious about their work. In contrast, when physicians recognize and challenge problematic thoughts and focus on what they love about medicine, they feel good and interact with patients and coworkers in positive and self-reinforcing ways.

Mindfulness can help reduce psychological stress and increase personal fulfillment. Mindfulness is characterized as being in the present moment, fully accepting “what is,” and having a sense of gratitude and compassion for self and others.⁴⁰ In practice, mindfulness involves being intentional.

Dahl and colleagues⁴¹ describe a framework for human flourishing that includes 4 core dimensions of well-being (awareness, insight, connection, and purpose) that are all closely linked to mindful, intentional living. Based on their work, it is apparent that those who maintain a “heightened and flexible attentiveness” to their thoughts and feelings are likely to benefit by experiencing “improved mental health and psychological well-being.”⁴¹

However, the utility of CBT and mindfulness practices depends on receptivity to psychological interventions. Individuals who are not receptive may be hesitant to use these practices or likely will not benefit from them. Given these limitations of behavioral interventions, it would be helpful if more attention were paid to preventing and managing physician stress and burnout, especially through research focused on organizational changes.

Continue to: Supportive relationships are powerful

Supportive relationships are powerful. Finally, to enhance social wellness, it would be difficult to overstate the potential benefits of positive, supportive, close relationships.⁴² However, the demands of a career in medicine, starting in medical school, have the potential for inhibiting (rather than enhancing) close relationships.

Placing value on relationships with friends and family members is essential. As Dr. M began experiencing burnout, he felt increasingly lonely, yet he isolated himself from those who cared about him. Dr. A felt lonely at home, even though she was surrounded by family. Physicians are often reluctant to initiate vulnerable communication with others, believing “no one wants to hear about my problems.” However, by realizing the need for help and asking friends and family for emotional support, physicians can improve their wellness. Fostering supportive relationships can help provide the resilience needed to address organizational stressors.

Tackling organizational challenges

Long hours and pressure to see large numbers of patients (production demands) are a challenge across practice settings. Limiting work hours has been effective in improving the well-being of physician trainees but has had an inconsistent effect on burnout.^43,44

Organizations can offer flexible scheduling, and physicians considering limiting work hours may switch to part-time status or shift work. However, decreasing work hours may have the unintended consequence of increased stress as some physicians feel pressure to do more in less time.⁴⁵ Therefore, it’s important to set clear boundaries around work time and when and where work tasks are completed (eg, home vs office).

How we use technology matters. Given­ technology’s ever-increasing role in medicine, organizations must identify and use the most efficient, effective technology for managing clerical processes. When physicians participate in these decisions and share their experiences, technology is likely to be more user-friendly and impose less stress.⁴⁶

Continue to: If technology contributes to stress...

When physicians recognize and challenge problematic thoughts and focus on what they love about medicine, they feel good and interact with patients and coworkers in positive ways.

If technology contributes to stress by being too complex or impractical, it’s important to identify individuals in the workplace (eg, IT support or “super-users”) to help address these challenges. Organizations can implement multidisciplinary teams to address EHR challenges and decrease physician stress and burnout by training support staff to assist with clerical duties, allowing physicians to focus on patient care.^47,48 Such organizational-­directed interventions will be most successful when physicians are included in the decision-making process.⁴⁷

Take on leadership roles to influence change. Leadership may be formal (involving a title and authority) or informal (leading by example). Health care organizations that are committed to the well-being of physicians will make the effort to improve the systems in which physicians work. Physicians working in organizations that are reluctant to change have several choices: implement individual strategies, take on leadership roles to influence change, or reconsider their fit for the organization. Physicians in solo practice might consider joining others in solo practices to share systems (call, phone triage, technical resources, etc) to implement some of these interventions.

Dr. A and Dr. M implement new wellness strategies

Dr. A and Dr. M have recently committed to addressing stressors in their lives and improving their wellness. Dr. A has become more assertive at work, highlighting her need for additional resources to function effectively. In response, her practice has hired scribes to assist in documenting visits. This success has inspired Dr. A to pay attention to her lifestyle choices. Gradually, she has begun to exercise and engage in healthy eating.

