Case Example

A 37-year-old female never smoker presents to your clinic with progressive dyspnea over the past 15 years. She reports dyspnea on exertion, wheezing, chronic nasal congestion, and difficulty sleeping that started a year after she returned from military deployment to Iraq. She has been unable to exercise, even at low intensity, for the past 5 years, despite being previously active. She has experienced some symptom improvement by taking an albuterol inhaler as needed, loratadine (10 mg), and fluticasone nasal spray (50 mcg). She occasionally uses famotidine for reflux (40 mg). She deployed to Southwest Asia for 12 months (2002-2003) and was primarily stationed in Qayyarah West, an Air Force base in the Mosul district in northern Iraq. She reports exposure during deployment to the fire in the Al-Mishraq sulfur mine, located approximately 25 km north of Qayyarah West, as well as dust storms and burn pits. She currently works as a medical assistant. Her examination is remarkable for normal bronchovesicular breath sounds without any wheezing or crackles on pulmonary evaluation. Her body mass index is 31. You obtain a chest radiograph and spirometry, which are both normal.

The veteran reports feeling frustrated as she has had multiple specialty evaluations in community clinics without receiving a diagnosis, despite worsening symptoms. She reports that she added her information to the Airborne Hazards and Open Burn Pit Registry (AHOBPR). She recently received a letter from the US Department of Veterans Affairs (VA) Post-Deployment Cardiopulmonary Evaluation Network (PDCEN) and is asking you whether she should participate in the PDCEN specialty evaluation. You are not familiar with the military experiences she has described or the programs she asks you about; however, you would like to know more to best care for your patient.

Background

The year 2021 marked the 20th anniversary of the September 11 attacks and the launch of the Global War on Terrorism. Almost 3 million US military personnel have been deployed in support of these operations along with about 300,000 US civilian contractors and thousands of troops from more than 40 nations.^1-3

Deployment after 2001 to Afghanistan and the Southwest Asia theater of operations, which includes but is not limited to Iraq, Kuwait, and Saudi Arabia, has been associated with increased prevalence of dyspnea and cough as well as diagnoses of asthma, chronic obstructive pulmonary disease (COPD), and other chronic respiratory diseases.^4-9 Expert committees convened by the National Academies of Sciences, Engineering, and Medicine concluded that deployment to the Southwest Asia region and Afghanistan was associated with respiratory symptoms of cough, wheeze, and shortness of breath and might be associated with long-term health effects, particularly in vulnerable (eg, individuals with asthma) or highly exposed populations (eg, those assigned to work at burn pits).^10,11 Several reports have found constrictive bronchiolitis, emphysema, granulomatous inflammation, and pigment deposition on lung biopsy in deployed persons with unexplained dyspnea and subtle, or normal, clinical findings.^12-14

Respiratory hazards associated with deployment to Southwest Asia and Afghanistan are unique and varied. These exposures include blast injuries and a variety of particulate matter sources, such as burn pit combustion byproducts, aeroallergens, and dust storms.^7,8,15,16 One air sampling study conducted at 15 deployment sites in Southwest Asia and Afghanistan found mean fine particulate matter (PM_2.5) levels were as much as 10 times greater than sampling sites in both rural and urban cities in the United States; all sites sampled exceeded military exposure guidelines (65 µg/m³ for 1 year).^17,18 Long-term exposure to PM_2.5 has been associated with the development of chronic respiratory and cardiovascular disease; therefore, there has been considerable attention to the respiratory (and nonrespiratory) health of deployed military personnel.¹⁹

Concerns regarding the association between deployment and lung disease led to the creation of the national VA Airborne Hazards and Open Burn Pit Registry (AHOBPR) in 2014 and consists of (1) an online questionnaire to document deployment and medical history, exposure concerns, and symptoms; and (2) an optional in-person or virtual clinical health evaluation at the individual’s local VA medical center or military treatment facility (MTF). As of March 2022, more than 300,000 individuals have completed the online questionnaire of which about 30% declined the optional clinical health evaluation.

The clinical evaluation available to AHOBPR participants has not yet been described in the literature. Therefore, our objectives are to examine AHOBPR clinical evaluation data and review its application throughout the VA. In addition, we will also describe a parallel effort by the VA PDCEN, which is to provide comprehensive multiday clinical evaluations for unique AHOBPR participants with unexplained dyspnea and self-reported respiratory disease. A secondary aim of this publication is to disseminate information to health care professionals (HCPs) within and outside of the VA to aid in the referral and evaluation of previously deployed veterans who experience unexplained dyspnea.

AHOBPR Overview

The AHOBPR is an online questionnaire and optional in-person health evaluation that includes 7 major categories targeting deployment history, symptoms, medical history, health concerns, residential history, nonmilitary occupational history, nonmilitary environmental exposures, and health care utilization. The VA Defense Information Repository is used to obtain service dates for the service member/veteran, conflict involvement, and primary location during deployment. The questionnaire portion of the AHOBPR is administered online. It currently is open to all veterans who served in the Southwest Asia theater of operations (including Iraq, Kuwait, and Egypt) any time after August 2, 1990, or Afghanistan, Djibouti, Syria, or Uzbekistan after September 11, 2001. Veterans are eligible for completing the AHOBPR and optional health evaluation at no cost to the veteran regardless of VA benefits or whether they are currently enrolled in VA health care. Though the focus of the present manuscript is to profile a VA program, it is important to note that the US Department of Defense (DoD) is an active partner with the VA in the promotion of the AHOBPR to service members and similarly provides health evaluations for active-duty service members (including activating Reserve and Guard) through their local MTF.

We reviewed and analyzed AHOBPR operations and VA data from 2014 to 2020. Our analyses were limited to veterans seeking evaluation as well as their corresponding symptoms and HCP’s clinical impression from the electronic health record. As of September 20, 2021, 267,125 individuals completed the AHOBPR. The mean age was 43 years (range, 19-84), and the majority were male (86%) and served in the Army (58%). Open-air burn pits (91%), engine maintenance (38.8%), and convoy operations (71.7%) were the most common deployment-related exposures.

The optional in-person AHOBPR health evaluation may be requested by the veteran after completing the online questionnaire and is performed at the veteran’s local VA facility. The evaluation is most often completed by an environmental health clinician or primary care practitioner (PCP). A variety of resources are available to providers for training on this topic, including fact sheets, webinars, monthly calls, conferences, and accredited e-learning.²⁰ As part of the clinical evaluation, the veteran’s chief concerns are assessed and evaluated. At the time of our analysis, 24,578 clinical examinations were performed across 126 VA medical facilities, with considerable geographic variation. Veterans receiving evaluations were predominantly male (89%) with a median age of 46.0 years (IQR, 15). Veterans’ major respiratory concerns included dyspnea (45.1%), decreased exercise ability (34.8%), and cough > 3 weeks (30.3%) (Table). After clinical evaluation by a VA or MTF HCP, 47.8% were found to have a respiratory diagnosis, including asthma (30.1%), COPD (12.8%), and bronchitis (11.9%).

Post-Deployment Cardiopulmonary Evaluation Network Clinical Evaluation

In May 2019, the VA established the Airborne Hazards and Burn Pits Center of Excellence (AHBPCE). One of the AHBPCE’s objectives is to deliver specialized care and consultation for veterans with concerns about their postdeployment health, including, but not limited to, unexplained dyspnea. To meet this objective, the AHBPCE developed the PDCEN, a national network consisting of specialty HCPs from 5 VA medical centers—located in San Francisco, California; Denver, Colorado; Baltimore, Maryland; Ann Arbor, Michigan; and East Orange, New Jersey. Collectively, the PDCEN has developed a standardized approach for the comprehensive clinical evaluation of unexplained dyspnea that is implemented uniformly across sites. Staff at the PDCEN screen the AHOBPR to identify veterans with features of respiratory disease and invite them to participate in an in-person evaluation at the nearest PDCEN site. Given the specialty expertise (detailed below) within the Network, the PDCEN focuses on complex cases that are resource intensive. To address complex cases of unexplained dyspnea, the PDCEN has developed a core clinical evaluation approach (Figure).

The first step in a veteran’s PDCEN evaluation entails a set of detailed questionnaires that request information about the veteran’s current respiratory, sleep, and mental health symptoms and any associated medical diagnoses. Questionnaires also identify potential exposures to military burn pits, sulfur mine and oil field fires, diesel exhaust fumes, dust storms, urban pollution, explosions/blasts, and chemical weapons. In addition, the questionnaires include deployment geographic location, which may inform future estimates of particulate matter exposure.²¹ Prior VA and non-VA evaluations and testing of their respiratory concerns are obtained for review. Exposure and health records from the DoD are also reviewed when available.

The next step in the PDCEN evaluation comprises comprehensive testing, including complete pulmonary function testing, methacholine challenge, cardiopulmonary exercise testing, forced oscillometry and exhaled nitric oxide testing, paired high-resolution inspiratory and expiratory chest computed tomography (CT) imaging, sinus CT imaging, direct flexible laryngoscopy, echocardiography, polysomnography, and laboratory blood testing. The testing process is managed by local site coordinators and varies by institution based on availability of each testing modality and subspecialist appointments.

Once testing is completed, the veteran is evaluated by a team of HCPs, including physicians from the disciplines of pulmonary medicine, environmental and occupational health, sleep medicine, otolaryngology and speech pathology, and mental health (when appropriate). After the clinical evaluation has been completed, this team of expert HCPs at each site convenes to provide a final summary review visit intended to be a comprehensive assessment of the veteran’s primary health concerns. The 3 primary objectives of this final review are to inform the veteran of (1) what respiratory and related conditions they have; (2) whether the conditions is/are deployment related; and (3) what treatments and/or follow-up care may enhance their current state of health in partnership with their local HCPs. The PDCEN does not provide ongoing management of any conditions identified during the veteran’s evaluation but communicates findings and recommendations to the veteran and their PCP for long-term care.

Discussion

The AHOBPR was established in response to mounting concerns that service members and veterans were experiencing adverse health effects that might be attributable to deployment-related exposures. Nearly half of all patients currently enrolled in the AHOBPR report dyspnea, and about one-third have decreased exercise tolerance and/or cough. Of those who completed the questionnaire and the subsequent in-person and generalized AHOBPR examination, our interim analysis showed that about half were assigned a respiratory diagnosis. Yet for many veterans, their breathing symptoms remained unexplained or did not respond to treatment.

While the AHOBPR and related examinations address the needs of many veterans, others may require more comprehensive examination. The PDCEN attends to the latter by providing more detailed and comprehensive clinical evaluations of veterans with deployment-related respiratory health concerns and seeks to learn from these evaluations by analyzing data obtained from veterans across sites. As such, the PDCEN hopes not only to improve the health of individual veterans, but also create standard practices for both VA and non-VA community evaluation of veterans exposed to respiratory hazards during deployment.

One of the major challenges in the field of postdeployment respiratory health is the lack of clear universal language or case definitions that encompass the veteran’s clinical concerns. In an influential case series published in 2011, 38 (77%) of 49 soldiers with history of airborne hazard exposure and unexplained exercise intolerance were reported to have histopathology consistent with constrictive bronchiolitis on surgical lung biopsy.¹⁴ Subsequent publications have described other histopathologic features in deployed military personnel, including granulomatous inflammation, interstitial lung disease, emphysema, and pleuritis.^12-14 Reconciling these findings from surgical lung biopsy with the clinical presentation and noninvasive studies has proved difficult. Therefore, several groups of investigators have proposed terms, including postdeployment respiratory syndrome, deployment-related distal lung disease, and Iraq/Afghanistan War lung injury to describe the increased respiratory symptoms and variety of histopathologic and imaging findings in this population.^9,12,22 At present, there remains a lack of consensus on terminology and case definitions as well as the role of military environmental exposures in exacerbating and/or causing these conditions. As HCPs, it is important to appreciate and acknowledge that the ambiguity and controversy pertaining to terminology, causation, and service connections are a common source of frustration experienced by veterans, which are increasingly reflected among reports in popular media and lay press.

A second and related challenge in the field of postdeployment respiratory health that contributes to veteran and HCP frustration is that many of the aforementioned abnormalities described on surgical lung biopsy are not readily identifiable on noninvasive tests, including traditional interpretation of pulmonary function tests or chest CT imaging.^12-14,22 Thus, underlying conditions could be overlooked and veterans’ concerns and symptoms may be dismissed or misattributed to other comorbid conditions. While surgical lung biopsies may offer diagnostic clarity in identifying lung disease, there are significant procedural risks of surgical and anesthetic complications. Furthermore, a definitive diagnosis does not necessarily guarantee a clear treatment plan. For example, there are no current therapies approved by the US Food and Drug Administration for the treatment of constrictive bronchiolitis.

Research efforts are underway, including within the PDCEN, to evaluate a more sensitive and noninvasive assessment of the small airways that may even reduce or eliminate the need for surgical lung biopsy. In contrast to traditional pulmonary function testing, which is helpful for evaluation of the larger airways, forced oscillation technique can be used noninvasively, using pressure oscillations to evaluate for diseases of the smaller airways and has been used in the veteran population and in those exposed to dust from the World Trade Center disaster.^23-25 Multiple breath washout technique provides a lung clearance index that is determined by the number of lung turnovers it takes to clear the lungs of an inert gas (eg, sulfur hexafluoride, nitrogen). Elevated lung clearance index values suggest ventilation heterogeneity and have been shown to be higher among deployed veterans with dyspnea.^26,27 Finally, advanced CT analytic techniques may help identify functional small airways disease and are higher in deployed service members with constrictive bronchiolitis on surgical lung biopsy.²⁸ These innovative noninvasive techniques are experimental but promising, especially as part of a broader evaluation of small airways disease.

AHOBPR clinical evaluations represent an initial step to better understand postdeployment health conditions available to all AHOBPR participants. The PDCEN clinical evaluation extends the AHOBPR evaluation by providing specialty care for certain veterans requiring more comprehensive evaluation while systematically collecting and analyzing clinical data to advance the field. The VA is committed to leveraging these data and all available expertise to provide a clear description of the spectrum of disease in this population and improve our ability to diagnose, follow, and treat respiratory health conditions occurring after deployment to Southwest Asia and Afghanistan.

Case Conclusion

The veteran was referred to a PDCEN site and underwent a comprehensive multidisciplinary evaluation. Pulmonary function testing showed lung volumes and vital capacity within the predicted normal range, mild air trapping, and a low diffusion capacity for carbon monoxide. Methacholine challenge testing was normal; however, forced oscillometry suggested small airways obstruction. A high-resolution CT showed air trapping without parenchymal changes. Cardiopulmonary exercise testing demonstrated a peak exercise capacity within the predicted normal range but low breathing reserve. Otolaryngology evaluation including laryngoscopy suggested chronic nonallergic rhinitis.

At the end of the veteran’s evaluation, a summary review reported nonallergic rhinitis and distal airway obstruction consistent with small airways disease. Both were reported as most likely related to deployment given her significant environmental exposures and the temporal relationship with her deployment and symptom onset as well as lack of other identifiable causes. A more precise histopathologic diagnosis could be firmly established with a surgical lung biopsy, but after shared decision making with a PDCEN HCP, the patient declined to undergo this invasive procedure. After you review the summary review and recommendations from the PDCEN group, you start the veteran on intranasal steroids and a combined inhaled corticosteroid/long-acting β agonist inhaler as well as refer the veteran to pulmonary rehabilitation. After several weeks, she reports an improvement in sleep and nasal symptoms but continues to experience residual exercise intolerance.

This case serves as an example of the significant limitations that a previously active and healthy patient can develop after deployment to Southwest Asia and Afghanistan. Encouraging this veteran to complete the AHOBPR allowed her to be considered for a PDCEN evaluation that provided the opportunity to undergo a comprehensive noninvasive evaluation of her chronic dyspnea. In doing so, she obtained 2 important diagnoses and data from her evaluation will help establish best practices for standardized evaluations of respiratory concerns following deployment. Through the AHOBPR and PDCEN, the VA seeks to better understand postdeployment health conditions, their relationship to military and environmental exposures, and how best to diagnose and treat these conditions.

Acknowledgments

This work was supported by the US Department of Veterans Affairs (VA) Airborne Hazards and Burn Pits Center of Excellence (Public Law 115-929). The authors acknowledge support and contributions from Dr. Eric Shuping and leadership at VA’s Health Outcomes Military Exposures office as well as the New Jersey War Related Illness and Injury Study Center. In addition, we thank Erin McRoberts and Rajeev Swarup for their contributions to the Post-Deployment Cardiopulmonary Evaluation Network. Post-Deployment Cardiopulmonary Evaluation Network members:

Mehrdad Arjomandi, Caroline Davis, Michelle DeLuca, Nancy Eager, Courtney A. Eberhardt, Michael J. Falvo, Timothy Foley, Fiona A.S. Graff, Deborah Heaney, Stella E. Hines, Rachel E. Howard, Nisha Jani, Sheena Kamineni, Silpa Krefft, Mary L. Langlois, Helen Lozier, Simran K. Matharu, Anisa Moore, Lydia Patrick-DeLuca, Edward Pickering, Alexander Rabin, Michelle Robertson, Samantha L. Rogers, Aaron H. Schneider, Anand Shah, Anays Sotolongo, Jennifer H. Therkorn, Rebecca I. Toczylowski, Matthew Watson, Alison D. Wilczynski, Ian W. Wilson, Romi A. Yount.

Case Example

A 37-year-old female never smoker presents to your clinic with progressive dyspnea over the past 15 years. She reports dyspnea on exertion, wheezing, chronic nasal congestion, and difficulty sleeping that started a year after she returned from military deployment to Iraq. She has been unable to exercise, even at low intensity, for the past 5 years, despite being previously active. She has experienced some symptom improvement by taking an albuterol inhaler as needed, loratadine (10 mg), and fluticasone nasal spray (50 mcg). She occasionally uses famotidine for reflux (40 mg). She deployed to Southwest Asia for 12 months (2002-2003) and was primarily stationed in Qayyarah West, an Air Force base in the Mosul district in northern Iraq. She reports exposure during deployment to the fire in the Al-Mishraq sulfur mine, located approximately 25 km north of Qayyarah West, as well as dust storms and burn pits. She currently works as a medical assistant. Her examination is remarkable for normal bronchovesicular breath sounds without any wheezing or crackles on pulmonary evaluation. Her body mass index is 31. You obtain a chest radiograph and spirometry, which are both normal.

The veteran reports feeling frustrated as she has had multiple specialty evaluations in community clinics without receiving a diagnosis, despite worsening symptoms. She reports that she added her information to the Airborne Hazards and Open Burn Pit Registry (AHOBPR). She recently received a letter from the US Department of Veterans Affairs (VA) Post-Deployment Cardiopulmonary Evaluation Network (PDCEN) and is asking you whether she should participate in the PDCEN specialty evaluation. You are not familiar with the military experiences she has described or the programs she asks you about; however, you would like to know more to best care for your patient.

