Commentary

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

EXPERT COMMENTARY

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

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

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

Details of the study

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

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

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

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

Study strengths and limitations

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

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

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

EXPERT COMMENTARY

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

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

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

Details of the study

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

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

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

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

Study strengths and limitations

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

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

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

EXPERT COMMENTARY

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

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

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

Details of the study

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

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

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

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

Study strengths and limitations

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

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

It was a quiet day. I got up around 3 o’clock in the afternoon for my shift at 6 p.m. I was shaking off the cobwebs and making coffee at our front window that overlooked Brown Street in North Philadelphia. I looked out the window and saw a man stumbling down the street, grabbing his abdomen and yelling for help. There was nobody else around so I went outside to see what was going on.

He was in his 50s or 60s, bleeding and obviously in distress. I had him sit down. Then I ran back inside and grabbed a dish towel and some exam gloves that I had in the house.

I ran back out and assessed him. A bullet had gone through one of his hands, but he had other wounds. I had to expose him, so I trauma stripped him on the sidewalk. I got his pants and his shirt off and saw a gunshot going through his lower pelvis. He was bleeding out from there.

I got the towel and started applying deep pressure down into the iliac vein in case they hit something, which I found out later, they had. I held it there. The man was just lying there begging not to die.

I’m someone who is very calm, maybe abnormally calm, as people tell me. I try to use that during my resuscitations and traumas. Just keeping everybody calm makes the situation easier. Afterwards, people asked me, “Weren’t you worried that you were going to get shot?” That does happen in North Philadelphia. But it didn’t even cross my mind.

I didn’t have to think at all about what I was doing. We saw so many gunshots, especially at Einstein Medical Center. We saw them daily. I’d sometimes get more than half a dozen gunshots in one shift.

So, I was holding pressure and some people started to come over. I got somebody to call 911 and asked the man about his medical history. I found out he had diabetes. Five or 10 minutes later, EMS showed up. They looked pretty stunned when I was able to give the handoff presentation to them. I told them what happened and his back-story. I wanted to make sure they would check his sugar and take extra precautions.

They got him on the stretcher, and he eventually made it to the hospital where he had surgery. They had to have a vascular surgeon work on him. I called later, and they told me, “Yeah, he’s alive.” But that’s about the extent of the update I got.

After the ambulance left, it was kind of chaos. All the neighbors poured out of their houses. People were panicked, talking and getting excited about it. I didn’t know, but everyone else had actually been home the whole time. They didn’t come out until then.

I went back inside and tried to get ready for work. I wasn’t planning on talking to the media, but my next door neighbor just walked the news camera crew over to my house and knocked on my door. I wasn’t exactly dressed to be on TV, but they talked to me on camera, and it was on the news later that night.

I went to work and didn’t say anything about it. To be honest, I was trying to avoid telling anyone. Our team had a close-knit bond, and we would often tease each other when we received any type of recognition.

Naturally one of my attendings saw it on the local news and told everybody. So, I got a lot of happy harassment for quite some time. Someone baked me a cake that said, “Hero of Fairmount” (the Philly neighborhood in which I live). Someone else printed out a photo of me that said, “Stop the Bleed Hero of Fairmount,” and put it on every single computer screen.

The man came to see me about 2 weeks later (a neighbor told him where I lived). The man was very tearful and gave me a big hug. We just embraced for a while, and he said how thankful he was. He brought me a bottle of wine, which I thought was really nice.

He told me what happened to him: There was a lot of construction on our street and he was the contractor overseeing a couple of home remodels and demolitions. Sometimes he paid workers in cash and carried it with him. Somebody had tipped off somebody else that he was going to be there that day. The contractor walked into one of the houses and a guy in a ski mask waited there with a gun. The guy shot him and took the cash. The bullet went through his hand into his pelvis.

I had never had to deal with something that intense before outside of work. Most of it really comes down to the basics – the ABCs and bleeding control. You do whatever you can with what you have. In this case, it was just a dish towel, gloves, and my hands to put as much pressure as possible.