Dr. M has begun to utilize resources at his medical center to improve his EHR efficiency and patient flow. He has taken steps to address his financial concerns, developing a budget and spending judiciously. He practices mindfulness and ensures that he gets at least 7 hours of sleep per night, improving his mental and physical health. By doing so, he has more energy to connect with friends, ­exercise, and date.

CORRESPONDENCE
Margaret L. Smith, MD, MPH, MHSA, KUMC, Family Medicine and Community Health, 3901 Rainbow Boulevard – Mailstop 4010, Kansas City, KS 66160; msmith33@kumc.edu

Meet Dr. A and Dr. M

Dr. A is a 50-year-old family physician who provides prenatal care in a busy practice. She sees patients in eight 4-hour clinic sessions per week and is on inpatient call 1 week out of every 2 months. Dr. A has become disillusioned with her practice. She typically works until 7 pm and arrives home exhausted, with little energy to interact with her family. She spends hours in the evenings and on weekends completing charts and answering phone calls. Dr. A is concerned because she recently gained weight and lacks an established fitness routine. The COVID-19 pandemic made life more difficult as she dealt with the risk of getting infected and the changing recommendations for treatment and prevention. After 20 years of practice, Dr. A wonders whether she should leave clinical medicine.

Dr. M is a single, 32-year-old family physician working at an academic medical center. Dr. M is unhappy in his job, is trying to grow his practice, and views himself as having little impact or autonomy. He finds himself lost while navigating the electronic health record (EHR) and struggles to be efficient in the clinic. Dr. M has multiple administrative responsibilities that require him to work evenings and weekends. Debt from medical school loans also motivates him to moonlight several weekends per month. Over the past few months, Dr. M has become frustrated and discouraged, making his depression more difficult to manage. He feels drained by the time he arrives home, where he lives alone. He has stopped exercising, socializing with friends, and dating. Dr. M often wonders if he is in the wrong profession.

Defining burnout, stress, and wellness

Dr. A and Dr. M are experiencing symptoms of burnout, common to physicians and other health care professionals. Recent studies showed an increase in burnout during the COVID-19 pandemic.^1,2 In a survey using the Maslach Burnout Inventory (MBI), approximately 44% of physicians reported at least one symptom of burnout.³ After adjusting for age, gender, relationship status, and hours worked per week, physicians were found to be at greater risk for burnout than nonphysician workers.³ The latest Medscape physician burnout survey found an increase in burnout among US physicians from 42% in 2021 to 47% in 2022 during the COVID-19 pandemic.¹ Rates of burnout were even higher among family physicians and other frontline (eg, emergency, infectious disease, and critical care) physicians.¹

Burnout has 3 key dimensions: (1) overwhelming exhaustion; (2) feelings of cynicism and detachment from the job; and (3) a sense of ineffectiveness and lack of accomplishment.⁴ The MBI is considered the standard tool for research in the field of burnout and has been repeatedly assessed for reliability and validity.⁴ The original MBI includes such items as: “I feel emotionally drained from my work,” “I feel like I’m working too hard on my job,” and “I worry that this job is hardening me emotionally.”⁵

According to the World Health Organization, burnout is an occupational phenomenon associated with chronic work-related stress that is not successfully managed.⁶ This definition emphasizes work stress as the cause of burnout, thus highlighting the importance of addressing the work environment.⁷ Physician burnout can affect physician health and wellness and the quality of patient care.^8-13 Because of the cost of burnout to individuals and the health care system, it is important to understand stressors that can lead to physician burnout.

Stress has been described as “physical, mental, or emotional strain or tension … when a person perceives that demands exceed the personal and social resources the individual is able to mobilize.”¹⁴ Work-related sources of stress affecting practicing physicians include long workdays, multiple bureaucratic tasks, lack of autonomy/control, and complex patients.^1,15

The COVID-19 pandemic is a stressor that increased physicians’ exposure to patient suffering and deaths and physicians’ vulnerability to disease at work.¹⁶ Physicians taking care of patients with COVID-19 risk infection and the possibility of infecting others.Online health records are another source of stress for many physicians.^17,18 Access to online health records on personal devices can blur the line between work and home. For each hour of direct patient contact, a physician spends an additional 2 hours interacting with an EHR.¹⁹ Among family physicians and other primary care physicians, increased EHR interaction outside clinic hours has been associated with decreased workplace satisfaction and increased rates of burnout.^11,19,20 Time spent on non-patient-facing clinical tasks, such as peer-to-peer reviews and billing queries, contributes more to burnout than clinic time alone.¹⁷

Continue to: These and other organizational factors...