Background

The year 2021 marked the 20th anniversary of the September 11 attacks and the launch of the Global War on Terrorism. Almost 3 million US military personnel have been deployed in support of these operations along with about 300,000 US civilian contractors and thousands of troops from more than 40 nations.^1-3

Deployment after 2001 to Afghanistan and the Southwest Asia theater of operations, which includes but is not limited to Iraq, Kuwait, and Saudi Arabia, has been associated with increased prevalence of dyspnea and cough as well as diagnoses of asthma, chronic obstructive pulmonary disease (COPD), and other chronic respiratory diseases.^4-9 Expert committees convened by the National Academies of Sciences, Engineering, and Medicine concluded that deployment to the Southwest Asia region and Afghanistan was associated with respiratory symptoms of cough, wheeze, and shortness of breath and might be associated with long-term health effects, particularly in vulnerable (eg, individuals with asthma) or highly exposed populations (eg, those assigned to work at burn pits).^10,11 Several reports have found constrictive bronchiolitis, emphysema, granulomatous inflammation, and pigment deposition on lung biopsy in deployed persons with unexplained dyspnea and subtle, or normal, clinical findings.^12-14

Respiratory hazards associated with deployment to Southwest Asia and Afghanistan are unique and varied. These exposures include blast injuries and a variety of particulate matter sources, such as burn pit combustion byproducts, aeroallergens, and dust storms.^7,8,15,16 One air sampling study conducted at 15 deployment sites in Southwest Asia and Afghanistan found mean fine particulate matter (PM_2.5) levels were as much as 10 times greater than sampling sites in both rural and urban cities in the United States; all sites sampled exceeded military exposure guidelines (65 µg/m³ for 1 year).^17,18 Long-term exposure to PM_2.5 has been associated with the development of chronic respiratory and cardiovascular disease; therefore, there has been considerable attention to the respiratory (and nonrespiratory) health of deployed military personnel.¹⁹

Concerns regarding the association between deployment and lung disease led to the creation of the national VA Airborne Hazards and Open Burn Pit Registry (AHOBPR) in 2014 and consists of (1) an online questionnaire to document deployment and medical history, exposure concerns, and symptoms; and (2) an optional in-person or virtual clinical health evaluation at the individual’s local VA medical center or military treatment facility (MTF). As of March 2022, more than 300,000 individuals have completed the online questionnaire of which about 30% declined the optional clinical health evaluation.

The clinical evaluation available to AHOBPR participants has not yet been described in the literature. Therefore, our objectives are to examine AHOBPR clinical evaluation data and review its application throughout the VA. In addition, we will also describe a parallel effort by the VA PDCEN, which is to provide comprehensive multiday clinical evaluations for unique AHOBPR participants with unexplained dyspnea and self-reported respiratory disease. A secondary aim of this publication is to disseminate information to health care professionals (HCPs) within and outside of the VA to aid in the referral and evaluation of previously deployed veterans who experience unexplained dyspnea.

AHOBPR Overview

The AHOBPR is an online questionnaire and optional in-person health evaluation that includes 7 major categories targeting deployment history, symptoms, medical history, health concerns, residential history, nonmilitary occupational history, nonmilitary environmental exposures, and health care utilization. The VA Defense Information Repository is used to obtain service dates for the service member/veteran, conflict involvement, and primary location during deployment. The questionnaire portion of the AHOBPR is administered online. It currently is open to all veterans who served in the Southwest Asia theater of operations (including Iraq, Kuwait, and Egypt) any time after August 2, 1990, or Afghanistan, Djibouti, Syria, or Uzbekistan after September 11, 2001. Veterans are eligible for completing the AHOBPR and optional health evaluation at no cost to the veteran regardless of VA benefits or whether they are currently enrolled in VA health care. Though the focus of the present manuscript is to profile a VA program, it is important to note that the US Department of Defense (DoD) is an active partner with the VA in the promotion of the AHOBPR to service members and similarly provides health evaluations for active-duty service members (including activating Reserve and Guard) through their local MTF.

We reviewed and analyzed AHOBPR operations and VA data from 2014 to 2020. Our analyses were limited to veterans seeking evaluation as well as their corresponding symptoms and HCP’s clinical impression from the electronic health record. As of September 20, 2021, 267,125 individuals completed the AHOBPR. The mean age was 43 years (range, 19-84), and the majority were male (86%) and served in the Army (58%). Open-air burn pits (91%), engine maintenance (38.8%), and convoy operations (71.7%) were the most common deployment-related exposures.

The optional in-person AHOBPR health evaluation may be requested by the veteran after completing the online questionnaire and is performed at the veteran’s local VA facility. The evaluation is most often completed by an environmental health clinician or primary care practitioner (PCP). A variety of resources are available to providers for training on this topic, including fact sheets, webinars, monthly calls, conferences, and accredited e-learning.²⁰ As part of the clinical evaluation, the veteran’s chief concerns are assessed and evaluated. At the time of our analysis, 24,578 clinical examinations were performed across 126 VA medical facilities, with considerable geographic variation. Veterans receiving evaluations were predominantly male (89%) with a median age of 46.0 years (IQR, 15). Veterans’ major respiratory concerns included dyspnea (45.1%), decreased exercise ability (34.8%), and cough > 3 weeks (30.3%) (Table). After clinical evaluation by a VA or MTF HCP, 47.8% were found to have a respiratory diagnosis, including asthma (30.1%), COPD (12.8%), and bronchitis (11.9%).

Post-Deployment Cardiopulmonary Evaluation Network Clinical Evaluation

In May 2019, the VA established the Airborne Hazards and Burn Pits Center of Excellence (AHBPCE). One of the AHBPCE’s objectives is to deliver specialized care and consultation for veterans with concerns about their postdeployment health, including, but not limited to, unexplained dyspnea. To meet this objective, the AHBPCE developed the PDCEN, a national network consisting of specialty HCPs from 5 VA medical centers—located in San Francisco, California; Denver, Colorado; Baltimore, Maryland; Ann Arbor, Michigan; and East Orange, New Jersey. Collectively, the PDCEN has developed a standardized approach for the comprehensive clinical evaluation of unexplained dyspnea that is implemented uniformly across sites. Staff at the PDCEN screen the AHOBPR to identify veterans with features of respiratory disease and invite them to participate in an in-person evaluation at the nearest PDCEN site. Given the specialty expertise (detailed below) within the Network, the PDCEN focuses on complex cases that are resource intensive. To address complex cases of unexplained dyspnea, the PDCEN has developed a core clinical evaluation approach (Figure).

The first step in a veteran’s PDCEN evaluation entails a set of detailed questionnaires that request information about the veteran’s current respiratory, sleep, and mental health symptoms and any associated medical diagnoses. Questionnaires also identify potential exposures to military burn pits, sulfur mine and oil field fires, diesel exhaust fumes, dust storms, urban pollution, explosions/blasts, and chemical weapons. In addition, the questionnaires include deployment geographic location, which may inform future estimates of particulate matter exposure.²¹ Prior VA and non-VA evaluations and testing of their respiratory concerns are obtained for review. Exposure and health records from the DoD are also reviewed when available.

The next step in the PDCEN evaluation comprises comprehensive testing, including complete pulmonary function testing, methacholine challenge, cardiopulmonary exercise testing, forced oscillometry and exhaled nitric oxide testing, paired high-resolution inspiratory and expiratory chest computed tomography (CT) imaging, sinus CT imaging, direct flexible laryngoscopy, echocardiography, polysomnography, and laboratory blood testing. The testing process is managed by local site coordinators and varies by institution based on availability of each testing modality and subspecialist appointments.

Once testing is completed, the veteran is evaluated by a team of HCPs, including physicians from the disciplines of pulmonary medicine, environmental and occupational health, sleep medicine, otolaryngology and speech pathology, and mental health (when appropriate). After the clinical evaluation has been completed, this team of expert HCPs at each site convenes to provide a final summary review visit intended to be a comprehensive assessment of the veteran’s primary health concerns. The 3 primary objectives of this final review are to inform the veteran of (1) what respiratory and related conditions they have; (2) whether the conditions is/are deployment related; and (3) what treatments and/or follow-up care may enhance their current state of health in partnership with their local HCPs. The PDCEN does not provide ongoing management of any conditions identified during the veteran’s evaluation but communicates findings and recommendations to the veteran and their PCP for long-term care.

Discussion

The AHOBPR was established in response to mounting concerns that service members and veterans were experiencing adverse health effects that might be attributable to deployment-related exposures. Nearly half of all patients currently enrolled in the AHOBPR report dyspnea, and about one-third have decreased exercise tolerance and/or cough. Of those who completed the questionnaire and the subsequent in-person and generalized AHOBPR examination, our interim analysis showed that about half were assigned a respiratory diagnosis. Yet for many veterans, their breathing symptoms remained unexplained or did not respond to treatment.

While the AHOBPR and related examinations address the needs of many veterans, others may require more comprehensive examination. The PDCEN attends to the latter by providing more detailed and comprehensive clinical evaluations of veterans with deployment-related respiratory health concerns and seeks to learn from these evaluations by analyzing data obtained from veterans across sites. As such, the PDCEN hopes not only to improve the health of individual veterans, but also create standard practices for both VA and non-VA community evaluation of veterans exposed to respiratory hazards during deployment.

One of the major challenges in the field of postdeployment respiratory health is the lack of clear universal language or case definitions that encompass the veteran’s clinical concerns. In an influential case series published in 2011, 38 (77%) of 49 soldiers with history of airborne hazard exposure and unexplained exercise intolerance were reported to have histopathology consistent with constrictive bronchiolitis on surgical lung biopsy.¹⁴ Subsequent publications have described other histopathologic features in deployed military personnel, including granulomatous inflammation, interstitial lung disease, emphysema, and pleuritis.^12-14 Reconciling these findings from surgical lung biopsy with the clinical presentation and noninvasive studies has proved difficult. Therefore, several groups of investigators have proposed terms, including postdeployment respiratory syndrome, deployment-related distal lung disease, and Iraq/Afghanistan War lung injury to describe the increased respiratory symptoms and variety of histopathologic and imaging findings in this population.^9,12,22 At present, there remains a lack of consensus on terminology and case definitions as well as the role of military environmental exposures in exacerbating and/or causing these conditions. As HCPs, it is important to appreciate and acknowledge that the ambiguity and controversy pertaining to terminology, causation, and service connections are a common source of frustration experienced by veterans, which are increasingly reflected among reports in popular media and lay press.

A second and related challenge in the field of postdeployment respiratory health that contributes to veteran and HCP frustration is that many of the aforementioned abnormalities described on surgical lung biopsy are not readily identifiable on noninvasive tests, including traditional interpretation of pulmonary function tests or chest CT imaging.^12-14,22 Thus, underlying conditions could be overlooked and veterans’ concerns and symptoms may be dismissed or misattributed to other comorbid conditions. While surgical lung biopsies may offer diagnostic clarity in identifying lung disease, there are significant procedural risks of surgical and anesthetic complications. Furthermore, a definitive diagnosis does not necessarily guarantee a clear treatment plan. For example, there are no current therapies approved by the US Food and Drug Administration for the treatment of constrictive bronchiolitis.

Research efforts are underway, including within the PDCEN, to evaluate a more sensitive and noninvasive assessment of the small airways that may even reduce or eliminate the need for surgical lung biopsy. In contrast to traditional pulmonary function testing, which is helpful for evaluation of the larger airways, forced oscillation technique can be used noninvasively, using pressure oscillations to evaluate for diseases of the smaller airways and has been used in the veteran population and in those exposed to dust from the World Trade Center disaster.^23-25 Multiple breath washout technique provides a lung clearance index that is determined by the number of lung turnovers it takes to clear the lungs of an inert gas (eg, sulfur hexafluoride, nitrogen). Elevated lung clearance index values suggest ventilation heterogeneity and have been shown to be higher among deployed veterans with dyspnea.^26,27 Finally, advanced CT analytic techniques may help identify functional small airways disease and are higher in deployed service members with constrictive bronchiolitis on surgical lung biopsy.²⁸ These innovative noninvasive techniques are experimental but promising, especially as part of a broader evaluation of small airways disease.

AHOBPR clinical evaluations represent an initial step to better understand postdeployment health conditions available to all AHOBPR participants. The PDCEN clinical evaluation extends the AHOBPR evaluation by providing specialty care for certain veterans requiring more comprehensive evaluation while systematically collecting and analyzing clinical data to advance the field. The VA is committed to leveraging these data and all available expertise to provide a clear description of the spectrum of disease in this population and improve our ability to diagnose, follow, and treat respiratory health conditions occurring after deployment to Southwest Asia and Afghanistan.

Case Conclusion

The veteran was referred to a PDCEN site and underwent a comprehensive multidisciplinary evaluation. Pulmonary function testing showed lung volumes and vital capacity within the predicted normal range, mild air trapping, and a low diffusion capacity for carbon monoxide. Methacholine challenge testing was normal; however, forced oscillometry suggested small airways obstruction. A high-resolution CT showed air trapping without parenchymal changes. Cardiopulmonary exercise testing demonstrated a peak exercise capacity within the predicted normal range but low breathing reserve. Otolaryngology evaluation including laryngoscopy suggested chronic nonallergic rhinitis.

At the end of the veteran’s evaluation, a summary review reported nonallergic rhinitis and distal airway obstruction consistent with small airways disease. Both were reported as most likely related to deployment given her significant environmental exposures and the temporal relationship with her deployment and symptom onset as well as lack of other identifiable causes. A more precise histopathologic diagnosis could be firmly established with a surgical lung biopsy, but after shared decision making with a PDCEN HCP, the patient declined to undergo this invasive procedure. After you review the summary review and recommendations from the PDCEN group, you start the veteran on intranasal steroids and a combined inhaled corticosteroid/long-acting β agonist inhaler as well as refer the veteran to pulmonary rehabilitation. After several weeks, she reports an improvement in sleep and nasal symptoms but continues to experience residual exercise intolerance.

This case serves as an example of the significant limitations that a previously active and healthy patient can develop after deployment to Southwest Asia and Afghanistan. Encouraging this veteran to complete the AHOBPR allowed her to be considered for a PDCEN evaluation that provided the opportunity to undergo a comprehensive noninvasive evaluation of her chronic dyspnea. In doing so, she obtained 2 important diagnoses and data from her evaluation will help establish best practices for standardized evaluations of respiratory concerns following deployment. Through the AHOBPR and PDCEN, the VA seeks to better understand postdeployment health conditions, their relationship to military and environmental exposures, and how best to diagnose and treat these conditions.

Acknowledgments

This work was supported by the US Department of Veterans Affairs (VA) Airborne Hazards and Burn Pits Center of Excellence (Public Law 115-929). The authors acknowledge support and contributions from Dr. Eric Shuping and leadership at VA’s Health Outcomes Military Exposures office as well as the New Jersey War Related Illness and Injury Study Center. In addition, we thank Erin McRoberts and Rajeev Swarup for their contributions to the Post-Deployment Cardiopulmonary Evaluation Network. Post-Deployment Cardiopulmonary Evaluation Network members:

Mehrdad Arjomandi, Caroline Davis, Michelle DeLuca, Nancy Eager, Courtney A. Eberhardt, Michael J. Falvo, Timothy Foley, Fiona A.S. Graff, Deborah Heaney, Stella E. Hines, Rachel E. Howard, Nisha Jani, Sheena Kamineni, Silpa Krefft, Mary L. Langlois, Helen Lozier, Simran K. Matharu, Anisa Moore, Lydia Patrick-DeLuca, Edward Pickering, Alexander Rabin, Michelle Robertson, Samantha L. Rogers, Aaron H. Schneider, Anand Shah, Anays Sotolongo, Jennifer H. Therkorn, Rebecca I. Toczylowski, Matthew Watson, Alison D. Wilczynski, Ian W. Wilson, Romi A. Yount.

Case Example

A 37-year-old female never smoker presents to your clinic with progressive dyspnea over the past 15 years. She reports dyspnea on exertion, wheezing, chronic nasal congestion, and difficulty sleeping that started a year after she returned from military deployment to Iraq. She has been unable to exercise, even at low intensity, for the past 5 years, despite being previously active. She has experienced some symptom improvement by taking an albuterol inhaler as needed, loratadine (10 mg), and fluticasone nasal spray (50 mcg). She occasionally uses famotidine for reflux (40 mg). She deployed to Southwest Asia for 12 months (2002-2003) and was primarily stationed in Qayyarah West, an Air Force base in the Mosul district in northern Iraq. She reports exposure during deployment to the fire in the Al-Mishraq sulfur mine, located approximately 25 km north of Qayyarah West, as well as dust storms and burn pits. She currently works as a medical assistant. Her examination is remarkable for normal bronchovesicular breath sounds without any wheezing or crackles on pulmonary evaluation. Her body mass index is 31. You obtain a chest radiograph and spirometry, which are both normal.

The veteran reports feeling frustrated as she has had multiple specialty evaluations in community clinics without receiving a diagnosis, despite worsening symptoms. She reports that she added her information to the Airborne Hazards and Open Burn Pit Registry (AHOBPR). She recently received a letter from the US Department of Veterans Affairs (VA) Post-Deployment Cardiopulmonary Evaluation Network (PDCEN) and is asking you whether she should participate in the PDCEN specialty evaluation. You are not familiar with the military experiences she has described or the programs she asks you about; however, you would like to know more to best care for your patient.

Background

The year 2021 marked the 20th anniversary of the September 11 attacks and the launch of the Global War on Terrorism. Almost 3 million US military personnel have been deployed in support of these operations along with about 300,000 US civilian contractors and thousands of troops from more than 40 nations.^1-3

Deployment after 2001 to Afghanistan and the Southwest Asia theater of operations, which includes but is not limited to Iraq, Kuwait, and Saudi Arabia, has been associated with increased prevalence of dyspnea and cough as well as diagnoses of asthma, chronic obstructive pulmonary disease (COPD), and other chronic respiratory diseases.^4-9 Expert committees convened by the National Academies of Sciences, Engineering, and Medicine concluded that deployment to the Southwest Asia region and Afghanistan was associated with respiratory symptoms of cough, wheeze, and shortness of breath and might be associated with long-term health effects, particularly in vulnerable (eg, individuals with asthma) or highly exposed populations (eg, those assigned to work at burn pits).^10,11 Several reports have found constrictive bronchiolitis, emphysema, granulomatous inflammation, and pigment deposition on lung biopsy in deployed persons with unexplained dyspnea and subtle, or normal, clinical findings.^12-14

Respiratory hazards associated with deployment to Southwest Asia and Afghanistan are unique and varied. These exposures include blast injuries and a variety of particulate matter sources, such as burn pit combustion byproducts, aeroallergens, and dust storms.^7,8,15,16 One air sampling study conducted at 15 deployment sites in Southwest Asia and Afghanistan found mean fine particulate matter (PM_2.5) levels were as much as 10 times greater than sampling sites in both rural and urban cities in the United States; all sites sampled exceeded military exposure guidelines (65 µg/m³ for 1 year).^17,18 Long-term exposure to PM_2.5 has been associated with the development of chronic respiratory and cardiovascular disease; therefore, there has been considerable attention to the respiratory (and nonrespiratory) health of deployed military personnel.¹⁹

Concerns regarding the association between deployment and lung disease led to the creation of the national VA Airborne Hazards and Open Burn Pit Registry (AHOBPR) in 2014 and consists of (1) an online questionnaire to document deployment and medical history, exposure concerns, and symptoms; and (2) an optional in-person or virtual clinical health evaluation at the individual’s local VA medical center or military treatment facility (MTF). As of March 2022, more than 300,000 individuals have completed the online questionnaire of which about 30% declined the optional clinical health evaluation.