It really was strange that I happened to be looking out the window at that moment. I don’t know if it was just a coincidence. The man told me he believed God had put somebody there at the right place at the right time to save his life. I just felt very fortunate to have been able to help him. I never saw him again.

I think something like this gives you a little confidence that you can actually do something and make a meaningful impact anywhere when it’s needed. It lets you know that you’re capable of doing it. You always think about it, but you don’t know until it happens.

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

It was a quiet day. I got up around 3 o’clock in the afternoon for my shift at 6 p.m. I was shaking off the cobwebs and making coffee at our front window that overlooked Brown Street in North Philadelphia. I looked out the window and saw a man stumbling down the street, grabbing his abdomen and yelling for help. There was nobody else around so I went outside to see what was going on.

He was in his 50s or 60s, bleeding and obviously in distress. I had him sit down. Then I ran back inside and grabbed a dish towel and some exam gloves that I had in the house.

I ran back out and assessed him. A bullet had gone through one of his hands, but he had other wounds. I had to expose him, so I trauma stripped him on the sidewalk. I got his pants and his shirt off and saw a gunshot going through his lower pelvis. He was bleeding out from there.

I got the towel and started applying deep pressure down into the iliac vein in case they hit something, which I found out later, they had. I held it there. The man was just lying there begging not to die.

I’m someone who is very calm, maybe abnormally calm, as people tell me. I try to use that during my resuscitations and traumas. Just keeping everybody calm makes the situation easier. Afterwards, people asked me, “Weren’t you worried that you were going to get shot?” That does happen in North Philadelphia. But it didn’t even cross my mind.

I didn’t have to think at all about what I was doing. We saw so many gunshots, especially at Einstein Medical Center. We saw them daily. I’d sometimes get more than half a dozen gunshots in one shift.

So, I was holding pressure and some people started to come over. I got somebody to call 911 and asked the man about his medical history. I found out he had diabetes. Five or 10 minutes later, EMS showed up. They looked pretty stunned when I was able to give the handoff presentation to them. I told them what happened and his back-story. I wanted to make sure they would check his sugar and take extra precautions.

They got him on the stretcher, and he eventually made it to the hospital where he had surgery. They had to have a vascular surgeon work on him. I called later, and they told me, “Yeah, he’s alive.” But that’s about the extent of the update I got.

After the ambulance left, it was kind of chaos. All the neighbors poured out of their houses. People were panicked, talking and getting excited about it. I didn’t know, but everyone else had actually been home the whole time. They didn’t come out until then.

I went back inside and tried to get ready for work. I wasn’t planning on talking to the media, but my next door neighbor just walked the news camera crew over to my house and knocked on my door. I wasn’t exactly dressed to be on TV, but they talked to me on camera, and it was on the news later that night.

I went to work and didn’t say anything about it. To be honest, I was trying to avoid telling anyone. Our team had a close-knit bond, and we would often tease each other when we received any type of recognition.

Naturally one of my attendings saw it on the local news and told everybody. So, I got a lot of happy harassment for quite some time. Someone baked me a cake that said, “Hero of Fairmount” (the Philly neighborhood in which I live). Someone else printed out a photo of me that said, “Stop the Bleed Hero of Fairmount,” and put it on every single computer screen.

The man came to see me about 2 weeks later (a neighbor told him where I lived). The man was very tearful and gave me a big hug. We just embraced for a while, and he said how thankful he was. He brought me a bottle of wine, which I thought was really nice.

He told me what happened to him: There was a lot of construction on our street and he was the contractor overseeing a couple of home remodels and demolitions. Sometimes he paid workers in cash and carried it with him. Somebody had tipped off somebody else that he was going to be there that day. The contractor walked into one of the houses and a guy in a ski mask waited there with a gun. The guy shot him and took the cash. The bullet went through his hand into his pelvis.