A physician burnout survey found an increase in burnout among US physicians from 42% in 2021 to 47% in 2022 during the COVID-19 pandemic.

These and other organizational factors contribute to the stress experienced by physicians. Many describe themselves as feeling consumed by their work. At the beginning of the COVID-19 pandemic, physicians (and the rest of the health care team) had to quickly­ learn how to conduct virtual office visits. Clerical responsibilities increased as patients relied more on patient portals and telephone calls to receive care.

Who is predisposed to burnout? Although burnout is a work-related syndrome, studies have shown an increase in burnout associated with individual (ie, personal) factors. For example, female physicians have been shown to have higher rates of burnout compared with male physicians.^1,3 The stress of balancing the demands of the profession can begin during medical school and residency, with younger physicians having nearly­ twice the risk for stress-related symptoms when compared with older colleagues.^15,20-23 Having a child younger than 21 years old, and other personal factors related to balancing family and life demands, increases the likelihood of burnout.^11,21,22

Physicians with certain personality types and predispositions are at increased risk for burnout.^23-25 For example, neuroticism on the Big Five Personality Inventory (one of the most well-known of the psychology inventories) is associated with an increased risk for burnout. Neuroticism may manifest as sadness or related emotional dysregulation (eg, irritability, anxiety).²⁶ Other traits measured by the Big Five Personality Inventory include extraversion, agreeableness, conscientiousness, and openness to experience.²⁶

Physicians who were depressed were more likely to experience burnout symptoms (87.5%); however, only 26.2% of physicians experiencing burnout were diagnosed as having depression.

A history of depression is also associated with an increased risk for burnout.²⁷ Although depression and burnout are separate conditions, a 2016 study found significant overlap between the two.²⁷ Physicians in this study who were depressed were more likely to experience burnout symptoms (87.5%); however, only 26.2% of physicians experiencing burnout were diagnosed as having depression.²⁷ Rates of depression are higher among physicians when compared with nonphysicians, yet physicians are less likely to seek help due to fear of stigma and potential licensing concerns.^28,29 Because of this, when physicians experience depressive symptoms, they may respond by working harder rather than seeking professional counseling or emotional support. They might believe that “asking for help is a sign of weakness,” thus sacrificing their wellness.

Wellness encompasses a sense of thriving characterized by thoughts and feelings of contentment, joy, and fulfillment—and the absence of severe distress.³⁰ Wellness is a multifaceted condition that includes physical, psychological, and social aspects of an individual’s personal and professional life. Individuals experience a sense of wellness when they nurture their physical selves, minds, and relationships. People experience a sense of wellness when they balance their schedules, eat well, and maintain physical activity. Making time to enjoy family and friends also contributes to wellness.

Continue to: The culture of medicine often rewards...

The culture of medicine often rewards physician attitudes and behaviors that detract from wellness.³¹ Physicians internalize the culture of medicine that promotes perfectionism and downplays personal vulnerability.³² Physicians are reluctant to protect and preserve their wellness, believing self-sacrifice makes them good doctors. Physicians may spend countless hours counseling patients on the importance of wellness, but then work when ill or neglect their personal health needs and self-care—potentially decreasing their resilience and increasing the risk for burnout.³¹

Two paths to managing stress and preventing burnout

Patel and colleagues distinguish between 2 burnout intervention categories: (1) those that focus on individual physicians and (2) those that focus on the organizational environment.³³ We find these distinctions useful and offer strategies for enhancing individual physician wellness (TABLE 1^34-41). Similar to West and colleagues,¹¹ we offer strategies for addressing organizational sources of stress (TABLE 2^42-48). The following text describes these burnout intervention categories, emphasizing increasing self-care and changes that enable physicians to adapt effectively.

The recommendations outlined in this article are based on published stress and burnout literature, as well as the experiences of the authors. However, the number of randomized controlled studies of interventions aimed at reducing physician stress and burnout is limited. In addition, strategies proposed to reduce burnout in other professions may not address the unique stressors physicians encounter. Hence, our recommendations are limited. We have included interventions that seem optimal for individual physicians and the organizations that employ them.