The clinical evaluation available to AHOBPR participants has not yet been described in the literature. Therefore, our objectives are to examine AHOBPR clinical evaluation data and review its application throughout the VA. In addition, we will also describe a parallel effort by the VA PDCEN, which is to provide comprehensive multiday clinical evaluations for unique AHOBPR participants with unexplained dyspnea and self-reported respiratory disease. A secondary aim of this publication is to disseminate information to health care professionals (HCPs) within and outside of the VA to aid in the referral and evaluation of previously deployed veterans who experience unexplained dyspnea.

AHOBPR Overview

The AHOBPR is an online questionnaire and optional in-person health evaluation that includes 7 major categories targeting deployment history, symptoms, medical history, health concerns, residential history, nonmilitary occupational history, nonmilitary environmental exposures, and health care utilization. The VA Defense Information Repository is used to obtain service dates for the service member/veteran, conflict involvement, and primary location during deployment. The questionnaire portion of the AHOBPR is administered online. It currently is open to all veterans who served in the Southwest Asia theater of operations (including Iraq, Kuwait, and Egypt) any time after August 2, 1990, or Afghanistan, Djibouti, Syria, or Uzbekistan after September 11, 2001. Veterans are eligible for completing the AHOBPR and optional health evaluation at no cost to the veteran regardless of VA benefits or whether they are currently enrolled in VA health care. Though the focus of the present manuscript is to profile a VA program, it is important to note that the US Department of Defense (DoD) is an active partner with the VA in the promotion of the AHOBPR to service members and similarly provides health evaluations for active-duty service members (including activating Reserve and Guard) through their local MTF.

We reviewed and analyzed AHOBPR operations and VA data from 2014 to 2020. Our analyses were limited to veterans seeking evaluation as well as their corresponding symptoms and HCP’s clinical impression from the electronic health record. As of September 20, 2021, 267,125 individuals completed the AHOBPR. The mean age was 43 years (range, 19-84), and the majority were male (86%) and served in the Army (58%). Open-air burn pits (91%), engine maintenance (38.8%), and convoy operations (71.7%) were the most common deployment-related exposures.

The optional in-person AHOBPR health evaluation may be requested by the veteran after completing the online questionnaire and is performed at the veteran’s local VA facility. The evaluation is most often completed by an environmental health clinician or primary care practitioner (PCP). A variety of resources are available to providers for training on this topic, including fact sheets, webinars, monthly calls, conferences, and accredited e-learning.²⁰ As part of the clinical evaluation, the veteran’s chief concerns are assessed and evaluated. At the time of our analysis, 24,578 clinical examinations were performed across 126 VA medical facilities, with considerable geographic variation. Veterans receiving evaluations were predominantly male (89%) with a median age of 46.0 years (IQR, 15). Veterans’ major respiratory concerns included dyspnea (45.1%), decreased exercise ability (34.8%), and cough > 3 weeks (30.3%) (Table). After clinical evaluation by a VA or MTF HCP, 47.8% were found to have a respiratory diagnosis, including asthma (30.1%), COPD (12.8%), and bronchitis (11.9%).

Post-Deployment Cardiopulmonary Evaluation Network Clinical Evaluation

In May 2019, the VA established the Airborne Hazards and Burn Pits Center of Excellence (AHBPCE). One of the AHBPCE’s objectives is to deliver specialized care and consultation for veterans with concerns about their postdeployment health, including, but not limited to, unexplained dyspnea. To meet this objective, the AHBPCE developed the PDCEN, a national network consisting of specialty HCPs from 5 VA medical centers—located in San Francisco, California; Denver, Colorado; Baltimore, Maryland; Ann Arbor, Michigan; and East Orange, New Jersey. Collectively, the PDCEN has developed a standardized approach for the comprehensive clinical evaluation of unexplained dyspnea that is implemented uniformly across sites. Staff at the PDCEN screen the AHOBPR to identify veterans with features of respiratory disease and invite them to participate in an in-person evaluation at the nearest PDCEN site. Given the specialty expertise (detailed below) within the Network, the PDCEN focuses on complex cases that are resource intensive. To address complex cases of unexplained dyspnea, the PDCEN has developed a core clinical evaluation approach (Figure).

The first step in a veteran’s PDCEN evaluation entails a set of detailed questionnaires that request information about the veteran’s current respiratory, sleep, and mental health symptoms and any associated medical diagnoses. Questionnaires also identify potential exposures to military burn pits, sulfur mine and oil field fires, diesel exhaust fumes, dust storms, urban pollution, explosions/blasts, and chemical weapons. In addition, the questionnaires include deployment geographic location, which may inform future estimates of particulate matter exposure.²¹ Prior VA and non-VA evaluations and testing of their respiratory concerns are obtained for review. Exposure and health records from the DoD are also reviewed when available.

The next step in the PDCEN evaluation comprises comprehensive testing, including complete pulmonary function testing, methacholine challenge, cardiopulmonary exercise testing, forced oscillometry and exhaled nitric oxide testing, paired high-resolution inspiratory and expiratory chest computed tomography (CT) imaging, sinus CT imaging, direct flexible laryngoscopy, echocardiography, polysomnography, and laboratory blood testing. The testing process is managed by local site coordinators and varies by institution based on availability of each testing modality and subspecialist appointments.

Once testing is completed, the veteran is evaluated by a team of HCPs, including physicians from the disciplines of pulmonary medicine, environmental and occupational health, sleep medicine, otolaryngology and speech pathology, and mental health (when appropriate). After the clinical evaluation has been completed, this team of expert HCPs at each site convenes to provide a final summary review visit intended to be a comprehensive assessment of the veteran’s primary health concerns. The 3 primary objectives of this final review are to inform the veteran of (1) what respiratory and related conditions they have; (2) whether the conditions is/are deployment related; and (3) what treatments and/or follow-up care may enhance their current state of health in partnership with their local HCPs. The PDCEN does not provide ongoing management of any conditions identified during the veteran’s evaluation but communicates findings and recommendations to the veteran and their PCP for long-term care.

Discussion

The AHOBPR was established in response to mounting concerns that service members and veterans were experiencing adverse health effects that might be attributable to deployment-related exposures. Nearly half of all patients currently enrolled in the AHOBPR report dyspnea, and about one-third have decreased exercise tolerance and/or cough. Of those who completed the questionnaire and the subsequent in-person and generalized AHOBPR examination, our interim analysis showed that about half were assigned a respiratory diagnosis. Yet for many veterans, their breathing symptoms remained unexplained or did not respond to treatment.

While the AHOBPR and related examinations address the needs of many veterans, others may require more comprehensive examination. The PDCEN attends to the latter by providing more detailed and comprehensive clinical evaluations of veterans with deployment-related respiratory health concerns and seeks to learn from these evaluations by analyzing data obtained from veterans across sites. As such, the PDCEN hopes not only to improve the health of individual veterans, but also create standard practices for both VA and non-VA community evaluation of veterans exposed to respiratory hazards during deployment.

One of the major challenges in the field of postdeployment respiratory health is the lack of clear universal language or case definitions that encompass the veteran’s clinical concerns. In an influential case series published in 2011, 38 (77%) of 49 soldiers with history of airborne hazard exposure and unexplained exercise intolerance were reported to have histopathology consistent with constrictive bronchiolitis on surgical lung biopsy.¹⁴ Subsequent publications have described other histopathologic features in deployed military personnel, including granulomatous inflammation, interstitial lung disease, emphysema, and pleuritis.^12-14 Reconciling these findings from surgical lung biopsy with the clinical presentation and noninvasive studies has proved difficult. Therefore, several groups of investigators have proposed terms, including postdeployment respiratory syndrome, deployment-related distal lung disease, and Iraq/Afghanistan War lung injury to describe the increased respiratory symptoms and variety of histopathologic and imaging findings in this population.^9,12,22 At present, there remains a lack of consensus on terminology and case definitions as well as the role of military environmental exposures in exacerbating and/or causing these conditions. As HCPs, it is important to appreciate and acknowledge that the ambiguity and controversy pertaining to terminology, causation, and service connections are a common source of frustration experienced by veterans, which are increasingly reflected among reports in popular media and lay press.

A second and related challenge in the field of postdeployment respiratory health that contributes to veteran and HCP frustration is that many of the aforementioned abnormalities described on surgical lung biopsy are not readily identifiable on noninvasive tests, including traditional interpretation of pulmonary function tests or chest CT imaging.^12-14,22 Thus, underlying conditions could be overlooked and veterans’ concerns and symptoms may be dismissed or misattributed to other comorbid conditions. While surgical lung biopsies may offer diagnostic clarity in identifying lung disease, there are significant procedural risks of surgical and anesthetic complications. Furthermore, a definitive diagnosis does not necessarily guarantee a clear treatment plan. For example, there are no current therapies approved by the US Food and Drug Administration for the treatment of constrictive bronchiolitis.

Research efforts are underway, including within the PDCEN, to evaluate a more sensitive and noninvasive assessment of the small airways that may even reduce or eliminate the need for surgical lung biopsy. In contrast to traditional pulmonary function testing, which is helpful for evaluation of the larger airways, forced oscillation technique can be used noninvasively, using pressure oscillations to evaluate for diseases of the smaller airways and has been used in the veteran population and in those exposed to dust from the World Trade Center disaster.^23-25 Multiple breath washout technique provides a lung clearance index that is determined by the number of lung turnovers it takes to clear the lungs of an inert gas (eg, sulfur hexafluoride, nitrogen). Elevated lung clearance index values suggest ventilation heterogeneity and have been shown to be higher among deployed veterans with dyspnea.^26,27 Finally, advanced CT analytic techniques may help identify functional small airways disease and are higher in deployed service members with constrictive bronchiolitis on surgical lung biopsy.²⁸ These innovative noninvasive techniques are experimental but promising, especially as part of a broader evaluation of small airways disease.

AHOBPR clinical evaluations represent an initial step to better understand postdeployment health conditions available to all AHOBPR participants. The PDCEN clinical evaluation extends the AHOBPR evaluation by providing specialty care for certain veterans requiring more comprehensive evaluation while systematically collecting and analyzing clinical data to advance the field. The VA is committed to leveraging these data and all available expertise to provide a clear description of the spectrum of disease in this population and improve our ability to diagnose, follow, and treat respiratory health conditions occurring after deployment to Southwest Asia and Afghanistan.

Case Conclusion

The veteran was referred to a PDCEN site and underwent a comprehensive multidisciplinary evaluation. Pulmonary function testing showed lung volumes and vital capacity within the predicted normal range, mild air trapping, and a low diffusion capacity for carbon monoxide. Methacholine challenge testing was normal; however, forced oscillometry suggested small airways obstruction. A high-resolution CT showed air trapping without parenchymal changes. Cardiopulmonary exercise testing demonstrated a peak exercise capacity within the predicted normal range but low breathing reserve. Otolaryngology evaluation including laryngoscopy suggested chronic nonallergic rhinitis.

At the end of the veteran’s evaluation, a summary review reported nonallergic rhinitis and distal airway obstruction consistent with small airways disease. Both were reported as most likely related to deployment given her significant environmental exposures and the temporal relationship with her deployment and symptom onset as well as lack of other identifiable causes. A more precise histopathologic diagnosis could be firmly established with a surgical lung biopsy, but after shared decision making with a PDCEN HCP, the patient declined to undergo this invasive procedure. After you review the summary review and recommendations from the PDCEN group, you start the veteran on intranasal steroids and a combined inhaled corticosteroid/long-acting β agonist inhaler as well as refer the veteran to pulmonary rehabilitation. After several weeks, she reports an improvement in sleep and nasal symptoms but continues to experience residual exercise intolerance.

This case serves as an example of the significant limitations that a previously active and healthy patient can develop after deployment to Southwest Asia and Afghanistan. Encouraging this veteran to complete the AHOBPR allowed her to be considered for a PDCEN evaluation that provided the opportunity to undergo a comprehensive noninvasive evaluation of her chronic dyspnea. In doing so, she obtained 2 important diagnoses and data from her evaluation will help establish best practices for standardized evaluations of respiratory concerns following deployment. Through the AHOBPR and PDCEN, the VA seeks to better understand postdeployment health conditions, their relationship to military and environmental exposures, and how best to diagnose and treat these conditions.

Acknowledgments

This work was supported by the US Department of Veterans Affairs (VA) Airborne Hazards and Burn Pits Center of Excellence (Public Law 115-929). The authors acknowledge support and contributions from Dr. Eric Shuping and leadership at VA’s Health Outcomes Military Exposures office as well as the New Jersey War Related Illness and Injury Study Center. In addition, we thank Erin McRoberts and Rajeev Swarup for their contributions to the Post-Deployment Cardiopulmonary Evaluation Network. Post-Deployment Cardiopulmonary Evaluation Network members:

Mehrdad Arjomandi, Caroline Davis, Michelle DeLuca, Nancy Eager, Courtney A. Eberhardt, Michael J. Falvo, Timothy Foley, Fiona A.S. Graff, Deborah Heaney, Stella E. Hines, Rachel E. Howard, Nisha Jani, Sheena Kamineni, Silpa Krefft, Mary L. Langlois, Helen Lozier, Simran K. Matharu, Anisa Moore, Lydia Patrick-DeLuca, Edward Pickering, Alexander Rabin, Michelle Robertson, Samantha L. Rogers, Aaron H. Schneider, Anand Shah, Anays Sotolongo, Jennifer H. Therkorn, Rebecca I. Toczylowski, Matthew Watson, Alison D. Wilczynski, Ian W. Wilson, Romi A. Yount.

In the past 10 years, artificial intelligence (AI) applications have exploded in numerous fields, including medicine. Myriad publications report that the use of AI in health care is increasing, and AI has shown utility in many medical specialties, eg, pathology, radiology, and oncology.^1,2

In cancer pathology, AI was able not only to detect various cancers, but also to subtype and grade them. In addition, AI could predict survival, the success of therapeutic response, and underlying mutations from histopathologic images.³ In other medical fields, AI applications are as notable. For example, in imaging specialties like radiology, ophthalmology, dermatology, and gastroenterology, AI is being used for image recognition, enhancement, and segmentation. In addition, AI is beneficial for predicting disease progression, survival, and response to therapy in other medical specialties. Finally, AI may help with administrative tasks like scheduling.

However, many obstacles to successfully implementing AI programs in the clinical setting exist, including clinical data limitations and ethical use of data, trust in the AI models, regulatory barriers, and lack of clinical buy-in due to insufficient basic AI understanding.² To address these barriers to successful clinical AI implementation, we decided to create a formal governing body at James A. Haley Veterans’ Hospital in Tampa, Florida. Accordingly, the hospital AI committee charter was officially approved on July 22, 2021. Our model could be used by both US Department of Veterans Affairs (VA) and non-VA hospitals throughout the country.

AI Committee

The vision of the AI committee is to improve outcomes and experiences for our veterans by developing trustworthy AI capabilities to support the VA mission. The mission is to build robust capacity in AI to create and apply innovative AI solutions and transform the VA by facilitating a learning environment that supports the delivery of world-class benefits and services to our veterans. Our vision and mission are aligned with the VA National AI Institute. ⁴

The AI Committee comprises 7 subcommittees: ethics, AI clinical product evaluation, education, data sharing and acquisition, research, 3D printing, and improvement and innovation. The role of the ethics subcommittee is to ensure the ethical and equitable implementation of clinical AI. We created the ethics subcommittee guidelines based on the World Health Organization ethics and governance of AI for health documents.⁵ They include 6 basic principles: protecting human autonomy; promoting human well-being and safety and the public interest; ensuring transparency, explainability, and intelligibility; fostering responsibility and accountability; ensuring inclusiveness and equity; and promoting AI that is responsive and sustainable (Table 1).

Implementations

After a comprehensive evaluation, we implemented 2 ClearRead (Riverain Technologies) AI radiology solutions. ClearRead CT Vessel Suppress produces a secondary series of computed tomography (CT) images, suppressing vessels and other normal structures within the lungs to improve nodule detectability, and ClearRead Xray Bone Suppress, which increases the visibility of soft tissue in standard chest X-rays by suppressing the bone on the digital image without the need for 2 exposures.

The role of the education subcommittee is to educate the staff about AI and how it can improve patient care. Every Friday, we email an AI article of the week to our practitioners. In addition, we publish a newsletter, and we organize an annual AI conference. The first conference in 2022 included speakers from the National AI Institute, Moffitt Cancer Center, the University of South Florida, and our facility.

As the name indicates, the data sharing and acquisition subcommittee oversees preparing data for our clinical and research projects. The role of the research subcommittee is to coordinate and promote AI research with the ultimate goal of improving patient care.

Other Technologies

Although 3D printing does not fall under the umbrella of AI, we have decided to include it in our future-oriented AI committee. We created an online 3D printing course to promote the technology throughout the VA. We 3D print organ models to help surgeons prepare for complicated operations. In addition, together with our colleagues from the University of Florida, we used 3D printing to address the shortage of swabs for COVID-19 testing. The VA Sunshine Healthcare Network (Veterans Integrated Services Network 8) has an active Innovation and Improvement Committee. ⁹ Our improvement and innovation subcommittee serves as a coordinating body with the network committee .

Conclusions

Through the hospital AI committee, we believe that we may overcome many obstacles to successfully implementing AI applications in the clinical setting, including the ethical use of data, trust in the AI models, regulatory barriers, and lack of clinical buy-in due to insufficient basic AI knowledge.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital.

In the past 10 years, artificial intelligence (AI) applications have exploded in numerous fields, including medicine. Myriad publications report that the use of AI in health care is increasing, and AI has shown utility in many medical specialties, eg, pathology, radiology, and oncology.^1,2

In cancer pathology, AI was able not only to detect various cancers, but also to subtype and grade them. In addition, AI could predict survival, the success of therapeutic response, and underlying mutations from histopathologic images.³ In other medical fields, AI applications are as notable. For example, in imaging specialties like radiology, ophthalmology, dermatology, and gastroenterology, AI is being used for image recognition, enhancement, and segmentation. In addition, AI is beneficial for predicting disease progression, survival, and response to therapy in other medical specialties. Finally, AI may help with administrative tasks like scheduling.

However, many obstacles to successfully implementing AI programs in the clinical setting exist, including clinical data limitations and ethical use of data, trust in the AI models, regulatory barriers, and lack of clinical buy-in due to insufficient basic AI understanding.² To address these barriers to successful clinical AI implementation, we decided to create a formal governing body at James A. Haley Veterans’ Hospital in Tampa, Florida. Accordingly, the hospital AI committee charter was officially approved on July 22, 2021. Our model could be used by both US Department of Veterans Affairs (VA) and non-VA hospitals throughout the country.

AI Committee

The vision of the AI committee is to improve outcomes and experiences for our veterans by developing trustworthy AI capabilities to support the VA mission. The mission is to build robust capacity in AI to create and apply innovative AI solutions and transform the VA by facilitating a learning environment that supports the delivery of world-class benefits and services to our veterans. Our vision and mission are aligned with the VA National AI Institute. ⁴

The AI Committee comprises 7 subcommittees: ethics, AI clinical product evaluation, education, data sharing and acquisition, research, 3D printing, and improvement and innovation. The role of the ethics subcommittee is to ensure the ethical and equitable implementation of clinical AI. We created the ethics subcommittee guidelines based on the World Health Organization ethics and governance of AI for health documents.⁵ They include 6 basic principles: protecting human autonomy; promoting human well-being and safety and the public interest; ensuring transparency, explainability, and intelligibility; fostering responsibility and accountability; ensuring inclusiveness and equity; and promoting AI that is responsive and sustainable (Table 1).