I had never had to deal with something that intense before outside of work. Most of it really comes down to the basics – the ABCs and bleeding control. You do whatever you can with what you have. In this case, it was just a dish towel, gloves, and my hands to put as much pressure as possible.

It really was strange that I happened to be looking out the window at that moment. I don’t know if it was just a coincidence. The man told me he believed God had put somebody there at the right place at the right time to save his life. I just felt very fortunate to have been able to help him. I never saw him again.

I think something like this gives you a little confidence that you can actually do something and make a meaningful impact anywhere when it’s needed. It lets you know that you’re capable of doing it. You always think about it, but you don’t know until it happens.

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

It was a quiet day. I got up around 3 o’clock in the afternoon for my shift at 6 p.m. I was shaking off the cobwebs and making coffee at our front window that overlooked Brown Street in North Philadelphia. I looked out the window and saw a man stumbling down the street, grabbing his abdomen and yelling for help. There was nobody else around so I went outside to see what was going on.

He was in his 50s or 60s, bleeding and obviously in distress. I had him sit down. Then I ran back inside and grabbed a dish towel and some exam gloves that I had in the house.

I ran back out and assessed him. A bullet had gone through one of his hands, but he had other wounds. I had to expose him, so I trauma stripped him on the sidewalk. I got his pants and his shirt off and saw a gunshot going through his lower pelvis. He was bleeding out from there.

I got the towel and started applying deep pressure down into the iliac vein in case they hit something, which I found out later, they had. I held it there. The man was just lying there begging not to die.

I’m someone who is very calm, maybe abnormally calm, as people tell me. I try to use that during my resuscitations and traumas. Just keeping everybody calm makes the situation easier. Afterwards, people asked me, “Weren’t you worried that you were going to get shot?” That does happen in North Philadelphia. But it didn’t even cross my mind.

I didn’t have to think at all about what I was doing. We saw so many gunshots, especially at Einstein Medical Center. We saw them daily. I’d sometimes get more than half a dozen gunshots in one shift.

So, I was holding pressure and some people started to come over. I got somebody to call 911 and asked the man about his medical history. I found out he had diabetes. Five or 10 minutes later, EMS showed up. They looked pretty stunned when I was able to give the handoff presentation to them. I told them what happened and his back-story. I wanted to make sure they would check his sugar and take extra precautions.

They got him on the stretcher, and he eventually made it to the hospital where he had surgery. They had to have a vascular surgeon work on him. I called later, and they told me, “Yeah, he’s alive.” But that’s about the extent of the update I got.

After the ambulance left, it was kind of chaos. All the neighbors poured out of their houses. People were panicked, talking and getting excited about it. I didn’t know, but everyone else had actually been home the whole time. They didn’t come out until then.

I went back inside and tried to get ready for work. I wasn’t planning on talking to the media, but my next door neighbor just walked the news camera crew over to my house and knocked on my door. I wasn’t exactly dressed to be on TV, but they talked to me on camera, and it was on the news later that night.

I went to work and didn’t say anything about it. To be honest, I was trying to avoid telling anyone. Our team had a close-knit bond, and we would often tease each other when we received any type of recognition.

Naturally one of my attendings saw it on the local news and told everybody. So, I got a lot of happy harassment for quite some time. Someone baked me a cake that said, “Hero of Fairmount” (the Philly neighborhood in which I live). Someone else printed out a photo of me that said, “Stop the Bleed Hero of Fairmount,” and put it on every single computer screen.

The man came to see me about 2 weeks later (a neighbor told him where I lived). The man was very tearful and gave me a big hug. We just embraced for a while, and he said how thankful he was. He brought me a bottle of wine, which I thought was really nice.

He told me what happened to him: There was a lot of construction on our street and he was the contractor overseeing a couple of home remodels and demolitions. Sometimes he paid workers in cash and carried it with him. Somebody had tipped off somebody else that he was going to be there that day. The contractor walked into one of the houses and a guy in a ski mask waited there with a gun. The guy shot him and took the cash. The bullet went through his hand into his pelvis.