Individual strategies target physical, psychological, and social wellness

Physician wellness strategies are divided into 3 categories: physical, psychological, and social wellness. Most strategies to improve physical wellness are widely known, evidence based, and recommended to patients by physicians.^34-36 For example, most physicians advise their patients to eat healthy balanced meals, avoid unhealthy foods and beverages, maintain a healthy body weight, get daily exercise and adequate sleep, avoid excessive alcohol use, and abstain from tobacco use. However, discrepancies between physicians’ advice to patients and their own behaviors are common. Simply stated, physicians are well advised to follow their own advice regarding physical self-care.

CBT and mindfulness are key to psychological wellness. Recommendations for enhancing psychological wellness are primarily derived from cognitive behavioral therapy (CBT) and mindfulness principles and practices.^37,38 CBT has been called the “gold standard” of psychotherapy, based on the breadth of research demonstrating that “no other form of psychotherapy has been shown to be systematically superior to CBT.”³⁹

Continue to: CBT is based on the premise...

CBT is based on the premise that individuals’ thoughts and beliefs largely determine how they feel (emotions) and act (behaviors). Certain thoughts lead to positive feelings and effective behaviors, while others lead to negative feelings and less effective behaviors. For example, when a physician has self-critical or helpless thoughts (eg, “I’m just no good at managing my life”), they are more likely to feel unhappy and abandon problem-solving. In contrast, when a physician has self-affirming or hopeful thoughts (eg, “This is difficult, but I have the personal resources to succeed”), they are more likely to feel confident and act to solve problems.

Physicians vacillate between these thoughts and beliefs, and their emotions and behaviors follow accordingly. When hyper-focused on “the hassles of medicine,” physicians feel defeated, depressed, and anxious about their work. In contrast, when physicians recognize and challenge problematic thoughts and focus on what they love about medicine, they feel good and interact with patients and coworkers in positive and self-reinforcing ways.

Mindfulness can help reduce psychological stress and increase personal fulfillment. Mindfulness is characterized as being in the present moment, fully accepting “what is,” and having a sense of gratitude and compassion for self and others.⁴⁰ In practice, mindfulness involves being intentional.

Dahl and colleagues⁴¹ describe a framework for human flourishing that includes 4 core dimensions of well-being (awareness, insight, connection, and purpose) that are all closely linked to mindful, intentional living. Based on their work, it is apparent that those who maintain a “heightened and flexible attentiveness” to their thoughts and feelings are likely to benefit by experiencing “improved mental health and psychological well-being.”⁴¹

However, the utility of CBT and mindfulness practices depends on receptivity to psychological interventions. Individuals who are not receptive may be hesitant to use these practices or likely will not benefit from them. Given these limitations of behavioral interventions, it would be helpful if more attention were paid to preventing and managing physician stress and burnout, especially through research focused on organizational changes.

Continue to: Supportive relationships are powerful

Supportive relationships are powerful. Finally, to enhance social wellness, it would be difficult to overstate the potential benefits of positive, supportive, close relationships.⁴² However, the demands of a career in medicine, starting in medical school, have the potential for inhibiting (rather than enhancing) close relationships.

Placing value on relationships with friends and family members is essential. As Dr. M began experiencing burnout, he felt increasingly lonely, yet he isolated himself from those who cared about him. Dr. A felt lonely at home, even though she was surrounded by family. Physicians are often reluctant to initiate vulnerable communication with others, believing “no one wants to hear about my problems.” However, by realizing the need for help and asking friends and family for emotional support, physicians can improve their wellness. Fostering supportive relationships can help provide the resilience needed to address organizational stressors.

Tackling organizational challenges

Long hours and pressure to see large numbers of patients (production demands) are a challenge across practice settings. Limiting work hours has been effective in improving the well-being of physician trainees but has had an inconsistent effect on burnout.^43,44

Organizations can offer flexible scheduling, and physicians considering limiting work hours may switch to part-time status or shift work. However, decreasing work hours may have the unintended consequence of increased stress as some physicians feel pressure to do more in less time.⁴⁵ Therefore, it’s important to set clear boundaries around work time and when and where work tasks are completed (eg, home vs office).