Implementations

After a comprehensive evaluation, we implemented 2 ClearRead (Riverain Technologies) AI radiology solutions. ClearRead CT Vessel Suppress produces a secondary series of computed tomography (CT) images, suppressing vessels and other normal structures within the lungs to improve nodule detectability, and ClearRead Xray Bone Suppress, which increases the visibility of soft tissue in standard chest X-rays by suppressing the bone on the digital image without the need for 2 exposures.

The role of the education subcommittee is to educate the staff about AI and how it can improve patient care. Every Friday, we email an AI article of the week to our practitioners. In addition, we publish a newsletter, and we organize an annual AI conference. The first conference in 2022 included speakers from the National AI Institute, Moffitt Cancer Center, the University of South Florida, and our facility.

As the name indicates, the data sharing and acquisition subcommittee oversees preparing data for our clinical and research projects. The role of the research subcommittee is to coordinate and promote AI research with the ultimate goal of improving patient care.

Other Technologies

Although 3D printing does not fall under the umbrella of AI, we have decided to include it in our future-oriented AI committee. We created an online 3D printing course to promote the technology throughout the VA. We 3D print organ models to help surgeons prepare for complicated operations. In addition, together with our colleagues from the University of Florida, we used 3D printing to address the shortage of swabs for COVID-19 testing. The VA Sunshine Healthcare Network (Veterans Integrated Services Network 8) has an active Innovation and Improvement Committee. ⁹ Our improvement and innovation subcommittee serves as a coordinating body with the network committee .

Conclusions

Through the hospital AI committee, we believe that we may overcome many obstacles to successfully implementing AI applications in the clinical setting, including the ethical use of data, trust in the AI models, regulatory barriers, and lack of clinical buy-in due to insufficient basic AI knowledge.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital.

In the past 10 years, artificial intelligence (AI) applications have exploded in numerous fields, including medicine. Myriad publications report that the use of AI in health care is increasing, and AI has shown utility in many medical specialties, eg, pathology, radiology, and oncology.^1,2

In cancer pathology, AI was able not only to detect various cancers, but also to subtype and grade them. In addition, AI could predict survival, the success of therapeutic response, and underlying mutations from histopathologic images.³ In other medical fields, AI applications are as notable. For example, in imaging specialties like radiology, ophthalmology, dermatology, and gastroenterology, AI is being used for image recognition, enhancement, and segmentation. In addition, AI is beneficial for predicting disease progression, survival, and response to therapy in other medical specialties. Finally, AI may help with administrative tasks like scheduling.

However, many obstacles to successfully implementing AI programs in the clinical setting exist, including clinical data limitations and ethical use of data, trust in the AI models, regulatory barriers, and lack of clinical buy-in due to insufficient basic AI understanding.² To address these barriers to successful clinical AI implementation, we decided to create a formal governing body at James A. Haley Veterans’ Hospital in Tampa, Florida. Accordingly, the hospital AI committee charter was officially approved on July 22, 2021. Our model could be used by both US Department of Veterans Affairs (VA) and non-VA hospitals throughout the country.

AI Committee

The vision of the AI committee is to improve outcomes and experiences for our veterans by developing trustworthy AI capabilities to support the VA mission. The mission is to build robust capacity in AI to create and apply innovative AI solutions and transform the VA by facilitating a learning environment that supports the delivery of world-class benefits and services to our veterans. Our vision and mission are aligned with the VA National AI Institute. ⁴

The AI Committee comprises 7 subcommittees: ethics, AI clinical product evaluation, education, data sharing and acquisition, research, 3D printing, and improvement and innovation. The role of the ethics subcommittee is to ensure the ethical and equitable implementation of clinical AI. We created the ethics subcommittee guidelines based on the World Health Organization ethics and governance of AI for health documents.⁵ They include 6 basic principles: protecting human autonomy; promoting human well-being and safety and the public interest; ensuring transparency, explainability, and intelligibility; fostering responsibility and accountability; ensuring inclusiveness and equity; and promoting AI that is responsive and sustainable (Table 1).

Implementations

After a comprehensive evaluation, we implemented 2 ClearRead (Riverain Technologies) AI radiology solutions. ClearRead CT Vessel Suppress produces a secondary series of computed tomography (CT) images, suppressing vessels and other normal structures within the lungs to improve nodule detectability, and ClearRead Xray Bone Suppress, which increases the visibility of soft tissue in standard chest X-rays by suppressing the bone on the digital image without the need for 2 exposures.

The role of the education subcommittee is to educate the staff about AI and how it can improve patient care. Every Friday, we email an AI article of the week to our practitioners. In addition, we publish a newsletter, and we organize an annual AI conference. The first conference in 2022 included speakers from the National AI Institute, Moffitt Cancer Center, the University of South Florida, and our facility.

As the name indicates, the data sharing and acquisition subcommittee oversees preparing data for our clinical and research projects. The role of the research subcommittee is to coordinate and promote AI research with the ultimate goal of improving patient care.

Other Technologies

Although 3D printing does not fall under the umbrella of AI, we have decided to include it in our future-oriented AI committee. We created an online 3D printing course to promote the technology throughout the VA. We 3D print organ models to help surgeons prepare for complicated operations. In addition, together with our colleagues from the University of Florida, we used 3D printing to address the shortage of swabs for COVID-19 testing. The VA Sunshine Healthcare Network (Veterans Integrated Services Network 8) has an active Innovation and Improvement Committee. ⁹ Our improvement and innovation subcommittee serves as a coordinating body with the network committee .

Conclusions

Through the hospital AI committee, we believe that we may overcome many obstacles to successfully implementing AI applications in the clinical setting, including the ethical use of data, trust in the AI models, regulatory barriers, and lack of clinical buy-in due to insufficient basic AI knowledge.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital.

Reinfection rates are low after treating hepatitis C virus in people taking opioid agonist therapy (OAT), even among those who still inject drugs, according to a new study.

The findings, which are based on prospective data from 13 countries, including the United States, and were published in Annals of Internal Medicine (2022 Aug 8. doi: 10.7326/M21-4119), should encourage physicians to treat HCV in people with a history of injection drug use, said lead author Jason Grebely, PhD. They should also pressure payers to lift reimbursement restrictions on the same population.

“Direct-acting antiviral medications for HCV infection are safe and effective among people receiving OAT and people with recent injecting-drug use,” the investigators wrote. “Concerns remain, however, that HCV reinfection may reduce the benefits of cure among people who inject drugs and compromise HCV elimination efforts.”

They explored these concerns through a 3-year extension of the phase 3 CO-STAR trial that evaluated elbasvir and grazoprevir in people consistently taking OAT. Participants in the CO-STAR trial, which had a 96% sustained virologic response rate among those who completed therapy, could elect to participate in the present study, offering a prospective look at long-term reinfection.

Out of 296 participants in the CO-STAR trial, 286 were evaluable for reinfection and 199 enrolled in the present extension. The majority were White (79.4%) and male (75.9%), with most taking methadone (79%), followed by buprenorphine (20%). At 6 months, 40 out of 191 respondents (21%) reported injection-drug use in the previous month. At the 3-year mark, 26 out of 142 respondents (18%) disclosed injection-drug use in the previous month.

For all participants in the CO-STAR trial, the overall rate of reinfection at 3 years was 1.7 per 100 person-years (95% confidence interval, 0.8-3.0), which is lower than the rate reported in systematic reviews (3.8 per 100 person-years), according to the investigators.

In the extension analysis, the 3-year reinfection rate was lower still, at 1.2 per 100 person-years. The rate was slightly higher among people who reported injection-drug use in the previous month (1.9 per 100 person-years), and slightly lower among those who did not report injection-drug use in the prior month (0.5 per 100 person-years). More pronounced differences in reinfection were observed among participants who shared needles (6.4 per 100 person-years), versus those who didn’t share needles (1.5 per 100 person years).
 

Low reinfection rate may help facilitate removal of reimbursement restrictions

“Most of the reinfections in this study occurred within 24 weeks of completing treatment, suggesting that this is a key period for optimizing treatment of opioid use disorder and for providing access to needle and syringe programs that have documented benefits in preventing HCV transmission,” the investigators wrote.

This is one of the largest observational studies of its kind to date, bolstered by “excellent study retention” and a “well-characterized cohort,” with findings that should prompt real-world action, said Dr. Grebely, who is head of the hepatitis C and drug use group in the viral hepatitis clinical research program at the Kirby Institute, University of New South Wales, Sydney.

“Given that reinfection has often been cited ... by some providers as a reason for not offering treatment to people receiving OAT, the low reinfection rate in this study will be incredibly important for guiding practice and ensuring therapy is not withheld from this group,” Dr. Grebely said in an interview. “In terms of policy implications, these data may also help to facilitate the removal of reimbursement restrictions based on recent drug/alcohol use criteria that are in place among many payers in the United States.”
 

More research needed to determine optimal intervention strategies

Carl Latkin, PhD, professor and vice chair of the department of health, behavior, and society at Johns Hopkins University, Baltimore, called the present publication a “great article and well-done study with long-term follow-up.”

Dr. Latkin, who investigates biobehavioral interventions for disadvantaged communities, said the reported rate of reinfection is “very low among a group of current and former injectors.”

Affirming Dr. Grebely’s call for supportive practices by physicians and payers, Dr. Latkin said: “The study highlights the importance of improving access to medication for opioid use disorder. This level of treatment adherence in this group is much higher than for many other medications. Given these data, it would be difficult for payers to have a rational reason for blanket restrictions for HCV treatment among people who use drugs.”

Dr. Latkin explained that “it isn’t simply injection drug use per se” that drives HCV reinfection; instead, he cited social factors, such as lack of housing, as well as withdrawal symptoms, especially among those without access to medications for opioid use disorder (MOUD).

Dr. Latkin and Grebely also agreed that more research is needed to determine optimal intervention strategies.

Dr. Grebely called for one to enhance HCV testing and linkage to care, a topic he covered in a recent review article (Lancet Gastroenterol Hepatol. 2022 May;7[5]:426-45.).

Dr. Latkin said that, while it’s clear that “syringe services programs, accessible HCV treatment, and MOUD are needed,” it is unclear how much coverage is necessary for a given population.

Findings support critical nature of needle and syringe exchange programs

Sarah M. Kattakuzhy, MD, an associate professor in the division of clinical care & research at the Institute of Human Virology, University of Maryland, Baltimore, agreed that the findings “support the critical nature of needle and syringe exchange programs.”

“As most cities in the United States fall well below the high coverage needle and syringe program threshold required to maximally prevent disease transmission, the study serves as a push toward an evidence-based harm reduction policy,” she said.

Dr. Kattakuzhy he added that the study “supports the need to longitudinally engage individuals after HCV treatment to monitor reinfection risk behaviors and test for reinfection,” she continued.

When it came to translating all the data to populations in the United States, she offered a more guarded view.

“Critically, the study population included only individuals who were engaged with OAT and adherent for 3 or more months, selecting to a population of individuals with high adherence and engagement in care,” Dr. Kattakuzhy said in an interview. “As such, the study findings are not applicable to other cross sections of the drug-using community, including individuals not engaged in OAT, and cohorts with higher rates of ongoing injection drug use. Furthermore, there are known genetic impacts on spontaneous clearance, and emerging data on the immunology of reinfection.

“Studies with a focus on less engaged, higher-risk, and minority populations with active drug use are required to answer the remaining questions in HCV reinfection,” she said.

The study was supported by Merck, the Australian Government Department of Health, and the Australian National Health and Medical Research Council. Dr. Grebely disclosed receiving funding from Cepheid, the manufacturer of the Xpert HCV assay. The other investigators disclosed additional relationships with Gilead, AbbVie, Cepheid, and others. Dr. Latkin and Dr. Kattakuzhy disclosed no relevant conflicts of interest.

Reinfection rates are low after treating hepatitis C virus in people taking opioid agonist therapy (OAT), even among those who still inject drugs, according to a new study.

The findings, which are based on prospective data from 13 countries, including the United States, and were published in Annals of Internal Medicine (2022 Aug 8. doi: 10.7326/M21-4119), should encourage physicians to treat HCV in people with a history of injection drug use, said lead author Jason Grebely, PhD. They should also pressure payers to lift reimbursement restrictions on the same population.

“Direct-acting antiviral medications for HCV infection are safe and effective among people receiving OAT and people with recent injecting-drug use,” the investigators wrote. “Concerns remain, however, that HCV reinfection may reduce the benefits of cure among people who inject drugs and compromise HCV elimination efforts.”

They explored these concerns through a 3-year extension of the phase 3 CO-STAR trial that evaluated elbasvir and grazoprevir in people consistently taking OAT. Participants in the CO-STAR trial, which had a 96% sustained virologic response rate among those who completed therapy, could elect to participate in the present study, offering a prospective look at long-term reinfection.

Out of 296 participants in the CO-STAR trial, 286 were evaluable for reinfection and 199 enrolled in the present extension. The majority were White (79.4%) and male (75.9%), with most taking methadone (79%), followed by buprenorphine (20%). At 6 months, 40 out of 191 respondents (21%) reported injection-drug use in the previous month. At the 3-year mark, 26 out of 142 respondents (18%) disclosed injection-drug use in the previous month.

For all participants in the CO-STAR trial, the overall rate of reinfection at 3 years was 1.7 per 100 person-years (95% confidence interval, 0.8-3.0), which is lower than the rate reported in systematic reviews (3.8 per 100 person-years), according to the investigators.

In the extension analysis, the 3-year reinfection rate was lower still, at 1.2 per 100 person-years. The rate was slightly higher among people who reported injection-drug use in the previous month (1.9 per 100 person-years), and slightly lower among those who did not report injection-drug use in the prior month (0.5 per 100 person-years). More pronounced differences in reinfection were observed among participants who shared needles (6.4 per 100 person-years), versus those who didn’t share needles (1.5 per 100 person years).
 

Low reinfection rate may help facilitate removal of reimbursement restrictions

“Most of the reinfections in this study occurred within 24 weeks of completing treatment, suggesting that this is a key period for optimizing treatment of opioid use disorder and for providing access to needle and syringe programs that have documented benefits in preventing HCV transmission,” the investigators wrote.

This is one of the largest observational studies of its kind to date, bolstered by “excellent study retention” and a “well-characterized cohort,” with findings that should prompt real-world action, said Dr. Grebely, who is head of the hepatitis C and drug use group in the viral hepatitis clinical research program at the Kirby Institute, University of New South Wales, Sydney.

“Given that reinfection has often been cited ... by some providers as a reason for not offering treatment to people receiving OAT, the low reinfection rate in this study will be incredibly important for guiding practice and ensuring therapy is not withheld from this group,” Dr. Grebely said in an interview. “In terms of policy implications, these data may also help to facilitate the removal of reimbursement restrictions based on recent drug/alcohol use criteria that are in place among many payers in the United States.”
 

More research needed to determine optimal intervention strategies

Carl Latkin, PhD, professor and vice chair of the department of health, behavior, and society at Johns Hopkins University, Baltimore, called the present publication a “great article and well-done study with long-term follow-up.”

Dr. Latkin, who investigates biobehavioral interventions for disadvantaged communities, said the reported rate of reinfection is “very low among a group of current and former injectors.”

Affirming Dr. Grebely’s call for supportive practices by physicians and payers, Dr. Latkin said: “The study highlights the importance of improving access to medication for opioid use disorder. This level of treatment adherence in this group is much higher than for many other medications. Given these data, it would be difficult for payers to have a rational reason for blanket restrictions for HCV treatment among people who use drugs.”

Dr. Latkin explained that “it isn’t simply injection drug use per se” that drives HCV reinfection; instead, he cited social factors, such as lack of housing, as well as withdrawal symptoms, especially among those without access to medications for opioid use disorder (MOUD).

Dr. Latkin and Grebely also agreed that more research is needed to determine optimal intervention strategies.

Dr. Grebely called for one to enhance HCV testing and linkage to care, a topic he covered in a recent review article (Lancet Gastroenterol Hepatol. 2022 May;7[5]:426-45.).

Dr. Latkin said that, while it’s clear that “syringe services programs, accessible HCV treatment, and MOUD are needed,” it is unclear how much coverage is necessary for a given population.

Findings support critical nature of needle and syringe exchange programs

Sarah M. Kattakuzhy, MD, an associate professor in the division of clinical care & research at the Institute of Human Virology, University of Maryland, Baltimore, agreed that the findings “support the critical nature of needle and syringe exchange programs.”

“As most cities in the United States fall well below the high coverage needle and syringe program threshold required to maximally prevent disease transmission, the study serves as a push toward an evidence-based harm reduction policy,” she said.

Dr. Kattakuzhy he added that the study “supports the need to longitudinally engage individuals after HCV treatment to monitor reinfection risk behaviors and test for reinfection,” she continued.

When it came to translating all the data to populations in the United States, she offered a more guarded view.

“Critically, the study population included only individuals who were engaged with OAT and adherent for 3 or more months, selecting to a population of individuals with high adherence and engagement in care,” Dr. Kattakuzhy said in an interview. “As such, the study findings are not applicable to other cross sections of the drug-using community, including individuals not engaged in OAT, and cohorts with higher rates of ongoing injection drug use. Furthermore, there are known genetic impacts on spontaneous clearance, and emerging data on the immunology of reinfection.

“Studies with a focus on less engaged, higher-risk, and minority populations with active drug use are required to answer the remaining questions in HCV reinfection,” she said.

The study was supported by Merck, the Australian Government Department of Health, and the Australian National Health and Medical Research Council. Dr. Grebely disclosed receiving funding from Cepheid, the manufacturer of the Xpert HCV assay. The other investigators disclosed additional relationships with Gilead, AbbVie, Cepheid, and others. Dr. Latkin and Dr. Kattakuzhy disclosed no relevant conflicts of interest.

Reinfection rates are low after treating hepatitis C virus in people taking opioid agonist therapy (OAT), even among those who still inject drugs, according to a new study.

The findings, which are based on prospective data from 13 countries, including the United States, and were published in Annals of Internal Medicine (2022 Aug 8. doi: 10.7326/M21-4119), should encourage physicians to treat HCV in people with a history of injection drug use, said lead author Jason Grebely, PhD. They should also pressure payers to lift reimbursement restrictions on the same population.

“Direct-acting antiviral medications for HCV infection are safe and effective among people receiving OAT and people with recent injecting-drug use,” the investigators wrote. “Concerns remain, however, that HCV reinfection may reduce the benefits of cure among people who inject drugs and compromise HCV elimination efforts.”

They explored these concerns through a 3-year extension of the phase 3 CO-STAR trial that evaluated elbasvir and grazoprevir in people consistently taking OAT. Participants in the CO-STAR trial, which had a 96% sustained virologic response rate among those who completed therapy, could elect to participate in the present study, offering a prospective look at long-term reinfection.

Out of 296 participants in the CO-STAR trial, 286 were evaluable for reinfection and 199 enrolled in the present extension. The majority were White (79.4%) and male (75.9%), with most taking methadone (79%), followed by buprenorphine (20%). At 6 months, 40 out of 191 respondents (21%) reported injection-drug use in the previous month. At the 3-year mark, 26 out of 142 respondents (18%) disclosed injection-drug use in the previous month.