I had never had to deal with something that intense before outside of work. Most of it really comes down to the basics – the ABCs and bleeding control. You do whatever you can with what you have. In this case, it was just a dish towel, gloves, and my hands to put as much pressure as possible.

It really was strange that I happened to be looking out the window at that moment. I don’t know if it was just a coincidence. The man told me he believed God had put somebody there at the right place at the right time to save his life. I just felt very fortunate to have been able to help him. I never saw him again.

I think something like this gives you a little confidence that you can actually do something and make a meaningful impact anywhere when it’s needed. It lets you know that you’re capable of doing it. You always think about it, but you don’t know until it happens.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The past few years have seen major transformations in the way health care websites operate and interact with patients. To stay competitive, it is important to ensure that your website is adapting to this changing environment, and that it continues adapting as future changes further impact its performance and ranking.

In mid-2018, a major Google algorithm change, known to the IT community as the “Medic Update,” significantly changed search criteria for most health and wellness websites. Another big update went live in late 2021. Websites that have not evolved with these changes have dropped in search rankings and provide a poorer user experience all around.

Many potential patients are searching for your services online, so your website cannot be an afterthought. Not only does it need to be designed with your target audience in mind, but it is also important to consider the metrics Google and other search engines now use when assessing the quality of your website so that patients will find it in the first place.

Here are some features that you (or your website company) need to prioritize to keep your site current and atop search results in 2023 and beyond.

Begin with an understandable URL. Search engines use URLs to determine how well your site, or a portion of it, matches search criteria. URLs also need to make sense to searchers, especially when they link specific areas of expertise (more on that in a minute). For example, a URL like “jonesdermatology.com/?p=89021” is meaningless to anyone except programmers; but “jonesdermatology.com/psoriasistreatments” obviously leads to a page about psoriasis treatments. Search engines look for not only the most relevant, but also the most helpful and user-friendly answers to a user’s query.

Incidentally, if the URL for your site is not your own name, you should register your name as a separate domain name – even if you never use it – to be sure that a trickster or troll, or someone with the same name but a bad reputation, doesn’t get it.

Continue with a good meta description. That’s the grayish text that follows the title and URL in search results. Searchers will read it to confirm that your site is what they seek, so make sure it describes exactly what you do, including any areas of special expertise.

Make your practice approachable with photos. New patients are more comfortable when they know what you look like, so real photos of you and your staff are always more effective than stock photos of models. Photos or a video tour of your office will reassure prospective patients that they will be visiting a clean, modern, professional facility.

Describe your principal services in detail. You never know which specific service a prospective patient is searching for, so describe everything you offer. Don’t try to summarize everything on a single page; relevance is determined by how deeply a topic is covered, so each principal service should have a detailed description on its own page. Not only will your skills become more visible to search engines, but you can also use the space to enumerate your qualifications and expertise in each area. Whenever possible, write your descriptions in question-and-answer form. Searchers tend to ask questions (“what is the best ... ?”), particularly in voice searches. Search engines increasingly value sites that ask and answer common questions.

Make your site interactive. “Interactivity” is a major buzzword in modern search engine parlance. Once searchers make an appointment, they stop searching. If they have to wait until the next day to call your office, they may keep looking – and might find a competitor with online scheduling. HIPAA-compliant chatbots, secure messaging, and online patient portals to access medical records, lab results, and other important information will also set your site apart.

Testimonials are essential. Amazon.com taught us that candid reviews from customers go a long way toward building the trust necessary to buy products and services, and nowhere is that truer than for medical services. According to one study, when it comes to finding a doctor, 88% of people trust online reviews as much as a personal recommendation. Loyal patients will be happy to write you glowing reviews; feature them prominently.