How we use technology matters. Given­ technology’s ever-increasing role in medicine, organizations must identify and use the most efficient, effective technology for managing clerical processes. When physicians participate in these decisions and share their experiences, technology is likely to be more user-friendly and impose less stress.⁴⁶

Continue to: If technology contributes to stress...

When physicians recognize and challenge problematic thoughts and focus on what they love about medicine, they feel good and interact with patients and coworkers in positive ways.

If technology contributes to stress by being too complex or impractical, it’s important to identify individuals in the workplace (eg, IT support or “super-users”) to help address these challenges. Organizations can implement multidisciplinary teams to address EHR challenges and decrease physician stress and burnout by training support staff to assist with clerical duties, allowing physicians to focus on patient care.^47,48 Such organizational-­directed interventions will be most successful when physicians are included in the decision-making process.⁴⁷

Take on leadership roles to influence change. Leadership may be formal (involving a title and authority) or informal (leading by example). Health care organizations that are committed to the well-being of physicians will make the effort to improve the systems in which physicians work. Physicians working in organizations that are reluctant to change have several choices: implement individual strategies, take on leadership roles to influence change, or reconsider their fit for the organization. Physicians in solo practice might consider joining others in solo practices to share systems (call, phone triage, technical resources, etc) to implement some of these interventions.

Dr. A and Dr. M implement new wellness strategies

Dr. A and Dr. M have recently committed to addressing stressors in their lives and improving their wellness. Dr. A has become more assertive at work, highlighting her need for additional resources to function effectively. In response, her practice has hired scribes to assist in documenting visits. This success has inspired Dr. A to pay attention to her lifestyle choices. Gradually, she has begun to exercise and engage in healthy eating.

Dr. M has begun to utilize resources at his medical center to improve his EHR efficiency and patient flow. He has taken steps to address his financial concerns, developing a budget and spending judiciously. He practices mindfulness and ensures that he gets at least 7 hours of sleep per night, improving his mental and physical health. By doing so, he has more energy to connect with friends, ­exercise, and date.

CORRESPONDENCE
Margaret L. Smith, MD, MPH, MHSA, KUMC, Family Medicine and Community Health, 3901 Rainbow Boulevard – Mailstop 4010, Kansas City, KS 66160; msmith33@kumc.edu

Meet Dr. A and Dr. M

Dr. A is a 50-year-old family physician who provides prenatal care in a busy practice. She sees patients in eight 4-hour clinic sessions per week and is on inpatient call 1 week out of every 2 months. Dr. A has become disillusioned with her practice. She typically works until 7 pm and arrives home exhausted, with little energy to interact with her family. She spends hours in the evenings and on weekends completing charts and answering phone calls. Dr. A is concerned because she recently gained weight and lacks an established fitness routine. The COVID-19 pandemic made life more difficult as she dealt with the risk of getting infected and the changing recommendations for treatment and prevention. After 20 years of practice, Dr. A wonders whether she should leave clinical medicine.

Dr. M is a single, 32-year-old family physician working at an academic medical center. Dr. M is unhappy in his job, is trying to grow his practice, and views himself as having little impact or autonomy. He finds himself lost while navigating the electronic health record (EHR) and struggles to be efficient in the clinic. Dr. M has multiple administrative responsibilities that require him to work evenings and weekends. Debt from medical school loans also motivates him to moonlight several weekends per month. Over the past few months, Dr. M has become frustrated and discouraged, making his depression more difficult to manage. He feels drained by the time he arrives home, where he lives alone. He has stopped exercising, socializing with friends, and dating. Dr. M often wonders if he is in the wrong profession.