For all participants in the CO-STAR trial, the overall rate of reinfection at 3 years was 1.7 per 100 person-years (95% confidence interval, 0.8-3.0), which is lower than the rate reported in systematic reviews (3.8 per 100 person-years), according to the investigators.

In the extension analysis, the 3-year reinfection rate was lower still, at 1.2 per 100 person-years. The rate was slightly higher among people who reported injection-drug use in the previous month (1.9 per 100 person-years), and slightly lower among those who did not report injection-drug use in the prior month (0.5 per 100 person-years). More pronounced differences in reinfection were observed among participants who shared needles (6.4 per 100 person-years), versus those who didn’t share needles (1.5 per 100 person years).
 

Low reinfection rate may help facilitate removal of reimbursement restrictions

“Most of the reinfections in this study occurred within 24 weeks of completing treatment, suggesting that this is a key period for optimizing treatment of opioid use disorder and for providing access to needle and syringe programs that have documented benefits in preventing HCV transmission,” the investigators wrote.

This is one of the largest observational studies of its kind to date, bolstered by “excellent study retention” and a “well-characterized cohort,” with findings that should prompt real-world action, said Dr. Grebely, who is head of the hepatitis C and drug use group in the viral hepatitis clinical research program at the Kirby Institute, University of New South Wales, Sydney.

“Given that reinfection has often been cited ... by some providers as a reason for not offering treatment to people receiving OAT, the low reinfection rate in this study will be incredibly important for guiding practice and ensuring therapy is not withheld from this group,” Dr. Grebely said in an interview. “In terms of policy implications, these data may also help to facilitate the removal of reimbursement restrictions based on recent drug/alcohol use criteria that are in place among many payers in the United States.”
 

More research needed to determine optimal intervention strategies

Carl Latkin, PhD, professor and vice chair of the department of health, behavior, and society at Johns Hopkins University, Baltimore, called the present publication a “great article and well-done study with long-term follow-up.”

Dr. Latkin, who investigates biobehavioral interventions for disadvantaged communities, said the reported rate of reinfection is “very low among a group of current and former injectors.”

Affirming Dr. Grebely’s call for supportive practices by physicians and payers, Dr. Latkin said: “The study highlights the importance of improving access to medication for opioid use disorder. This level of treatment adherence in this group is much higher than for many other medications. Given these data, it would be difficult for payers to have a rational reason for blanket restrictions for HCV treatment among people who use drugs.”

Dr. Latkin explained that “it isn’t simply injection drug use per se” that drives HCV reinfection; instead, he cited social factors, such as lack of housing, as well as withdrawal symptoms, especially among those without access to medications for opioid use disorder (MOUD).

Dr. Latkin and Grebely also agreed that more research is needed to determine optimal intervention strategies.

Dr. Grebely called for one to enhance HCV testing and linkage to care, a topic he covered in a recent review article (Lancet Gastroenterol Hepatol. 2022 May;7[5]:426-45.).

Dr. Latkin said that, while it’s clear that “syringe services programs, accessible HCV treatment, and MOUD are needed,” it is unclear how much coverage is necessary for a given population.

Findings support critical nature of needle and syringe exchange programs

Sarah M. Kattakuzhy, MD, an associate professor in the division of clinical care & research at the Institute of Human Virology, University of Maryland, Baltimore, agreed that the findings “support the critical nature of needle and syringe exchange programs.”

“As most cities in the United States fall well below the high coverage needle and syringe program threshold required to maximally prevent disease transmission, the study serves as a push toward an evidence-based harm reduction policy,” she said.

Dr. Kattakuzhy he added that the study “supports the need to longitudinally engage individuals after HCV treatment to monitor reinfection risk behaviors and test for reinfection,” she continued.

When it came to translating all the data to populations in the United States, she offered a more guarded view.

“Critically, the study population included only individuals who were engaged with OAT and adherent for 3 or more months, selecting to a population of individuals with high adherence and engagement in care,” Dr. Kattakuzhy said in an interview. “As such, the study findings are not applicable to other cross sections of the drug-using community, including individuals not engaged in OAT, and cohorts with higher rates of ongoing injection drug use. Furthermore, there are known genetic impacts on spontaneous clearance, and emerging data on the immunology of reinfection.

“Studies with a focus on less engaged, higher-risk, and minority populations with active drug use are required to answer the remaining questions in HCV reinfection,” she said.

The study was supported by Merck, the Australian Government Department of Health, and the Australian National Health and Medical Research Council. Dr. Grebely disclosed receiving funding from Cepheid, the manufacturer of the Xpert HCV assay. The other investigators disclosed additional relationships with Gilead, AbbVie, Cepheid, and others. Dr. Latkin and Dr. Kattakuzhy disclosed no relevant conflicts of interest.

Healthy children who are underweight in the first 2 years of life continue with a lower-than-average body mass index and height-for-age through age 10, according to new research.

The association was most pronounced for girls, as well as for children with lower growth rates, write the authors of the prospective Canadian cohort study published in JAMA Network Open.

The findings “highlight the importance of preventing underweight in early life,” because this can have “lasting effects” in later childhood, senior author Jonathon L. Maguire, MD, from St Michael’s Hospital Pediatric Clinic, and the University of Toronto said in an interview.
 

Methods and results

The study recruited 5,803 healthy children, mean age 4.07 months, between February 2008 and September 2020 during well-child visits at clinics in The Applied Research Group for Kids! (TARGet Kids!) practice-based research network in Canada. The study’s exclusion criteria included a premature birth, or a health condition affecting growth.

The primary outcome of the study was the child’s age- and sex-adjusted weight, also known as the body mass index z score (zBMI), between the ages of 2 and 10 years.

At baseline, a total of 550 children (9.5%) were classified as underweight, based on the World Health Organization definition of zBMI less than –2. Underweight children were more likely to be younger, have lower birth weight, and to report Asian maternal ethnicity, the researchers observed.

The study found that, compared with children with normal weight, those who were underweight in the first 2 years had lower zBMI at ages 5 and 10 years (–0.49 and –0.39 respectively). This meant that at 10 years old, they were a mean of 1.23 kg lighter than 10-year-olds who had been normal weight at age 2 years.

Height-for-age z score (HAZ) was also lower for underweight 2-year-olds (–0.24), making them a mean of 0.68 cm shorter than normal-weight 2-year-olds. This difference was attenuated at age 5 years.

Growth rate modified the association of underweight with both zBMI and HAZ. Among children who were underweight in the first 2 years, those with lower growth rate had lower zBMI at 10 years (–0.64) compared with those with average (–0.38) or high growth rate (0.11). Similarly, children who were underweight and had a lower growth rate at age 2 years also a lower HAZ at age 10 years (–0.12), compared with those with average (0.02) or high growth rates (0.16). These effects were more pronounced in girls.
 

Increased health risks linked with chronic underweight

This study did not assess the reasons for early underweight, Dr. Maguire commented in an interview. But, he cited challenges with dietary transitions as a possible explanation.

“Considerable dietary changes happen around 2 years of age with increasing diversity of foods as children transition from primarily liquid foods to primarily solid foods,” he noted.

Asked for comment on the study, Colleen Spees, PhD, associate professor in the division of medical dietetics and director of Hope lab at the Ohio State University, Columbus, said that “at age 10, it’s not surprising to see a lower zBMI and height-for-age in those that were underweight at age 2 with poor growth trajectories.”

Although, this is the first study she is aware of to document these findings in a Canadian cohort, “the results align with what we know about low birth weight and underweight infants and children in terms of linear growth trajectories from child stunting studies,” Dr. Spees said.

She said child stunting, which is more common in less developed countries where children have lower birth weights and greater socioeconomic and environmental risk factors, is defined by the WHO as impaired linear growth with adverse functional consequences.

“In short, a chronic underweight status in infants and young children can lead to greater risk of malnutrition, vitamin and mineral deficiencies, decreased immune function, as well as physical growth and development issues,” she said. “Hence, the most recent 2020-2025 Dietary Guidelines for Americans now includes both pregnancy, breastfeeding, and the first 2 years of life (referred to as the “first 1,000 days”) in their recommendations.”

She added that, if caregivers are concerned about their child’s weight, they should consult with their pediatrician to rule out any medical issues. If no medical issues are identified, they should ask for a referral to a pediatric dietitian.

The study was funded by the Canadian Institute of Health Research. Dr Maguire reported receiving grants from the CIHR, Physician Services, Ontario SPOR Support Unit, and Dairy Farmers of Canada during the conduct of the study and nonfinancial support from DDrops outside the submitted work. Other authors of the paper reported receiving grants from various institutions. Dr. Spees reported no relevant disclosures.

Healthy children who are underweight in the first 2 years of life continue with a lower-than-average body mass index and height-for-age through age 10, according to new research.

The association was most pronounced for girls, as well as for children with lower growth rates, write the authors of the prospective Canadian cohort study published in JAMA Network Open.

The findings “highlight the importance of preventing underweight in early life,” because this can have “lasting effects” in later childhood, senior author Jonathon L. Maguire, MD, from St Michael’s Hospital Pediatric Clinic, and the University of Toronto said in an interview.
 

Methods and results

The study recruited 5,803 healthy children, mean age 4.07 months, between February 2008 and September 2020 during well-child visits at clinics in The Applied Research Group for Kids! (TARGet Kids!) practice-based research network in Canada. The study’s exclusion criteria included a premature birth, or a health condition affecting growth.

The primary outcome of the study was the child’s age- and sex-adjusted weight, also known as the body mass index z score (zBMI), between the ages of 2 and 10 years.

At baseline, a total of 550 children (9.5%) were classified as underweight, based on the World Health Organization definition of zBMI less than –2. Underweight children were more likely to be younger, have lower birth weight, and to report Asian maternal ethnicity, the researchers observed.

The study found that, compared with children with normal weight, those who were underweight in the first 2 years had lower zBMI at ages 5 and 10 years (–0.49 and –0.39 respectively). This meant that at 10 years old, they were a mean of 1.23 kg lighter than 10-year-olds who had been normal weight at age 2 years.

Height-for-age z score (HAZ) was also lower for underweight 2-year-olds (–0.24), making them a mean of 0.68 cm shorter than normal-weight 2-year-olds. This difference was attenuated at age 5 years.

Growth rate modified the association of underweight with both zBMI and HAZ. Among children who were underweight in the first 2 years, those with lower growth rate had lower zBMI at 10 years (–0.64) compared with those with average (–0.38) or high growth rate (0.11). Similarly, children who were underweight and had a lower growth rate at age 2 years also a lower HAZ at age 10 years (–0.12), compared with those with average (0.02) or high growth rates (0.16). These effects were more pronounced in girls.
 

Increased health risks linked with chronic underweight

This study did not assess the reasons for early underweight, Dr. Maguire commented in an interview. But, he cited challenges with dietary transitions as a possible explanation.

“Considerable dietary changes happen around 2 years of age with increasing diversity of foods as children transition from primarily liquid foods to primarily solid foods,” he noted.

Asked for comment on the study, Colleen Spees, PhD, associate professor in the division of medical dietetics and director of Hope lab at the Ohio State University, Columbus, said that “at age 10, it’s not surprising to see a lower zBMI and height-for-age in those that were underweight at age 2 with poor growth trajectories.”

Although, this is the first study she is aware of to document these findings in a Canadian cohort, “the results align with what we know about low birth weight and underweight infants and children in terms of linear growth trajectories from child stunting studies,” Dr. Spees said.

She said child stunting, which is more common in less developed countries where children have lower birth weights and greater socioeconomic and environmental risk factors, is defined by the WHO as impaired linear growth with adverse functional consequences.

“In short, a chronic underweight status in infants and young children can lead to greater risk of malnutrition, vitamin and mineral deficiencies, decreased immune function, as well as physical growth and development issues,” she said. “Hence, the most recent 2020-2025 Dietary Guidelines for Americans now includes both pregnancy, breastfeeding, and the first 2 years of life (referred to as the “first 1,000 days”) in their recommendations.”

She added that, if caregivers are concerned about their child’s weight, they should consult with their pediatrician to rule out any medical issues. If no medical issues are identified, they should ask for a referral to a pediatric dietitian.

The study was funded by the Canadian Institute of Health Research. Dr Maguire reported receiving grants from the CIHR, Physician Services, Ontario SPOR Support Unit, and Dairy Farmers of Canada during the conduct of the study and nonfinancial support from DDrops outside the submitted work. Other authors of the paper reported receiving grants from various institutions. Dr. Spees reported no relevant disclosures.

Healthy children who are underweight in the first 2 years of life continue with a lower-than-average body mass index and height-for-age through age 10, according to new research.

The association was most pronounced for girls, as well as for children with lower growth rates, write the authors of the prospective Canadian cohort study published in JAMA Network Open.

The findings “highlight the importance of preventing underweight in early life,” because this can have “lasting effects” in later childhood, senior author Jonathon L. Maguire, MD, from St Michael’s Hospital Pediatric Clinic, and the University of Toronto said in an interview.
 

Methods and results

The study recruited 5,803 healthy children, mean age 4.07 months, between February 2008 and September 2020 during well-child visits at clinics in The Applied Research Group for Kids! (TARGet Kids!) practice-based research network in Canada. The study’s exclusion criteria included a premature birth, or a health condition affecting growth.

The primary outcome of the study was the child’s age- and sex-adjusted weight, also known as the body mass index z score (zBMI), between the ages of 2 and 10 years.

At baseline, a total of 550 children (9.5%) were classified as underweight, based on the World Health Organization definition of zBMI less than –2. Underweight children were more likely to be younger, have lower birth weight, and to report Asian maternal ethnicity, the researchers observed.

The study found that, compared with children with normal weight, those who were underweight in the first 2 years had lower zBMI at ages 5 and 10 years (–0.49 and –0.39 respectively). This meant that at 10 years old, they were a mean of 1.23 kg lighter than 10-year-olds who had been normal weight at age 2 years.

Height-for-age z score (HAZ) was also lower for underweight 2-year-olds (–0.24), making them a mean of 0.68 cm shorter than normal-weight 2-year-olds. This difference was attenuated at age 5 years.

Growth rate modified the association of underweight with both zBMI and HAZ. Among children who were underweight in the first 2 years, those with lower growth rate had lower zBMI at 10 years (–0.64) compared with those with average (–0.38) or high growth rate (0.11). Similarly, children who were underweight and had a lower growth rate at age 2 years also a lower HAZ at age 10 years (–0.12), compared with those with average (0.02) or high growth rates (0.16). These effects were more pronounced in girls.
 

Increased health risks linked with chronic underweight

This study did not assess the reasons for early underweight, Dr. Maguire commented in an interview. But, he cited challenges with dietary transitions as a possible explanation.

“Considerable dietary changes happen around 2 years of age with increasing diversity of foods as children transition from primarily liquid foods to primarily solid foods,” he noted.

Asked for comment on the study, Colleen Spees, PhD, associate professor in the division of medical dietetics and director of Hope lab at the Ohio State University, Columbus, said that “at age 10, it’s not surprising to see a lower zBMI and height-for-age in those that were underweight at age 2 with poor growth trajectories.”

Although, this is the first study she is aware of to document these findings in a Canadian cohort, “the results align with what we know about low birth weight and underweight infants and children in terms of linear growth trajectories from child stunting studies,” Dr. Spees said.

She said child stunting, which is more common in less developed countries where children have lower birth weights and greater socioeconomic and environmental risk factors, is defined by the WHO as impaired linear growth with adverse functional consequences.

“In short, a chronic underweight status in infants and young children can lead to greater risk of malnutrition, vitamin and mineral deficiencies, decreased immune function, as well as physical growth and development issues,” she said. “Hence, the most recent 2020-2025 Dietary Guidelines for Americans now includes both pregnancy, breastfeeding, and the first 2 years of life (referred to as the “first 1,000 days”) in their recommendations.”

She added that, if caregivers are concerned about their child’s weight, they should consult with their pediatrician to rule out any medical issues. If no medical issues are identified, they should ask for a referral to a pediatric dietitian.

The study was funded by the Canadian Institute of Health Research. Dr Maguire reported receiving grants from the CIHR, Physician Services, Ontario SPOR Support Unit, and Dairy Farmers of Canada during the conduct of the study and nonfinancial support from DDrops outside the submitted work. Other authors of the paper reported receiving grants from various institutions. Dr. Spees reported no relevant disclosures.

Pain is classified as chronic when it lasts or recurs for more than 3-6 months (“Classification of chronic pain” 2nd ed. Seattle: IASP Press, 1994). This universally accepted definition does not distinguish between physical and emotional pain. Categorically, pain is pain. Two prevalent chronic gynecologic diseases are closely related medically and emotionally. Forty percent to 50% of women with endometriosis have infertility; 30%-50% of women with infertility are found to have coexisting endometriosis. The approach to both is, typically, symptomatic treatment. In this month’s column, I examine the relationship between these ailments and how we can advise women on management.

Endometriosis is simply defined as the displacement of normal endometrial glands and stroma from their natural anatomical location to elsewhere in the body. With the recent identification of the disease in the spleen, endometriosis has been found in every organ system. Endometriosis is identified in 6%-10% of the general female population. The prevalence ranges from 2% to 11% among asymptomatic women and from 5% to 21% in women hospitalized for pelvic pain (Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15). Compared with fertile women, infertile women are six to eight times more likely to have endometriosis (Fertil Steril. 2012;98:591-8).

Retrograde menstruation is the presumed theory for the origins of endometriosis, that is, the reflux of menstrual debris containing active endometrial cells through the fallopian tubes into the peritoneal cavity (Am J Obstet Gynecol. 1927;14:422-69). Because of the varied etiologies of the most common symptoms of endometriosis, dysmenorrhea, dyspareunia, dyschezia, and infertility, women visit, on average, seven physicians before being diagnosed (Fertil Steril. 2011;96:366). The delay in promptly identifying endometriosis is further impaired by the lack of specific biomarkers, awareness, and inadequate evaluation (N Engl J Med. 2020;382:1244-56).

The 2008 U.S. health care costs for endometriosis were approximately $4,000 per affected woman, analogous to the costs for other chronic conditions such as type 2 diabetes, Crohn’s disease, and rheumatoid arthritis (Hum Reprod. 2012;27:1292-9). The management of symptoms further increases the financial burden because of the effect of the disease on physical, mental, sexual, and social well-being, as well as productivity (Health Qual Life Outcomes. 2019;17:123).

We have known the paradoxical relationship between the stage of endometriosis and symptoms: Women with low-stage disease may present with severe pain and/or infertility but those with advanced-stage disease may be asymptomatic. Endometriotic cells and tissue elicit a localized immune and inflammatory response with the production of cytokines, chemokines, and prostaglandins. Given the usual intra-abdominal location and the small size of implants, endometriosis requires a surgical diagnosis, ideally with histopathology for confirmation. However, imaging – transvaginal ultrasound or MRI – has more than 90% sensitivity and specificity for identifying endometriomas (Cochrane Database Syst Rev. 2016;2[2]:CD009591).