How does your site look on small screens? More than half of all searches are now made on smartphones, so the more mobile-friendly your site is, the higher it will be ranked. Prospective patients who are forced to scroll forever, or zoom in to tap a link, are likely to become frustrated and move on. Mobile searchers prefer sites that provide the best experience for the least amount of effort, and rankings tend to reflect that preference. You can test how easily a visitor can use your website on a mobile device with Google’s free Mobile-Friendly Test..

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

The past few years have seen major transformations in the way health care websites operate and interact with patients. To stay competitive, it is important to ensure that your website is adapting to this changing environment, and that it continues adapting as future changes further impact its performance and ranking.

In mid-2018, a major Google algorithm change, known to the IT community as the “Medic Update,” significantly changed search criteria for most health and wellness websites. Another big update went live in late 2021. Websites that have not evolved with these changes have dropped in search rankings and provide a poorer user experience all around.

Many potential patients are searching for your services online, so your website cannot be an afterthought. Not only does it need to be designed with your target audience in mind, but it is also important to consider the metrics Google and other search engines now use when assessing the quality of your website so that patients will find it in the first place.

Here are some features that you (or your website company) need to prioritize to keep your site current and atop search results in 2023 and beyond.

Begin with an understandable URL. Search engines use URLs to determine how well your site, or a portion of it, matches search criteria. URLs also need to make sense to searchers, especially when they link specific areas of expertise (more on that in a minute). For example, a URL like “jonesdermatology.com/?p=89021” is meaningless to anyone except programmers; but “jonesdermatology.com/psoriasistreatments” obviously leads to a page about psoriasis treatments. Search engines look for not only the most relevant, but also the most helpful and user-friendly answers to a user’s query.

Incidentally, if the URL for your site is not your own name, you should register your name as a separate domain name – even if you never use it – to be sure that a trickster or troll, or someone with the same name but a bad reputation, doesn’t get it.

Continue with a good meta description. That’s the grayish text that follows the title and URL in search results. Searchers will read it to confirm that your site is what they seek, so make sure it describes exactly what you do, including any areas of special expertise.

Make your practice approachable with photos. New patients are more comfortable when they know what you look like, so real photos of you and your staff are always more effective than stock photos of models. Photos or a video tour of your office will reassure prospective patients that they will be visiting a clean, modern, professional facility.

Describe your principal services in detail. You never know which specific service a prospective patient is searching for, so describe everything you offer. Don’t try to summarize everything on a single page; relevance is determined by how deeply a topic is covered, so each principal service should have a detailed description on its own page. Not only will your skills become more visible to search engines, but you can also use the space to enumerate your qualifications and expertise in each area. Whenever possible, write your descriptions in question-and-answer form. Searchers tend to ask questions (“what is the best ... ?”), particularly in voice searches. Search engines increasingly value sites that ask and answer common questions.

Make your site interactive. “Interactivity” is a major buzzword in modern search engine parlance. Once searchers make an appointment, they stop searching. If they have to wait until the next day to call your office, they may keep looking – and might find a competitor with online scheduling. HIPAA-compliant chatbots, secure messaging, and online patient portals to access medical records, lab results, and other important information will also set your site apart.

Testimonials are essential. Amazon.com taught us that candid reviews from customers go a long way toward building the trust necessary to buy products and services, and nowhere is that truer than for medical services. According to one study, when it comes to finding a doctor, 88% of people trust online reviews as much as a personal recommendation. Loyal patients will be happy to write you glowing reviews; feature them prominently.

How does your site look on small screens? More than half of all searches are now made on smartphones, so the more mobile-friendly your site is, the higher it will be ranked. Prospective patients who are forced to scroll forever, or zoom in to tap a link, are likely to become frustrated and move on. Mobile searchers prefer sites that provide the best experience for the least amount of effort, and rankings tend to reflect that preference. You can test how easily a visitor can use your website on a mobile device with Google’s free Mobile-Friendly Test..

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

The past few years have seen major transformations in the way health care websites operate and interact with patients. To stay competitive, it is important to ensure that your website is adapting to this changing environment, and that it continues adapting as future changes further impact its performance and ranking.