Defining burnout, stress, and wellness

Dr. A and Dr. M are experiencing symptoms of burnout, common to physicians and other health care professionals. Recent studies showed an increase in burnout during the COVID-19 pandemic.^1,2 In a survey using the Maslach Burnout Inventory (MBI), approximately 44% of physicians reported at least one symptom of burnout.³ After adjusting for age, gender, relationship status, and hours worked per week, physicians were found to be at greater risk for burnout than nonphysician workers.³ The latest Medscape physician burnout survey found an increase in burnout among US physicians from 42% in 2021 to 47% in 2022 during the COVID-19 pandemic.¹ Rates of burnout were even higher among family physicians and other frontline (eg, emergency, infectious disease, and critical care) physicians.¹

Burnout has 3 key dimensions: (1) overwhelming exhaustion; (2) feelings of cynicism and detachment from the job; and (3) a sense of ineffectiveness and lack of accomplishment.⁴ The MBI is considered the standard tool for research in the field of burnout and has been repeatedly assessed for reliability and validity.⁴ The original MBI includes such items as: “I feel emotionally drained from my work,” “I feel like I’m working too hard on my job,” and “I worry that this job is hardening me emotionally.”⁵

According to the World Health Organization, burnout is an occupational phenomenon associated with chronic work-related stress that is not successfully managed.⁶ This definition emphasizes work stress as the cause of burnout, thus highlighting the importance of addressing the work environment.⁷ Physician burnout can affect physician health and wellness and the quality of patient care.^8-13 Because of the cost of burnout to individuals and the health care system, it is important to understand stressors that can lead to physician burnout.

Stress has been described as “physical, mental, or emotional strain or tension … when a person perceives that demands exceed the personal and social resources the individual is able to mobilize.”¹⁴ Work-related sources of stress affecting practicing physicians include long workdays, multiple bureaucratic tasks, lack of autonomy/control, and complex patients.^1,15

The COVID-19 pandemic is a stressor that increased physicians’ exposure to patient suffering and deaths and physicians’ vulnerability to disease at work.¹⁶ Physicians taking care of patients with COVID-19 risk infection and the possibility of infecting others.Online health records are another source of stress for many physicians.^17,18 Access to online health records on personal devices can blur the line between work and home. For each hour of direct patient contact, a physician spends an additional 2 hours interacting with an EHR.¹⁹ Among family physicians and other primary care physicians, increased EHR interaction outside clinic hours has been associated with decreased workplace satisfaction and increased rates of burnout.^11,19,20 Time spent on non-patient-facing clinical tasks, such as peer-to-peer reviews and billing queries, contributes more to burnout than clinic time alone.¹⁷

Continue to: These and other organizational factors...

A physician burnout survey found an increase in burnout among US physicians from 42% in 2021 to 47% in 2022 during the COVID-19 pandemic.

These and other organizational factors contribute to the stress experienced by physicians. Many describe themselves as feeling consumed by their work. At the beginning of the COVID-19 pandemic, physicians (and the rest of the health care team) had to quickly­ learn how to conduct virtual office visits. Clerical responsibilities increased as patients relied more on patient portals and telephone calls to receive care.

Who is predisposed to burnout? Although burnout is a work-related syndrome, studies have shown an increase in burnout associated with individual (ie, personal) factors. For example, female physicians have been shown to have higher rates of burnout compared with male physicians.^1,3 The stress of balancing the demands of the profession can begin during medical school and residency, with younger physicians having nearly­ twice the risk for stress-related symptoms when compared with older colleagues.^15,20-23 Having a child younger than 21 years old, and other personal factors related to balancing family and life demands, increases the likelihood of burnout.^11,21,22

Physicians with certain personality types and predispositions are at increased risk for burnout.^23-25 For example, neuroticism on the Big Five Personality Inventory (one of the most well-known of the psychology inventories) is associated with an increased risk for burnout. Neuroticism may manifest as sadness or related emotional dysregulation (eg, irritability, anxiety).²⁶ Other traits measured by the Big Five Personality Inventory include extraversion, agreeableness, conscientiousness, and openness to experience.²⁶

Physicians who were depressed were more likely to experience burnout symptoms (87.5%); however, only 26.2% of physicians experiencing burnout were diagnosed as having depression.

A history of depression is also associated with an increased risk for burnout.²⁷ Although depression and burnout are separate conditions, a 2016 study found significant overlap between the two.²⁷ Physicians in this study who were depressed were more likely to experience burnout symptoms (87.5%); however, only 26.2% of physicians experiencing burnout were diagnosed as having depression.²⁷ Rates of depression are higher among physicians when compared with nonphysicians, yet physicians are less likely to seek help due to fear of stigma and potential licensing concerns.^28,29 Because of this, when physicians experience depressive symptoms, they may respond by working harder rather than seeking professional counseling or emotional support. They might believe that “asking for help is a sign of weakness,” thus sacrificing their wellness.