The effect of endometriosis on fertility, particularly in women with minimal to mild stages, is not clear, and many studies have been retrospective. Tubal factor infertility can be a result of endometriosis. Per the 2020 Cochrane Database Systemic Reviews (2020 Oct;2020[10]:CD011031), “Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis; no data were reported on live birth. There is moderate-quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only.” In women undergoing IVF, more advanced stages of endometriosis have reduced pregnancy outcomes as shown in recent meta-analyses (Obstet Gynecol. 2015;125:79-88).

The revised ASRM (rASRM) surgical staging classification of endometriosis has been widely used to describe the degree, although it poorly correlates with fertility potential (Fertil Steril. 2012;98:591-8). Women diagnosed with endometriosis may benefit from the Endometriosis Fertility Index (EFI), published in 2010 as a useful scoring system to predict postoperative non-IVF pregnancy rates (both by natural means and intrauterine insemination) based on patient characteristics, rASRM staging and “least function” score of the adnexa (Fertil Steril. 2010;94:1609-15).

Compared with diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. “Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions (Cochrane Database Syst Rev. 2020 Oct;2020[10]:CD011031).”

The treatment of endometriosis is directly related to the desire for and timing of fertility since therapy is often contraceptive, as opposed to surgery. Because endometriosis is exacerbated by estradiol, the mainstay of medical therapy is initially combined hormonal or progestin-only contraception as a means of reducing pelvic pain by reducing estradiol production and action, respectively. GnRH-agonist suppression of follicle stimulation hormone and luteinizing hormone remains the standard for inactivating endogenous estradiol. In 2018, the U.S. Food and Drug Administration approved elagolix for the treatment of pain associated with endometriosis – the first pill specifically approved for endometriosis pain relief. An off-label approach for women is letrozole, the aromatase inhibitor, to reduce circulating estradiol levels. Unfortunately, estradiol suppression cannot be used solely long term without add-back therapy, because of the risk of bone loss and vasomotor symptoms.

Excision of endometriomas adversely affects ovarian follicular reserve (as indicated by lower levels of anti-müllerian hormone and reduced ovarian antral follicle counts on ultrasound). For women who want to preserve their fertility, the potential benefits of surgery should be weighed against these negative effects. Surgical treatment of endometriosis in women without other identifiable infertility factors may improve rates of spontaneous pregnancy. In women with moderate to severe endometriosis, intrauterine insemination with ovarian stimulation may be of value, particularly with preceding GnRH-agonist therapy (J Endometr Pelvic Pain Disord. 2018;10[3]:158-73).

Despite the reduction in IVF outcomes in women with moderate to severe endometriosis, it remains unclear whether surgery improves the likelihood of pregnancy with IVF as does the concurrent use of prolonged GnRH agonist during IVF stimulation. (Fertil Steril. 2012;98:591-8).

Summary

• Medical therapy alone does not appear to improve fertility in endometriosis.
• Surgical treatment of endometriosis improves natural fertility, particularly in lower-stage endometriosis.
• EFI is a useful tool to predict postoperative natural fertility and assess the need for IVF.
• Despite advanced endometriosis reducing IVF outcomes, surgery or medical pretreatment to increase IVF success remains unproven.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Pain is classified as chronic when it lasts or recurs for more than 3-6 months (“Classification of chronic pain” 2nd ed. Seattle: IASP Press, 1994). This universally accepted definition does not distinguish between physical and emotional pain. Categorically, pain is pain. Two prevalent chronic gynecologic diseases are closely related medically and emotionally. Forty percent to 50% of women with endometriosis have infertility; 30%-50% of women with infertility are found to have coexisting endometriosis. The approach to both is, typically, symptomatic treatment. In this month’s column, I examine the relationship between these ailments and how we can advise women on management.

Endometriosis is simply defined as the displacement of normal endometrial glands and stroma from their natural anatomical location to elsewhere in the body. With the recent identification of the disease in the spleen, endometriosis has been found in every organ system. Endometriosis is identified in 6%-10% of the general female population. The prevalence ranges from 2% to 11% among asymptomatic women and from 5% to 21% in women hospitalized for pelvic pain (Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15). Compared with fertile women, infertile women are six to eight times more likely to have endometriosis (Fertil Steril. 2012;98:591-8).

Retrograde menstruation is the presumed theory for the origins of endometriosis, that is, the reflux of menstrual debris containing active endometrial cells through the fallopian tubes into the peritoneal cavity (Am J Obstet Gynecol. 1927;14:422-69). Because of the varied etiologies of the most common symptoms of endometriosis, dysmenorrhea, dyspareunia, dyschezia, and infertility, women visit, on average, seven physicians before being diagnosed (Fertil Steril. 2011;96:366). The delay in promptly identifying endometriosis is further impaired by the lack of specific biomarkers, awareness, and inadequate evaluation (N Engl J Med. 2020;382:1244-56).

The 2008 U.S. health care costs for endometriosis were approximately $4,000 per affected woman, analogous to the costs for other chronic conditions such as type 2 diabetes, Crohn’s disease, and rheumatoid arthritis (Hum Reprod. 2012;27:1292-9). The management of symptoms further increases the financial burden because of the effect of the disease on physical, mental, sexual, and social well-being, as well as productivity (Health Qual Life Outcomes. 2019;17:123).

We have known the paradoxical relationship between the stage of endometriosis and symptoms: Women with low-stage disease may present with severe pain and/or infertility but those with advanced-stage disease may be asymptomatic. Endometriotic cells and tissue elicit a localized immune and inflammatory response with the production of cytokines, chemokines, and prostaglandins. Given the usual intra-abdominal location and the small size of implants, endometriosis requires a surgical diagnosis, ideally with histopathology for confirmation. However, imaging – transvaginal ultrasound or MRI – has more than 90% sensitivity and specificity for identifying endometriomas (Cochrane Database Syst Rev. 2016;2[2]:CD009591).

The effect of endometriosis on fertility, particularly in women with minimal to mild stages, is not clear, and many studies have been retrospective. Tubal factor infertility can be a result of endometriosis. Per the 2020 Cochrane Database Systemic Reviews (2020 Oct;2020[10]:CD011031), “Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis; no data were reported on live birth. There is moderate-quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only.” In women undergoing IVF, more advanced stages of endometriosis have reduced pregnancy outcomes as shown in recent meta-analyses (Obstet Gynecol. 2015;125:79-88).

The revised ASRM (rASRM) surgical staging classification of endometriosis has been widely used to describe the degree, although it poorly correlates with fertility potential (Fertil Steril. 2012;98:591-8). Women diagnosed with endometriosis may benefit from the Endometriosis Fertility Index (EFI), published in 2010 as a useful scoring system to predict postoperative non-IVF pregnancy rates (both by natural means and intrauterine insemination) based on patient characteristics, rASRM staging and “least function” score of the adnexa (Fertil Steril. 2010;94:1609-15).

Compared with diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. “Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions (Cochrane Database Syst Rev. 2020 Oct;2020[10]:CD011031).”

The treatment of endometriosis is directly related to the desire for and timing of fertility since therapy is often contraceptive, as opposed to surgery. Because endometriosis is exacerbated by estradiol, the mainstay of medical therapy is initially combined hormonal or progestin-only contraception as a means of reducing pelvic pain by reducing estradiol production and action, respectively. GnRH-agonist suppression of follicle stimulation hormone and luteinizing hormone remains the standard for inactivating endogenous estradiol. In 2018, the U.S. Food and Drug Administration approved elagolix for the treatment of pain associated with endometriosis – the first pill specifically approved for endometriosis pain relief. An off-label approach for women is letrozole, the aromatase inhibitor, to reduce circulating estradiol levels. Unfortunately, estradiol suppression cannot be used solely long term without add-back therapy, because of the risk of bone loss and vasomotor symptoms.

Excision of endometriomas adversely affects ovarian follicular reserve (as indicated by lower levels of anti-müllerian hormone and reduced ovarian antral follicle counts on ultrasound). For women who want to preserve their fertility, the potential benefits of surgery should be weighed against these negative effects. Surgical treatment of endometriosis in women without other identifiable infertility factors may improve rates of spontaneous pregnancy. In women with moderate to severe endometriosis, intrauterine insemination with ovarian stimulation may be of value, particularly with preceding GnRH-agonist therapy (J Endometr Pelvic Pain Disord. 2018;10[3]:158-73).

Despite the reduction in IVF outcomes in women with moderate to severe endometriosis, it remains unclear whether surgery improves the likelihood of pregnancy with IVF as does the concurrent use of prolonged GnRH agonist during IVF stimulation. (Fertil Steril. 2012;98:591-8).

Summary

• Medical therapy alone does not appear to improve fertility in endometriosis.
• Surgical treatment of endometriosis improves natural fertility, particularly in lower-stage endometriosis.
• EFI is a useful tool to predict postoperative natural fertility and assess the need for IVF.
• Despite advanced endometriosis reducing IVF outcomes, surgery or medical pretreatment to increase IVF success remains unproven.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Pain is classified as chronic when it lasts or recurs for more than 3-6 months (“Classification of chronic pain” 2nd ed. Seattle: IASP Press, 1994). This universally accepted definition does not distinguish between physical and emotional pain. Categorically, pain is pain. Two prevalent chronic gynecologic diseases are closely related medically and emotionally. Forty percent to 50% of women with endometriosis have infertility; 30%-50% of women with infertility are found to have coexisting endometriosis. The approach to both is, typically, symptomatic treatment. In this month’s column, I examine the relationship between these ailments and how we can advise women on management.

Endometriosis is simply defined as the displacement of normal endometrial glands and stroma from their natural anatomical location to elsewhere in the body. With the recent identification of the disease in the spleen, endometriosis has been found in every organ system. Endometriosis is identified in 6%-10% of the general female population. The prevalence ranges from 2% to 11% among asymptomatic women and from 5% to 21% in women hospitalized for pelvic pain (Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15). Compared with fertile women, infertile women are six to eight times more likely to have endometriosis (Fertil Steril. 2012;98:591-8).

Retrograde menstruation is the presumed theory for the origins of endometriosis, that is, the reflux of menstrual debris containing active endometrial cells through the fallopian tubes into the peritoneal cavity (Am J Obstet Gynecol. 1927;14:422-69). Because of the varied etiologies of the most common symptoms of endometriosis, dysmenorrhea, dyspareunia, dyschezia, and infertility, women visit, on average, seven physicians before being diagnosed (Fertil Steril. 2011;96:366). The delay in promptly identifying endometriosis is further impaired by the lack of specific biomarkers, awareness, and inadequate evaluation (N Engl J Med. 2020;382:1244-56).

The 2008 U.S. health care costs for endometriosis were approximately $4,000 per affected woman, analogous to the costs for other chronic conditions such as type 2 diabetes, Crohn’s disease, and rheumatoid arthritis (Hum Reprod. 2012;27:1292-9). The management of symptoms further increases the financial burden because of the effect of the disease on physical, mental, sexual, and social well-being, as well as productivity (Health Qual Life Outcomes. 2019;17:123).

We have known the paradoxical relationship between the stage of endometriosis and symptoms: Women with low-stage disease may present with severe pain and/or infertility but those with advanced-stage disease may be asymptomatic. Endometriotic cells and tissue elicit a localized immune and inflammatory response with the production of cytokines, chemokines, and prostaglandins. Given the usual intra-abdominal location and the small size of implants, endometriosis requires a surgical diagnosis, ideally with histopathology for confirmation. However, imaging – transvaginal ultrasound or MRI – has more than 90% sensitivity and specificity for identifying endometriomas (Cochrane Database Syst Rev. 2016;2[2]:CD009591).

The effect of endometriosis on fertility, particularly in women with minimal to mild stages, is not clear, and many studies have been retrospective. Tubal factor infertility can be a result of endometriosis. Per the 2020 Cochrane Database Systemic Reviews (2020 Oct;2020[10]:CD011031), “Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis; no data were reported on live birth. There is moderate-quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only.” In women undergoing IVF, more advanced stages of endometriosis have reduced pregnancy outcomes as shown in recent meta-analyses (Obstet Gynecol. 2015;125:79-88).

The revised ASRM (rASRM) surgical staging classification of endometriosis has been widely used to describe the degree, although it poorly correlates with fertility potential (Fertil Steril. 2012;98:591-8). Women diagnosed with endometriosis may benefit from the Endometriosis Fertility Index (EFI), published in 2010 as a useful scoring system to predict postoperative non-IVF pregnancy rates (both by natural means and intrauterine insemination) based on patient characteristics, rASRM staging and “least function” score of the adnexa (Fertil Steril. 2010;94:1609-15).

Compared with diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. “Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions (Cochrane Database Syst Rev. 2020 Oct;2020[10]:CD011031).”

The treatment of endometriosis is directly related to the desire for and timing of fertility since therapy is often contraceptive, as opposed to surgery. Because endometriosis is exacerbated by estradiol, the mainstay of medical therapy is initially combined hormonal or progestin-only contraception as a means of reducing pelvic pain by reducing estradiol production and action, respectively. GnRH-agonist suppression of follicle stimulation hormone and luteinizing hormone remains the standard for inactivating endogenous estradiol. In 2018, the U.S. Food and Drug Administration approved elagolix for the treatment of pain associated with endometriosis – the first pill specifically approved for endometriosis pain relief. An off-label approach for women is letrozole, the aromatase inhibitor, to reduce circulating estradiol levels. Unfortunately, estradiol suppression cannot be used solely long term without add-back therapy, because of the risk of bone loss and vasomotor symptoms.

Excision of endometriomas adversely affects ovarian follicular reserve (as indicated by lower levels of anti-müllerian hormone and reduced ovarian antral follicle counts on ultrasound). For women who want to preserve their fertility, the potential benefits of surgery should be weighed against these negative effects. Surgical treatment of endometriosis in women without other identifiable infertility factors may improve rates of spontaneous pregnancy. In women with moderate to severe endometriosis, intrauterine insemination with ovarian stimulation may be of value, particularly with preceding GnRH-agonist therapy (J Endometr Pelvic Pain Disord. 2018;10[3]:158-73).

Despite the reduction in IVF outcomes in women with moderate to severe endometriosis, it remains unclear whether surgery improves the likelihood of pregnancy with IVF as does the concurrent use of prolonged GnRH agonist during IVF stimulation. (Fertil Steril. 2012;98:591-8).

Summary

• Medical therapy alone does not appear to improve fertility in endometriosis.
• Surgical treatment of endometriosis improves natural fertility, particularly in lower-stage endometriosis.
• EFI is a useful tool to predict postoperative natural fertility and assess the need for IVF.
• Despite advanced endometriosis reducing IVF outcomes, surgery or medical pretreatment to increase IVF success remains unproven.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Hormone therapy remains a topic for debate, but a constant in the 2 decades since the Women’s Health Initiative has been the demonstrated effectiveness for relief of vasomotor symptoms and reduction of fracture risk in menopausal women, according to the latest hormone therapy position statement of the North American Menopause Society.

“Healthcare professionals caring for menopausal women should understand the basic concepts of relative risk and absolute risk,” wrote Stephanie S. Faubion, MD, director of the Mayo Clinic Center for Women’s Health and medical director of NAMS, and members of the NAMS 2022 Hormone Therapy Position Statement Advisory Panel in Menopause.

The authors noted that the risks of hormone therapy vary considerably based on type, dose, duration, route of administration, timing of the start of therapy, and whether or not a progestogen is included.

The 2022 statement was commissioned to review new literature and identify the strength of recommendations and quality of evidence since the previous statement in 2017.

The current statement represents not so much a practice-changing update, “but rather that the literature has filled out in some areas,” Dr. Faubion said in an interview. “The recommendations overall haven’t changed,” she said. “The position statement reiterates that hormone therapy, which is significantly underutilized, remains a safe and effective treatment for menopause symptoms, which remain undertreated, with the benefits outweighing the risks for most healthy women who are within 10 years of menopause onset and under the age of 60 years,” she emphasized. “Individualizing therapy is key to maximizing benefits and minimizing risks,” she added.

Overall, the authors confirmed that hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM), and has been shown to prevent bone loss and fracture. The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used.

Risks and benefits should be stratified by age and time since the start of menopause, according to the statement.

For women younger than 60 years or within 10 years of the onset of menopause who have no contraindications, the potential benefits outweigh the risks in most cases for use of hormone therapy to manage vasomotor symptoms and to help prevent bone loss and reduce fracture risk.

For women who begin hormone therapy more than 10 or 20 years from the start of menopause, or who are aged 60 years and older, the risk-benefit ratio may be less favorable because of the increased absolute risk of coronary heart disease, stroke, venous thromboembolism, and dementia. However, strategies such as lower doses and transdermal administration may reduce this risk, according to the statement.

The authors continue to recommend that longer durations of hormone therapy be for documented indications, such as VMS relief, and that patients on longer duration of therapy be reassessed periodically as part of a shared decision-making process. Women with persistent VMS or quality of life issues, or those at risk for osteoporosis, may continue hormone therapy beyond age 60 or 65 years after appropriate evaluation and risk-benefit counseling.

Women with ongoing GSM without indications for systemic therapy whose GSM persists after over-the-counter therapies may try low-dose vaginal estrogen or other nonestrogen therapies regardless of age and for an extended duration if needed, according to the statement.
 

Challenges, research gaps, and goals

“Barriers to the use of hormone therapy include lack of access to high quality care,” Dr. Faubion said in an interview. The NAMS website, menopause.org, features an option to search for a NAMS-certified provider by ZIP code, she noted.

“Coverage of hormone therapy is highly variable and depends on the insurance company, but most women have access to one form or another with insurance coverage,” she said. “We need to continue to advocate for adequate coverage of menopause symptom treatments, including hormone therapy, so that women’s symptoms – which can significantly affect quality of life – are adequately managed.

“Additional research is needed on the thrombotic risk (venous thromboembolism, pulmonary embolism, and stroke) of oral versus transdermal therapies (including different formulations, doses, and durations of therapy),” Dr. Faubion told this news organization. “More clinical trial data are needed to confirm or refute the potential beneficial effects of hormone therapy on coronary heart disease and all-cause mortality when initiated in perimenopause or early postmenopause,” she said.

Other areas for research include “the breast effects of different estrogen preparations, including the role for selective estrogen receptor modulator (SERM) and tissue selective estrogen complex therapies, optimal progestogen or SERM regimens to prevent endometrial hyperplasia, the relationship between vasomotor symptoms and the risk for heart disease and cognitive changes, and the risks of premature ovarian insufficiency,” Dr. Faubion emphasized.

Looking ahead, “Studies are needed on the effects of longer use of low-dose vaginal estrogen therapy after breast or endometrial cancer, extended use of hormone therapy in women who are early initiators, improved tools to personalize or individualize benefits and risks of hormone therapy, and the role of aging and genetics,” said Dr. Faubion. Other areas for further research include “the long-term benefits and risks on women’s health of lifestyle modification or complementary or nonhormone therapies, if chosen in addition to or over hormone therapy for vasomotor symptoms, bone health, and cardiovascular disease risk reduction,” she added.

The complete statement was published in Menopause: The Journal of the North American Menopause Society.

The position statement received no outside funding. The authors had no financial conflicts to disclose.

Hormone therapy remains a topic for debate, but a constant in the 2 decades since the Women’s Health Initiative has been the demonstrated effectiveness for relief of vasomotor symptoms and reduction of fracture risk in menopausal women, according to the latest hormone therapy position statement of the North American Menopause Society.