In mid-2018, a major Google algorithm change, known to the IT community as the “Medic Update,” significantly changed search criteria for most health and wellness websites. Another big update went live in late 2021. Websites that have not evolved with these changes have dropped in search rankings and provide a poorer user experience all around.

Many potential patients are searching for your services online, so your website cannot be an afterthought. Not only does it need to be designed with your target audience in mind, but it is also important to consider the metrics Google and other search engines now use when assessing the quality of your website so that patients will find it in the first place.

Here are some features that you (or your website company) need to prioritize to keep your site current and atop search results in 2023 and beyond.

Begin with an understandable URL. Search engines use URLs to determine how well your site, or a portion of it, matches search criteria. URLs also need to make sense to searchers, especially when they link specific areas of expertise (more on that in a minute). For example, a URL like “jonesdermatology.com/?p=89021” is meaningless to anyone except programmers; but “jonesdermatology.com/psoriasistreatments” obviously leads to a page about psoriasis treatments. Search engines look for not only the most relevant, but also the most helpful and user-friendly answers to a user’s query.

Incidentally, if the URL for your site is not your own name, you should register your name as a separate domain name – even if you never use it – to be sure that a trickster or troll, or someone with the same name but a bad reputation, doesn’t get it.

Continue with a good meta description. That’s the grayish text that follows the title and URL in search results. Searchers will read it to confirm that your site is what they seek, so make sure it describes exactly what you do, including any areas of special expertise.

Make your practice approachable with photos. New patients are more comfortable when they know what you look like, so real photos of you and your staff are always more effective than stock photos of models. Photos or a video tour of your office will reassure prospective patients that they will be visiting a clean, modern, professional facility.

Describe your principal services in detail. You never know which specific service a prospective patient is searching for, so describe everything you offer. Don’t try to summarize everything on a single page; relevance is determined by how deeply a topic is covered, so each principal service should have a detailed description on its own page. Not only will your skills become more visible to search engines, but you can also use the space to enumerate your qualifications and expertise in each area. Whenever possible, write your descriptions in question-and-answer form. Searchers tend to ask questions (“what is the best ... ?”), particularly in voice searches. Search engines increasingly value sites that ask and answer common questions.

Make your site interactive. “Interactivity” is a major buzzword in modern search engine parlance. Once searchers make an appointment, they stop searching. If they have to wait until the next day to call your office, they may keep looking – and might find a competitor with online scheduling. HIPAA-compliant chatbots, secure messaging, and online patient portals to access medical records, lab results, and other important information will also set your site apart.

Testimonials are essential. Amazon.com taught us that candid reviews from customers go a long way toward building the trust necessary to buy products and services, and nowhere is that truer than for medical services. According to one study, when it comes to finding a doctor, 88% of people trust online reviews as much as a personal recommendation. Loyal patients will be happy to write you glowing reviews; feature them prominently.

How does your site look on small screens? More than half of all searches are now made on smartphones, so the more mobile-friendly your site is, the higher it will be ranked. Prospective patients who are forced to scroll forever, or zoom in to tap a link, are likely to become frustrated and move on. Mobile searchers prefer sites that provide the best experience for the least amount of effort, and rankings tend to reflect that preference. You can test how easily a visitor can use your website on a mobile device with Google’s free Mobile-Friendly Test..

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

In this patient, bacterial and viral cultures were taken and varicella zoster virus (VZV) was isolated. Additionally, Orthopox DNA by PCR and Monkeypox (mpox) virus DNA by PCR were detected. Herpes simplex virus and bacterial viral cultures were negative. Valacyclovir was started at the time of presentation and the patient’s lesions resolved without sequelae.