Wellness encompasses a sense of thriving characterized by thoughts and feelings of contentment, joy, and fulfillment—and the absence of severe distress.³⁰ Wellness is a multifaceted condition that includes physical, psychological, and social aspects of an individual’s personal and professional life. Individuals experience a sense of wellness when they nurture their physical selves, minds, and relationships. People experience a sense of wellness when they balance their schedules, eat well, and maintain physical activity. Making time to enjoy family and friends also contributes to wellness.

Continue to: The culture of medicine often rewards...

The culture of medicine often rewards physician attitudes and behaviors that detract from wellness.³¹ Physicians internalize the culture of medicine that promotes perfectionism and downplays personal vulnerability.³² Physicians are reluctant to protect and preserve their wellness, believing self-sacrifice makes them good doctors. Physicians may spend countless hours counseling patients on the importance of wellness, but then work when ill or neglect their personal health needs and self-care—potentially decreasing their resilience and increasing the risk for burnout.³¹

Two paths to managing stress and preventing burnout

Patel and colleagues distinguish between 2 burnout intervention categories: (1) those that focus on individual physicians and (2) those that focus on the organizational environment.³³ We find these distinctions useful and offer strategies for enhancing individual physician wellness (TABLE 1^34-41). Similar to West and colleagues,¹¹ we offer strategies for addressing organizational sources of stress (TABLE 2^42-48). The following text describes these burnout intervention categories, emphasizing increasing self-care and changes that enable physicians to adapt effectively.

The recommendations outlined in this article are based on published stress and burnout literature, as well as the experiences of the authors. However, the number of randomized controlled studies of interventions aimed at reducing physician stress and burnout is limited. In addition, strategies proposed to reduce burnout in other professions may not address the unique stressors physicians encounter. Hence, our recommendations are limited. We have included interventions that seem optimal for individual physicians and the organizations that employ them.

Individual strategies target physical, psychological, and social wellness

Physician wellness strategies are divided into 3 categories: physical, psychological, and social wellness. Most strategies to improve physical wellness are widely known, evidence based, and recommended to patients by physicians.^34-36 For example, most physicians advise their patients to eat healthy balanced meals, avoid unhealthy foods and beverages, maintain a healthy body weight, get daily exercise and adequate sleep, avoid excessive alcohol use, and abstain from tobacco use. However, discrepancies between physicians’ advice to patients and their own behaviors are common. Simply stated, physicians are well advised to follow their own advice regarding physical self-care.

CBT and mindfulness are key to psychological wellness. Recommendations for enhancing psychological wellness are primarily derived from cognitive behavioral therapy (CBT) and mindfulness principles and practices.^37,38 CBT has been called the “gold standard” of psychotherapy, based on the breadth of research demonstrating that “no other form of psychotherapy has been shown to be systematically superior to CBT.”³⁹

Continue to: CBT is based on the premise...

CBT is based on the premise that individuals’ thoughts and beliefs largely determine how they feel (emotions) and act (behaviors). Certain thoughts lead to positive feelings and effective behaviors, while others lead to negative feelings and less effective behaviors. For example, when a physician has self-critical or helpless thoughts (eg, “I’m just no good at managing my life”), they are more likely to feel unhappy and abandon problem-solving. In contrast, when a physician has self-affirming or hopeful thoughts (eg, “This is difficult, but I have the personal resources to succeed”), they are more likely to feel confident and act to solve problems.

Physicians vacillate between these thoughts and beliefs, and their emotions and behaviors follow accordingly. When hyper-focused on “the hassles of medicine,” physicians feel defeated, depressed, and anxious about their work. In contrast, when physicians recognize and challenge problematic thoughts and focus on what they love about medicine, they feel good and interact with patients and coworkers in positive and self-reinforcing ways.

Mindfulness can help reduce psychological stress and increase personal fulfillment. Mindfulness is characterized as being in the present moment, fully accepting “what is,” and having a sense of gratitude and compassion for self and others.⁴⁰ In practice, mindfulness involves being intentional.