“Healthcare professionals caring for menopausal women should understand the basic concepts of relative risk and absolute risk,” wrote Stephanie S. Faubion, MD, director of the Mayo Clinic Center for Women’s Health and medical director of NAMS, and members of the NAMS 2022 Hormone Therapy Position Statement Advisory Panel in Menopause.

The authors noted that the risks of hormone therapy vary considerably based on type, dose, duration, route of administration, timing of the start of therapy, and whether or not a progestogen is included.

The 2022 statement was commissioned to review new literature and identify the strength of recommendations and quality of evidence since the previous statement in 2017.

The current statement represents not so much a practice-changing update, “but rather that the literature has filled out in some areas,” Dr. Faubion said in an interview. “The recommendations overall haven’t changed,” she said. “The position statement reiterates that hormone therapy, which is significantly underutilized, remains a safe and effective treatment for menopause symptoms, which remain undertreated, with the benefits outweighing the risks for most healthy women who are within 10 years of menopause onset and under the age of 60 years,” she emphasized. “Individualizing therapy is key to maximizing benefits and minimizing risks,” she added.

Overall, the authors confirmed that hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM), and has been shown to prevent bone loss and fracture. The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used.

Risks and benefits should be stratified by age and time since the start of menopause, according to the statement.

For women younger than 60 years or within 10 years of the onset of menopause who have no contraindications, the potential benefits outweigh the risks in most cases for use of hormone therapy to manage vasomotor symptoms and to help prevent bone loss and reduce fracture risk.

For women who begin hormone therapy more than 10 or 20 years from the start of menopause, or who are aged 60 years and older, the risk-benefit ratio may be less favorable because of the increased absolute risk of coronary heart disease, stroke, venous thromboembolism, and dementia. However, strategies such as lower doses and transdermal administration may reduce this risk, according to the statement.

The authors continue to recommend that longer durations of hormone therapy be for documented indications, such as VMS relief, and that patients on longer duration of therapy be reassessed periodically as part of a shared decision-making process. Women with persistent VMS or quality of life issues, or those at risk for osteoporosis, may continue hormone therapy beyond age 60 or 65 years after appropriate evaluation and risk-benefit counseling.

Women with ongoing GSM without indications for systemic therapy whose GSM persists after over-the-counter therapies may try low-dose vaginal estrogen or other nonestrogen therapies regardless of age and for an extended duration if needed, according to the statement.
 

Challenges, research gaps, and goals

“Barriers to the use of hormone therapy include lack of access to high quality care,” Dr. Faubion said in an interview. The NAMS website, menopause.org, features an option to search for a NAMS-certified provider by ZIP code, she noted.

“Coverage of hormone therapy is highly variable and depends on the insurance company, but most women have access to one form or another with insurance coverage,” she said. “We need to continue to advocate for adequate coverage of menopause symptom treatments, including hormone therapy, so that women’s symptoms – which can significantly affect quality of life – are adequately managed.

“Additional research is needed on the thrombotic risk (venous thromboembolism, pulmonary embolism, and stroke) of oral versus transdermal therapies (including different formulations, doses, and durations of therapy),” Dr. Faubion told this news organization. “More clinical trial data are needed to confirm or refute the potential beneficial effects of hormone therapy on coronary heart disease and all-cause mortality when initiated in perimenopause or early postmenopause,” she said.

Other areas for research include “the breast effects of different estrogen preparations, including the role for selective estrogen receptor modulator (SERM) and tissue selective estrogen complex therapies, optimal progestogen or SERM regimens to prevent endometrial hyperplasia, the relationship between vasomotor symptoms and the risk for heart disease and cognitive changes, and the risks of premature ovarian insufficiency,” Dr. Faubion emphasized.

Looking ahead, “Studies are needed on the effects of longer use of low-dose vaginal estrogen therapy after breast or endometrial cancer, extended use of hormone therapy in women who are early initiators, improved tools to personalize or individualize benefits and risks of hormone therapy, and the role of aging and genetics,” said Dr. Faubion. Other areas for further research include “the long-term benefits and risks on women’s health of lifestyle modification or complementary or nonhormone therapies, if chosen in addition to or over hormone therapy for vasomotor symptoms, bone health, and cardiovascular disease risk reduction,” she added.

The complete statement was published in Menopause: The Journal of the North American Menopause Society.

The position statement received no outside funding. The authors had no financial conflicts to disclose.

Hormone therapy remains a topic for debate, but a constant in the 2 decades since the Women’s Health Initiative has been the demonstrated effectiveness for relief of vasomotor symptoms and reduction of fracture risk in menopausal women, according to the latest hormone therapy position statement of the North American Menopause Society.

“Healthcare professionals caring for menopausal women should understand the basic concepts of relative risk and absolute risk,” wrote Stephanie S. Faubion, MD, director of the Mayo Clinic Center for Women’s Health and medical director of NAMS, and members of the NAMS 2022 Hormone Therapy Position Statement Advisory Panel in Menopause.

The authors noted that the risks of hormone therapy vary considerably based on type, dose, duration, route of administration, timing of the start of therapy, and whether or not a progestogen is included.

The 2022 statement was commissioned to review new literature and identify the strength of recommendations and quality of evidence since the previous statement in 2017.

The current statement represents not so much a practice-changing update, “but rather that the literature has filled out in some areas,” Dr. Faubion said in an interview. “The recommendations overall haven’t changed,” she said. “The position statement reiterates that hormone therapy, which is significantly underutilized, remains a safe and effective treatment for menopause symptoms, which remain undertreated, with the benefits outweighing the risks for most healthy women who are within 10 years of menopause onset and under the age of 60 years,” she emphasized. “Individualizing therapy is key to maximizing benefits and minimizing risks,” she added.

Overall, the authors confirmed that hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM), and has been shown to prevent bone loss and fracture. The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used.

Risks and benefits should be stratified by age and time since the start of menopause, according to the statement.

For women younger than 60 years or within 10 years of the onset of menopause who have no contraindications, the potential benefits outweigh the risks in most cases for use of hormone therapy to manage vasomotor symptoms and to help prevent bone loss and reduce fracture risk.

For women who begin hormone therapy more than 10 or 20 years from the start of menopause, or who are aged 60 years and older, the risk-benefit ratio may be less favorable because of the increased absolute risk of coronary heart disease, stroke, venous thromboembolism, and dementia. However, strategies such as lower doses and transdermal administration may reduce this risk, according to the statement.

The authors continue to recommend that longer durations of hormone therapy be for documented indications, such as VMS relief, and that patients on longer duration of therapy be reassessed periodically as part of a shared decision-making process. Women with persistent VMS or quality of life issues, or those at risk for osteoporosis, may continue hormone therapy beyond age 60 or 65 years after appropriate evaluation and risk-benefit counseling.

Women with ongoing GSM without indications for systemic therapy whose GSM persists after over-the-counter therapies may try low-dose vaginal estrogen or other nonestrogen therapies regardless of age and for an extended duration if needed, according to the statement.
 

Challenges, research gaps, and goals

“Barriers to the use of hormone therapy include lack of access to high quality care,” Dr. Faubion said in an interview. The NAMS website, menopause.org, features an option to search for a NAMS-certified provider by ZIP code, she noted.

“Coverage of hormone therapy is highly variable and depends on the insurance company, but most women have access to one form or another with insurance coverage,” she said. “We need to continue to advocate for adequate coverage of menopause symptom treatments, including hormone therapy, so that women’s symptoms – which can significantly affect quality of life – are adequately managed.

“Additional research is needed on the thrombotic risk (venous thromboembolism, pulmonary embolism, and stroke) of oral versus transdermal therapies (including different formulations, doses, and durations of therapy),” Dr. Faubion told this news organization. “More clinical trial data are needed to confirm or refute the potential beneficial effects of hormone therapy on coronary heart disease and all-cause mortality when initiated in perimenopause or early postmenopause,” she said.

Other areas for research include “the breast effects of different estrogen preparations, including the role for selective estrogen receptor modulator (SERM) and tissue selective estrogen complex therapies, optimal progestogen or SERM regimens to prevent endometrial hyperplasia, the relationship between vasomotor symptoms and the risk for heart disease and cognitive changes, and the risks of premature ovarian insufficiency,” Dr. Faubion emphasized.

Looking ahead, “Studies are needed on the effects of longer use of low-dose vaginal estrogen therapy after breast or endometrial cancer, extended use of hormone therapy in women who are early initiators, improved tools to personalize or individualize benefits and risks of hormone therapy, and the role of aging and genetics,” said Dr. Faubion. Other areas for further research include “the long-term benefits and risks on women’s health of lifestyle modification or complementary or nonhormone therapies, if chosen in addition to or over hormone therapy for vasomotor symptoms, bone health, and cardiovascular disease risk reduction,” she added.

The complete statement was published in Menopause: The Journal of the North American Menopause Society.

The position statement received no outside funding. The authors had no financial conflicts to disclose.

PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.

The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).

For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.

Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.

Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
 

Mendelian randomization addresses complex issue

The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.

By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.

The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.

“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.

From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.

The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.

In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions

Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.


 

Data do not support low LDL-C as cognitive risk factor

Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.

“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”

In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.

“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.

Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.

PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.

The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).

For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.

Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.

Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
 

Mendelian randomization addresses complex issue

The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.

By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.

The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.

“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.

From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.

The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.

In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions

Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.


 

Data do not support low LDL-C as cognitive risk factor

Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.

“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”

In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.

“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.

Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.

PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.

The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).

For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.

Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.

Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
 

Mendelian randomization addresses complex issue

The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.

By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.

The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.

“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.

From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.

The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.

In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions

Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.


 

Data do not support low LDL-C as cognitive risk factor

Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.

“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”

In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.

“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.

Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.

People with elevated levels of protein prostasin seem to have a higher risk of developing diabetes and dying from cancer, according to a large, prospective, population-based study. The finding may provide new insights into why people with diabetes have an increased risk of cancer.

The study claims to be the first to investigate the link between plasma prostasin levels and cancer mortality, the study authors wrote in Diabetologia. The study analyzed plasma prostasin samples from 4,297 older adults (average age, 57.5 years) from the Malmö (Sweden) Diet and Cancer Study Cardiovascular Cohort.

“This study from the general population shows that prostasin, a protein that could be measured in blood, is associated with increased risk of developing diabetes,” senior author Gunnar Engström, MD, PhD, professor of epidemiology at Lund University in Malmö, Sweden, said in a comment. “Furthermore, it was associated with increased risk of death from cancer, especially in individuals with elevated glucose levels in the prediabetic range.

“The relationship between diabetes and cancer is poorly understood,” Dr. Engström said. “To our knowledge, this is the first big population study of prostasin and risk of diabetes.”

He noted previous studies have found a relationship between prostasin and cancer outcomes. “Prostasin could be a possible shared link between  the two diseases and the results could help us understand why individuals with diabetes have increased risk of cancer.”

Patients in the study were assigned to quartiles based on prostasin levels. Those in the highest quartile had almost twice the risk of prevalent diabetes than did those in the lowest quartile (adjusted odds ratio, 1.95; 95% confidence interval, 1.39-2.76; P < .0001).

During the follow-up periods of 21.9 years for diabetes and 23.5 years for cancer, on average, 702 participants developed diabetes and 651 died from cancer. Again, the analysis found a significantly higher adjusted hazard ratio for participants in the fourth quartile: about 75% higher for diabetes (HR, 1.76; 95% CI, 1.41-2.19; P < .0001), and, after multivariable analysis, about 40% higher for death from cancer (HR, 1.43; 95% CI, 1.14-1.8; P = .0008).
 

Potential diabetes-cancer ‘interaction’

The study also identified what it called “a significant interaction” between prostasin and fasting blood glucose for cancer mortality risk (P = .022). In patients with impaired fasting blood glucose levels at baseline, the risk for cancer mortality was about 50% greater with each standard deviation increase in prostasin (HR, 1.52; 95% CI, 1.07-2.16; P = .019). Those with normal fasting blood glucose at baseline had a significantly lower risk with each SD increase in prostasin (HR, 1.11; 95% CI, 1.01-1.21; P = .025).

Further research is needed to validate the potential of prostasin as a biomarker for diabetes and cancer risks, Dr. Engström said. “The results need to be replicated in other studies. A study of cancer mortality in a big cohort of diabetes patients would be of great interest. We also need to examine whether prostasin is causally related to cancer and/or diabetes, or whether prostasin could act as a valuable risk marker in clinical settings. If causal, there could a possible molecular target for treatment.”

He added: “Biomarkers of diabetes and cancer are of great interest in the era of personalized medicine, both for disease prevention and for treatment of those with established disease.”

Li-Mei Chen, MD, PhD, a research associate professor at the University of Central Florida, Orlando, has studied the role of prostasin in epidemiology. She noted that one of the challenges of using prostasin in clinical or research settings is the lack of a standardized assay, which the Malmö study acknowledged. Dr. Engström and colleagues wrote that “prostasin levels were measured in arbitrary units (NPX values), and thus could not be compared directly with absolute values.”

Dr. Chen pointed out that the study reported a lower range of 0.24 pg/mL and an upper range of 7,800 pg/mL.

This means that, “in different groups that measure prostasin, the absolute quantity could have a difference in the thousands or tens of thousands,” she said. “That makes the judgment difficult of whether for this person you have a high level of prostasin in the blood and the other one you don’t if the difference is over a thousandfold.”

The Malmö study used the Proseek Multiplex Oncology I panel to determine plasma prostasin concentration, but Dr. Chen noted that she couldn’t find any data validating the panel for measuring prostasin. “It’s really hard for me to say whether this is of value or not because if the method that generated the data is not verified by another method, you don’t really know what you’re measuring.

“If the data are questionable, it’s really hard to say whether it means whether it’s a marker for cancer or diabetes,” Dr. Chen added. “That’s the biggest question I have, but actually the authors realize that.”

Dr. Engström confirmed that, “if prostasin is used to identify patients with increased risk of diabetes and cancer mortality, we also need to develop standardized assays for clinical use.”

Dr. Engström and coauthors had no disclosures. The study received funding from the Swedish Heart Lung Foundation, the National Natural Science Foundation of China, and the Natural Science Foundation of Jiangsu Province. The Malmö Diet and Cancer study received grants from the Swedish Cancer Society, the Swedish Medical Research Council, AFA Insurance, the Albert Påhlsson and Gunnar Nilsson Foundations, Malmö City Council, and Lund University. Dr. Chen had no relevant disclosures.
 

People with elevated levels of protein prostasin seem to have a higher risk of developing diabetes and dying from cancer, according to a large, prospective, population-based study. The finding may provide new insights into why people with diabetes have an increased risk of cancer.

The study claims to be the first to investigate the link between plasma prostasin levels and cancer mortality, the study authors wrote in Diabetologia. The study analyzed plasma prostasin samples from 4,297 older adults (average age, 57.5 years) from the Malmö (Sweden) Diet and Cancer Study Cardiovascular Cohort.

“This study from the general population shows that prostasin, a protein that could be measured in blood, is associated with increased risk of developing diabetes,” senior author Gunnar Engström, MD, PhD, professor of epidemiology at Lund University in Malmö, Sweden, said in a comment. “Furthermore, it was associated with increased risk of death from cancer, especially in individuals with elevated glucose levels in the prediabetic range.

“The relationship between diabetes and cancer is poorly understood,” Dr. Engström said. “To our knowledge, this is the first big population study of prostasin and risk of diabetes.”

He noted previous studies have found a relationship between prostasin and cancer outcomes. “Prostasin could be a possible shared link between  the two diseases and the results could help us understand why individuals with diabetes have increased risk of cancer.”

Patients in the study were assigned to quartiles based on prostasin levels. Those in the highest quartile had almost twice the risk of prevalent diabetes than did those in the lowest quartile (adjusted odds ratio, 1.95; 95% confidence interval, 1.39-2.76; P < .0001).

During the follow-up periods of 21.9 years for diabetes and 23.5 years for cancer, on average, 702 participants developed diabetes and 651 died from cancer. Again, the analysis found a significantly higher adjusted hazard ratio for participants in the fourth quartile: about 75% higher for diabetes (HR, 1.76; 95% CI, 1.41-2.19; P < .0001), and, after multivariable analysis, about 40% higher for death from cancer (HR, 1.43; 95% CI, 1.14-1.8; P = .0008).
 

Potential diabetes-cancer ‘interaction’

The study also identified what it called “a significant interaction” between prostasin and fasting blood glucose for cancer mortality risk (P = .022). In patients with impaired fasting blood glucose levels at baseline, the risk for cancer mortality was about 50% greater with each standard deviation increase in prostasin (HR, 1.52; 95% CI, 1.07-2.16; P = .019). Those with normal fasting blood glucose at baseline had a significantly lower risk with each SD increase in prostasin (HR, 1.11; 95% CI, 1.01-1.21; P = .025).

Further research is needed to validate the potential of prostasin as a biomarker for diabetes and cancer risks, Dr. Engström said. “The results need to be replicated in other studies. A study of cancer mortality in a big cohort of diabetes patients would be of great interest. We also need to examine whether prostasin is causally related to cancer and/or diabetes, or whether prostasin could act as a valuable risk marker in clinical settings. If causal, there could a possible molecular target for treatment.”

He added: “Biomarkers of diabetes and cancer are of great interest in the era of personalized medicine, both for disease prevention and for treatment of those with established disease.”

Li-Mei Chen, MD, PhD, a research associate professor at the University of Central Florida, Orlando, has studied the role of prostasin in epidemiology. She noted that one of the challenges of using prostasin in clinical or research settings is the lack of a standardized assay, which the Malmö study acknowledged. Dr. Engström and colleagues wrote that “prostasin levels were measured in arbitrary units (NPX values), and thus could not be compared directly with absolute values.”

Dr. Chen pointed out that the study reported a lower range of 0.24 pg/mL and an upper range of 7,800 pg/mL.

This means that, “in different groups that measure prostasin, the absolute quantity could have a difference in the thousands or tens of thousands,” she said. “That makes the judgment difficult of whether for this person you have a high level of prostasin in the blood and the other one you don’t if the difference is over a thousandfold.”

The Malmö study used the Proseek Multiplex Oncology I panel to determine plasma prostasin concentration, but Dr. Chen noted that she couldn’t find any data validating the panel for measuring prostasin. “It’s really hard for me to say whether this is of value or not because if the method that generated the data is not verified by another method, you don’t really know what you’re measuring.

“If the data are questionable, it’s really hard to say whether it means whether it’s a marker for cancer or diabetes,” Dr. Chen added. “That’s the biggest question I have, but actually the authors realize that.”

Dr. Engström confirmed that, “if prostasin is used to identify patients with increased risk of diabetes and cancer mortality, we also need to develop standardized assays for clinical use.”

Dr. Engström and coauthors had no disclosures. The study received funding from the Swedish Heart Lung Foundation, the National Natural Science Foundation of China, and the Natural Science Foundation of Jiangsu Province. The Malmö Diet and Cancer study received grants from the Swedish Cancer Society, the Swedish Medical Research Council, AFA Insurance, the Albert Påhlsson and Gunnar Nilsson Foundations, Malmö City Council, and Lund University. Dr. Chen had no relevant disclosures.
 

People with elevated levels of protein prostasin seem to have a higher risk of developing diabetes and dying from cancer, according to a large, prospective, population-based study. The finding may provide new insights into why people with diabetes have an increased risk of cancer.