Mpox is a zoonotic double-stranded DNA virus that is part of the Orthopoxvirus family, including the West African and Central African variants. This disease presents similarly to smallpox, so most mpox research was conducted around the time smallpox was eradicated. It was not until 1970, when the disease was isolated from a patient with suspected smallpox in the Democratic Republic of the Congo (DRC), that human mpox was considered a distinct disease. An epidemic outbreak in the United States occurred in 2003 related to infected prairie dogs, and travel-related outbreaks have been more recently reported up until May 2022, in which mpox was reported in nonendemic areas including North America, Europe, and Australia. Most cases in this outbreak occurred in men who have sex with men (MSM), but this is not always the case, and mpox is not necessarily considered a sexually transmitted infection. Mpox presents similarly to smallpox and VZV, so using laboratory tests is important in diagnosing and tracking this disease.

Although it is not easily transmitted, the disease can spread through bodily secretions both directly and indirectly. Mpox typically begins with a prodrome that includes fever, headache, myalgia, and fatigue. This is followed by lymphadenopathy that precedes and coincides with rash development. The lymph nodes are firm, tender, may be painful, and are a defining factor in presentation that differs from smallpox and varicella. The rash typically starts on the face, then presents on the body in a centrifugal distribution. However, cases related to sexual transmission present with anogenital lesions. The lesions are characterized by a progression from maculopapular to vesiculopustular, and can vary widely in quantity.

Notably, individuals are contagious from the onset of the prodrome until the lesions have scabbed over and fallen off. The eruptive nature of the later lesions poses a threat of secondary infection, and is often accompanied by a second febrile period that signifies deterioration of the patient’s condition. Other signs of secondary infection are variable and include pulmonary symptoms, vomiting, diarrhea, ocular infections, and in rare cases, encephalitis. These sequelae are more common in unvaccinated and immunocompromised individuals. Long-term complications of mpox include pitted scarring from cutaneous lesions with children being more susceptible to severe disease. The mortality rate for the disease is very low. (As of May 10, 2023, there have been 30,395 mpox cases reported in the United States, and 42 deaths, according to the Centers for Disease Control and Prevention.)

There are a variety of diagnostic tests that can aid in mpox identification, but they are most strongly supported when combined with clinical and epidemiological data. The best, least invasive method includes collection of lesion exudate or crust on a swab, and viral DNA is best preserved by keeping the specimen in a cool, dry, and dark environment. PCR is considered the standard, and electron microscopy and immunohistochemistry are valid tests, but all modalities require sophisticated technicians with the proper laboratory equipment. This is limiting because many cases present in underserved areas that lack the facilities for proper, real-time analysis. Antigen and antibody-based tests can be used, but cross-reactivity of other orthopoxviridae limits confirmation of mpox infection. Vaccination status, history and location must be considered.

Vaccination is the chief form of prevention for mpox, although it is not considered entirely protective. Smallpox vaccination provides protection, but widespread administration of the vaccine is no longer practiced, and an estimated 70% of the global population is no longer vaccinated. Vaccination is recommended for anyone at risk of exposure, but as this is a live, attenuated vaccine, the immune status of the patient is important to keep in mind. Tecovirimat and other antiviral medications including cidofovir and brincidofovir may be considered in severe cases.

This case is unique as our patient, who had no known risk factors for mpox, presented with mpox and VZV, simultaneously. Although clinical presentation and epidemiological patterns between these diseases differ, there have been a limited number of cases of coinfection reported in the literature, mainly in the DRC where mpox is endemic. Diagnosis must be made by separate laboratory tests and there are differences in presentation between independent and coinfection for these viruses. Notably, patients with mpox/VZV coinfection may be less likely to present with lesions on the face, thorax, arms, palms, and soles than those with only mpox but experience a higher lesion burden than those afflicted by only VZV. Coinfection may be related to reactivation of dormant VZV, or increased susceptibility to secondary infection when infected with one virus.

This case and photo were submitted by Lucas Shapiro, BS, of the Dr. Kiran C. Patel College of Osteopathic Medicine at Nova Southeastern University, Fort Lauderdale, Fla., and Donna Bilu Martin, MD.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Macneil A et al. Clin Infect Dis. 2009 Jan 1;48(1):e6-8.