Dahl and colleagues⁴¹ describe a framework for human flourishing that includes 4 core dimensions of well-being (awareness, insight, connection, and purpose) that are all closely linked to mindful, intentional living. Based on their work, it is apparent that those who maintain a “heightened and flexible attentiveness” to their thoughts and feelings are likely to benefit by experiencing “improved mental health and psychological well-being.”⁴¹

However, the utility of CBT and mindfulness practices depends on receptivity to psychological interventions. Individuals who are not receptive may be hesitant to use these practices or likely will not benefit from them. Given these limitations of behavioral interventions, it would be helpful if more attention were paid to preventing and managing physician stress and burnout, especially through research focused on organizational changes.

Continue to: Supportive relationships are powerful

Supportive relationships are powerful. Finally, to enhance social wellness, it would be difficult to overstate the potential benefits of positive, supportive, close relationships.⁴² However, the demands of a career in medicine, starting in medical school, have the potential for inhibiting (rather than enhancing) close relationships.

Placing value on relationships with friends and family members is essential. As Dr. M began experiencing burnout, he felt increasingly lonely, yet he isolated himself from those who cared about him. Dr. A felt lonely at home, even though she was surrounded by family. Physicians are often reluctant to initiate vulnerable communication with others, believing “no one wants to hear about my problems.” However, by realizing the need for help and asking friends and family for emotional support, physicians can improve their wellness. Fostering supportive relationships can help provide the resilience needed to address organizational stressors.

Tackling organizational challenges

Long hours and pressure to see large numbers of patients (production demands) are a challenge across practice settings. Limiting work hours has been effective in improving the well-being of physician trainees but has had an inconsistent effect on burnout.^43,44

Organizations can offer flexible scheduling, and physicians considering limiting work hours may switch to part-time status or shift work. However, decreasing work hours may have the unintended consequence of increased stress as some physicians feel pressure to do more in less time.⁴⁵ Therefore, it’s important to set clear boundaries around work time and when and where work tasks are completed (eg, home vs office).

How we use technology matters. Given­ technology’s ever-increasing role in medicine, organizations must identify and use the most efficient, effective technology for managing clerical processes. When physicians participate in these decisions and share their experiences, technology is likely to be more user-friendly and impose less stress.⁴⁶

Continue to: If technology contributes to stress...

When physicians recognize and challenge problematic thoughts and focus on what they love about medicine, they feel good and interact with patients and coworkers in positive ways.

If technology contributes to stress by being too complex or impractical, it’s important to identify individuals in the workplace (eg, IT support or “super-users”) to help address these challenges. Organizations can implement multidisciplinary teams to address EHR challenges and decrease physician stress and burnout by training support staff to assist with clerical duties, allowing physicians to focus on patient care.^47,48 Such organizational-­directed interventions will be most successful when physicians are included in the decision-making process.⁴⁷

Take on leadership roles to influence change. Leadership may be formal (involving a title and authority) or informal (leading by example). Health care organizations that are committed to the well-being of physicians will make the effort to improve the systems in which physicians work. Physicians working in organizations that are reluctant to change have several choices: implement individual strategies, take on leadership roles to influence change, or reconsider their fit for the organization. Physicians in solo practice might consider joining others in solo practices to share systems (call, phone triage, technical resources, etc) to implement some of these interventions.

Dr. A and Dr. M implement new wellness strategies

Dr. A and Dr. M have recently committed to addressing stressors in their lives and improving their wellness. Dr. A has become more assertive at work, highlighting her need for additional resources to function effectively. In response, her practice has hired scribes to assist in documenting visits. This success has inspired Dr. A to pay attention to her lifestyle choices. Gradually, she has begun to exercise and engage in healthy eating.

Dr. M has begun to utilize resources at his medical center to improve his EHR efficiency and patient flow. He has taken steps to address his financial concerns, developing a budget and spending judiciously. He practices mindfulness and ensures that he gets at least 7 hours of sleep per night, improving his mental and physical health. By doing so, he has more energy to connect with friends, ­exercise, and date.

CORRESPONDENCE
Margaret L. Smith, MD, MPH, MHSA, KUMC, Family Medicine and Community Health, 3901 Rainbow Boulevard – Mailstop 4010, Kansas City, KS 66160; msmith33@kumc.edu