The study claims to be the first to investigate the link between plasma prostasin levels and cancer mortality, the study authors wrote in Diabetologia. The study analyzed plasma prostasin samples from 4,297 older adults (average age, 57.5 years) from the Malmö (Sweden) Diet and Cancer Study Cardiovascular Cohort.

“This study from the general population shows that prostasin, a protein that could be measured in blood, is associated with increased risk of developing diabetes,” senior author Gunnar Engström, MD, PhD, professor of epidemiology at Lund University in Malmö, Sweden, said in a comment. “Furthermore, it was associated with increased risk of death from cancer, especially in individuals with elevated glucose levels in the prediabetic range.

“The relationship between diabetes and cancer is poorly understood,” Dr. Engström said. “To our knowledge, this is the first big population study of prostasin and risk of diabetes.”

He noted previous studies have found a relationship between prostasin and cancer outcomes. “Prostasin could be a possible shared link between  the two diseases and the results could help us understand why individuals with diabetes have increased risk of cancer.”

Patients in the study were assigned to quartiles based on prostasin levels. Those in the highest quartile had almost twice the risk of prevalent diabetes than did those in the lowest quartile (adjusted odds ratio, 1.95; 95% confidence interval, 1.39-2.76; P < .0001).

During the follow-up periods of 21.9 years for diabetes and 23.5 years for cancer, on average, 702 participants developed diabetes and 651 died from cancer. Again, the analysis found a significantly higher adjusted hazard ratio for participants in the fourth quartile: about 75% higher for diabetes (HR, 1.76; 95% CI, 1.41-2.19; P < .0001), and, after multivariable analysis, about 40% higher for death from cancer (HR, 1.43; 95% CI, 1.14-1.8; P = .0008).
 

Potential diabetes-cancer ‘interaction’

The study also identified what it called “a significant interaction” between prostasin and fasting blood glucose for cancer mortality risk (P = .022). In patients with impaired fasting blood glucose levels at baseline, the risk for cancer mortality was about 50% greater with each standard deviation increase in prostasin (HR, 1.52; 95% CI, 1.07-2.16; P = .019). Those with normal fasting blood glucose at baseline had a significantly lower risk with each SD increase in prostasin (HR, 1.11; 95% CI, 1.01-1.21; P = .025).

Further research is needed to validate the potential of prostasin as a biomarker for diabetes and cancer risks, Dr. Engström said. “The results need to be replicated in other studies. A study of cancer mortality in a big cohort of diabetes patients would be of great interest. We also need to examine whether prostasin is causally related to cancer and/or diabetes, or whether prostasin could act as a valuable risk marker in clinical settings. If causal, there could a possible molecular target for treatment.”

He added: “Biomarkers of diabetes and cancer are of great interest in the era of personalized medicine, both for disease prevention and for treatment of those with established disease.”

Li-Mei Chen, MD, PhD, a research associate professor at the University of Central Florida, Orlando, has studied the role of prostasin in epidemiology. She noted that one of the challenges of using prostasin in clinical or research settings is the lack of a standardized assay, which the Malmö study acknowledged. Dr. Engström and colleagues wrote that “prostasin levels were measured in arbitrary units (NPX values), and thus could not be compared directly with absolute values.”

Dr. Chen pointed out that the study reported a lower range of 0.24 pg/mL and an upper range of 7,800 pg/mL.

This means that, “in different groups that measure prostasin, the absolute quantity could have a difference in the thousands or tens of thousands,” she said. “That makes the judgment difficult of whether for this person you have a high level of prostasin in the blood and the other one you don’t if the difference is over a thousandfold.”

The Malmö study used the Proseek Multiplex Oncology I panel to determine plasma prostasin concentration, but Dr. Chen noted that she couldn’t find any data validating the panel for measuring prostasin. “It’s really hard for me to say whether this is of value or not because if the method that generated the data is not verified by another method, you don’t really know what you’re measuring.

“If the data are questionable, it’s really hard to say whether it means whether it’s a marker for cancer or diabetes,” Dr. Chen added. “That’s the biggest question I have, but actually the authors realize that.”

Dr. Engström confirmed that, “if prostasin is used to identify patients with increased risk of diabetes and cancer mortality, we also need to develop standardized assays for clinical use.”

Dr. Engström and coauthors had no disclosures. The study received funding from the Swedish Heart Lung Foundation, the National Natural Science Foundation of China, and the Natural Science Foundation of Jiangsu Province. The Malmö Diet and Cancer study received grants from the Swedish Cancer Society, the Swedish Medical Research Council, AFA Insurance, the Albert Påhlsson and Gunnar Nilsson Foundations, Malmö City Council, and Lund University. Dr. Chen had no relevant disclosures.
 

More than half of patients with noninfectious acute anterior uveitis seen in ophthalmology clinics in a new cross-sectional study were found by rheumatologists to have spondyloarthritis (SpA), prompting the researchers to recommend referring “all patients with AAU reporting musculoskeletal symptoms to rheumatologists.”

The results also suggest that “rheumatologists should consider that SpA in AAU patients might present ‘atypically’ with no or mild back pain starting after the age of 45 years and lasting shorter than 3 months,” according to first author Judith Rademacher, MD, and colleagues at Charité–Universitätsmedizin Berlin, who published their work online in Arthritis & Rheumatology.

Jonathan Trobe, M.D./Wikimedia Commons/CC BY-SA 3.0

During July 2017–April 2021, the study team prospectively assessed 189 consecutive adult patients with noninfectious AAU at ophthalmology clinics in the Berlin area. The patients had rheumatologic examinations and underwent pelvic x-ray if they had back pain as well as MRI of sacroiliac joints regardless of back pain unless there was a contraindication. The patients had a mean age of nearly 41 years, and 54.5% were male.

Of the 189 patients with AAU, the researchers diagnosed SpA in 106, including 74 (70%) who had been previously undiagnosed. A total of 99 (93%) had predominately axial SpA, and 7 (7%) had peripheral SpA.

A multivariable logistic regression assessment found that male sex (odds ratio, 2.1; 95% confidence interval, 1.1-4.2), HLA-B27 positivity (OR, 6.3; 95% CI, 2.4-16.4), elevated C-reactive protein (OR, 4.8; 95% CI, 1.9-12.4), and psoriasis (OR, 12.5; 95% CI, 1.3-120.2) were significantly associated with SpA in patients with AAU. No ophthalmologic factors were significantly associated with SpA.

Among all patients, an adaptation of the Assessment of SpondyloArthritis International Society (ASAS) referral tool demonstrated lower specificity for SpA recognition than did the Dublin Uveitis Evaluation Tool (28% vs. 42%). The ASAS referral took had a slightly greater sensitivity than the Dublin Uveitis Evaluation Tool (80% vs. 78%).

“Taking into account only AAU patients without prior diagnosis of SpA, a rheumatologist would have to see 2.1 patients fulfilling the ASAS tool or 1.9 patients fulfilling the DUET to diagnose one patient with SpA. However, with both referral strategies more than 20% of SpA patients would have been missed,” the researchers wrote. “This might be due to an ‘unusual presentation’ of SpA in those patients as their back pain started more often after the age of 45 years, lasted shorter than 3 months and thus, ASAS classification criteria were less frequently fulfilled.”

The researchers acknowledged possible selection bias because 15 patients with an incomplete rheumatologic evaluation were excluded. MRI also was routinely done for sacroiliac joints alone, although it was possible for clinician to order spinal MRI. In addition, the researchers allowed patients with AAU into the study regardless of their current treatment, meaning that it may have been possible for some patients receiving biologic disease-modifying antirheumatic drugs to not be correctly identified as having SpA if the treatment improved their musculoskeletal symptoms.

Expert commentary

There are a number of diseases associated with SpA, including AAU, noted Kristine Kuhn, MD, PhD, an associate professor of medicine at the University of Colorado at Denver, Aurora, who was not involved in the study.

“As a rheumatologist, we are quite aware of [uveitis] as an association, and we are usually asking our patients about eye symptoms because of this association,” Dr. Kuhn said in an interview.

While just over half of the patients with AAU also met the criteria for SpA, “that doesn’t necessarily mean diagnosis per se because classification criteria are based on a series of features to homogenize a group of people for clinical research studies. So it doesn’t always align 100% with diagnosis, but it does give us an indication that a little of over half of people with anterior uveitis will have underlying spondyloarthritis and should be evaluated by a rheumatologist.”

Dr. Kuhn also highlighted the associations of male sex, HLA-B27 positivity, and concomitant presence of psoriasis. “I bring those up because I find those to be interesting associations. We have known those for years to be associated with axial spondyloarthritis, but when you look at the actual data, I would just put a little bit of caution to those conclusions.”

She pointed out that, although the link of male sex to SpA in patients with AAU was statistically significant, it is not a clinically meaningful association.

Dr. Kuhn also noted that caution should be used when interpreting the HLA-B27 positivity data. “The caution that I put there is that this was conducted in Germany, and we know that Northern European populations tend to be more enriched for HLA-B27 genes, so what that association would be in a more diverse population is unknown.

“I think ophthalmologists are really good when they see a patient with [acute]-onset anterior uveitis; they have a suspicion that there’s probably another systemic disease that they should be looking at. What this tells us as a physician community is that maybe we should lower the threshold for getting patients into rheumatology and looking at whether or not the patient has underlying spondyloarthritis,” she said.

AbbVie supported the study with an unrestricted research grant but had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Of the study’s 12 authors, 2 reported having no financial disclosures. All others reported financial relationships with pharmaceutical companies, including AbbVie.

More than half of patients with noninfectious acute anterior uveitis seen in ophthalmology clinics in a new cross-sectional study were found by rheumatologists to have spondyloarthritis (SpA), prompting the researchers to recommend referring “all patients with AAU reporting musculoskeletal symptoms to rheumatologists.”

The results also suggest that “rheumatologists should consider that SpA in AAU patients might present ‘atypically’ with no or mild back pain starting after the age of 45 years and lasting shorter than 3 months,” according to first author Judith Rademacher, MD, and colleagues at Charité–Universitätsmedizin Berlin, who published their work online in Arthritis & Rheumatology.

Jonathan Trobe, M.D./Wikimedia Commons/CC BY-SA 3.0

During July 2017–April 2021, the study team prospectively assessed 189 consecutive adult patients with noninfectious AAU at ophthalmology clinics in the Berlin area. The patients had rheumatologic examinations and underwent pelvic x-ray if they had back pain as well as MRI of sacroiliac joints regardless of back pain unless there was a contraindication. The patients had a mean age of nearly 41 years, and 54.5% were male.

Of the 189 patients with AAU, the researchers diagnosed SpA in 106, including 74 (70%) who had been previously undiagnosed. A total of 99 (93%) had predominately axial SpA, and 7 (7%) had peripheral SpA.

A multivariable logistic regression assessment found that male sex (odds ratio, 2.1; 95% confidence interval, 1.1-4.2), HLA-B27 positivity (OR, 6.3; 95% CI, 2.4-16.4), elevated C-reactive protein (OR, 4.8; 95% CI, 1.9-12.4), and psoriasis (OR, 12.5; 95% CI, 1.3-120.2) were significantly associated with SpA in patients with AAU. No ophthalmologic factors were significantly associated with SpA.

Among all patients, an adaptation of the Assessment of SpondyloArthritis International Society (ASAS) referral tool demonstrated lower specificity for SpA recognition than did the Dublin Uveitis Evaluation Tool (28% vs. 42%). The ASAS referral took had a slightly greater sensitivity than the Dublin Uveitis Evaluation Tool (80% vs. 78%).

“Taking into account only AAU patients without prior diagnosis of SpA, a rheumatologist would have to see 2.1 patients fulfilling the ASAS tool or 1.9 patients fulfilling the DUET to diagnose one patient with SpA. However, with both referral strategies more than 20% of SpA patients would have been missed,” the researchers wrote. “This might be due to an ‘unusual presentation’ of SpA in those patients as their back pain started more often after the age of 45 years, lasted shorter than 3 months and thus, ASAS classification criteria were less frequently fulfilled.”

The researchers acknowledged possible selection bias because 15 patients with an incomplete rheumatologic evaluation were excluded. MRI also was routinely done for sacroiliac joints alone, although it was possible for clinician to order spinal MRI. In addition, the researchers allowed patients with AAU into the study regardless of their current treatment, meaning that it may have been possible for some patients receiving biologic disease-modifying antirheumatic drugs to not be correctly identified as having SpA if the treatment improved their musculoskeletal symptoms.

Expert commentary

There are a number of diseases associated with SpA, including AAU, noted Kristine Kuhn, MD, PhD, an associate professor of medicine at the University of Colorado at Denver, Aurora, who was not involved in the study.

“As a rheumatologist, we are quite aware of [uveitis] as an association, and we are usually asking our patients about eye symptoms because of this association,” Dr. Kuhn said in an interview.

While just over half of the patients with AAU also met the criteria for SpA, “that doesn’t necessarily mean diagnosis per se because classification criteria are based on a series of features to homogenize a group of people for clinical research studies. So it doesn’t always align 100% with diagnosis, but it does give us an indication that a little of over half of people with anterior uveitis will have underlying spondyloarthritis and should be evaluated by a rheumatologist.”

Dr. Kuhn also highlighted the associations of male sex, HLA-B27 positivity, and concomitant presence of psoriasis. “I bring those up because I find those to be interesting associations. We have known those for years to be associated with axial spondyloarthritis, but when you look at the actual data, I would just put a little bit of caution to those conclusions.”

She pointed out that, although the link of male sex to SpA in patients with AAU was statistically significant, it is not a clinically meaningful association.

Dr. Kuhn also noted that caution should be used when interpreting the HLA-B27 positivity data. “The caution that I put there is that this was conducted in Germany, and we know that Northern European populations tend to be more enriched for HLA-B27 genes, so what that association would be in a more diverse population is unknown.

“I think ophthalmologists are really good when they see a patient with [acute]-onset anterior uveitis; they have a suspicion that there’s probably another systemic disease that they should be looking at. What this tells us as a physician community is that maybe we should lower the threshold for getting patients into rheumatology and looking at whether or not the patient has underlying spondyloarthritis,” she said.

AbbVie supported the study with an unrestricted research grant but had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Of the study’s 12 authors, 2 reported having no financial disclosures. All others reported financial relationships with pharmaceutical companies, including AbbVie.

More than half of patients with noninfectious acute anterior uveitis seen in ophthalmology clinics in a new cross-sectional study were found by rheumatologists to have spondyloarthritis (SpA), prompting the researchers to recommend referring “all patients with AAU reporting musculoskeletal symptoms to rheumatologists.”

The results also suggest that “rheumatologists should consider that SpA in AAU patients might present ‘atypically’ with no or mild back pain starting after the age of 45 years and lasting shorter than 3 months,” according to first author Judith Rademacher, MD, and colleagues at Charité–Universitätsmedizin Berlin, who published their work online in Arthritis & Rheumatology.

Jonathan Trobe, M.D./Wikimedia Commons/CC BY-SA 3.0

During July 2017–April 2021, the study team prospectively assessed 189 consecutive adult patients with noninfectious AAU at ophthalmology clinics in the Berlin area. The patients had rheumatologic examinations and underwent pelvic x-ray if they had back pain as well as MRI of sacroiliac joints regardless of back pain unless there was a contraindication. The patients had a mean age of nearly 41 years, and 54.5% were male.

Of the 189 patients with AAU, the researchers diagnosed SpA in 106, including 74 (70%) who had been previously undiagnosed. A total of 99 (93%) had predominately axial SpA, and 7 (7%) had peripheral SpA.

A multivariable logistic regression assessment found that male sex (odds ratio, 2.1; 95% confidence interval, 1.1-4.2), HLA-B27 positivity (OR, 6.3; 95% CI, 2.4-16.4), elevated C-reactive protein (OR, 4.8; 95% CI, 1.9-12.4), and psoriasis (OR, 12.5; 95% CI, 1.3-120.2) were significantly associated with SpA in patients with AAU. No ophthalmologic factors were significantly associated with SpA.

Among all patients, an adaptation of the Assessment of SpondyloArthritis International Society (ASAS) referral tool demonstrated lower specificity for SpA recognition than did the Dublin Uveitis Evaluation Tool (28% vs. 42%). The ASAS referral took had a slightly greater sensitivity than the Dublin Uveitis Evaluation Tool (80% vs. 78%).

“Taking into account only AAU patients without prior diagnosis of SpA, a rheumatologist would have to see 2.1 patients fulfilling the ASAS tool or 1.9 patients fulfilling the DUET to diagnose one patient with SpA. However, with both referral strategies more than 20% of SpA patients would have been missed,” the researchers wrote. “This might be due to an ‘unusual presentation’ of SpA in those patients as their back pain started more often after the age of 45 years, lasted shorter than 3 months and thus, ASAS classification criteria were less frequently fulfilled.”

The researchers acknowledged possible selection bias because 15 patients with an incomplete rheumatologic evaluation were excluded. MRI also was routinely done for sacroiliac joints alone, although it was possible for clinician to order spinal MRI. In addition, the researchers allowed patients with AAU into the study regardless of their current treatment, meaning that it may have been possible for some patients receiving biologic disease-modifying antirheumatic drugs to not be correctly identified as having SpA if the treatment improved their musculoskeletal symptoms.

Expert commentary

There are a number of diseases associated with SpA, including AAU, noted Kristine Kuhn, MD, PhD, an associate professor of medicine at the University of Colorado at Denver, Aurora, who was not involved in the study.

“As a rheumatologist, we are quite aware of [uveitis] as an association, and we are usually asking our patients about eye symptoms because of this association,” Dr. Kuhn said in an interview.

While just over half of the patients with AAU also met the criteria for SpA, “that doesn’t necessarily mean diagnosis per se because classification criteria are based on a series of features to homogenize a group of people for clinical research studies. So it doesn’t always align 100% with diagnosis, but it does give us an indication that a little of over half of people with anterior uveitis will have underlying spondyloarthritis and should be evaluated by a rheumatologist.”

Dr. Kuhn also highlighted the associations of male sex, HLA-B27 positivity, and concomitant presence of psoriasis. “I bring those up because I find those to be interesting associations. We have known those for years to be associated with axial spondyloarthritis, but when you look at the actual data, I would just put a little bit of caution to those conclusions.”

She pointed out that, although the link of male sex to SpA in patients with AAU was statistically significant, it is not a clinically meaningful association.

Dr. Kuhn also noted that caution should be used when interpreting the HLA-B27 positivity data. “The caution that I put there is that this was conducted in Germany, and we know that Northern European populations tend to be more enriched for HLA-B27 genes, so what that association would be in a more diverse population is unknown.

“I think ophthalmologists are really good when they see a patient with [acute]-onset anterior uveitis; they have a suspicion that there’s probably another systemic disease that they should be looking at. What this tells us as a physician community is that maybe we should lower the threshold for getting patients into rheumatology and looking at whether or not the patient has underlying spondyloarthritis,” she said.

AbbVie supported the study with an unrestricted research grant but had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Of the study’s 12 authors, 2 reported having no financial disclosures. All others reported financial relationships with pharmaceutical companies, including AbbVie.

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

A version of this article first appeared on Medscape.com.

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

A version of this article first appeared on Medscape.com.

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

A version of this article first appeared on Medscape.com.