2. Di Gennaro F et al. Microorganisms. 2022 Aug 12;10(8):1633.

3. Hughes CM et al. Am J Trop Med Hyg. 2020 Dec 7;104(2):604-11.

In this patient, bacterial and viral cultures were taken and varicella zoster virus (VZV) was isolated. Additionally, Orthopox DNA by PCR and Monkeypox (mpox) virus DNA by PCR were detected. Herpes simplex virus and bacterial viral cultures were negative. Valacyclovir was started at the time of presentation and the patient’s lesions resolved without sequelae.

Mpox is a zoonotic double-stranded DNA virus that is part of the Orthopoxvirus family, including the West African and Central African variants. This disease presents similarly to smallpox, so most mpox research was conducted around the time smallpox was eradicated. It was not until 1970, when the disease was isolated from a patient with suspected smallpox in the Democratic Republic of the Congo (DRC), that human mpox was considered a distinct disease. An epidemic outbreak in the United States occurred in 2003 related to infected prairie dogs, and travel-related outbreaks have been more recently reported up until May 2022, in which mpox was reported in nonendemic areas including North America, Europe, and Australia. Most cases in this outbreak occurred in men who have sex with men (MSM), but this is not always the case, and mpox is not necessarily considered a sexually transmitted infection. Mpox presents similarly to smallpox and VZV, so using laboratory tests is important in diagnosing and tracking this disease.

Although it is not easily transmitted, the disease can spread through bodily secretions both directly and indirectly. Mpox typically begins with a prodrome that includes fever, headache, myalgia, and fatigue. This is followed by lymphadenopathy that precedes and coincides with rash development. The lymph nodes are firm, tender, may be painful, and are a defining factor in presentation that differs from smallpox and varicella. The rash typically starts on the face, then presents on the body in a centrifugal distribution. However, cases related to sexual transmission present with anogenital lesions. The lesions are characterized by a progression from maculopapular to vesiculopustular, and can vary widely in quantity.

Notably, individuals are contagious from the onset of the prodrome until the lesions have scabbed over and fallen off. The eruptive nature of the later lesions poses a threat of secondary infection, and is often accompanied by a second febrile period that signifies deterioration of the patient’s condition. Other signs of secondary infection are variable and include pulmonary symptoms, vomiting, diarrhea, ocular infections, and in rare cases, encephalitis. These sequelae are more common in unvaccinated and immunocompromised individuals. Long-term complications of mpox include pitted scarring from cutaneous lesions with children being more susceptible to severe disease. The mortality rate for the disease is very low. (As of May 10, 2023, there have been 30,395 mpox cases reported in the United States, and 42 deaths, according to the Centers for Disease Control and Prevention.)

There are a variety of diagnostic tests that can aid in mpox identification, but they are most strongly supported when combined with clinical and epidemiological data. The best, least invasive method includes collection of lesion exudate or crust on a swab, and viral DNA is best preserved by keeping the specimen in a cool, dry, and dark environment. PCR is considered the standard, and electron microscopy and immunohistochemistry are valid tests, but all modalities require sophisticated technicians with the proper laboratory equipment. This is limiting because many cases present in underserved areas that lack the facilities for proper, real-time analysis. Antigen and antibody-based tests can be used, but cross-reactivity of other orthopoxviridae limits confirmation of mpox infection. Vaccination status, history and location must be considered.

Vaccination is the chief form of prevention for mpox, although it is not considered entirely protective. Smallpox vaccination provides protection, but widespread administration of the vaccine is no longer practiced, and an estimated 70% of the global population is no longer vaccinated. Vaccination is recommended for anyone at risk of exposure, but as this is a live, attenuated vaccine, the immune status of the patient is important to keep in mind. Tecovirimat and other antiviral medications including cidofovir and brincidofovir may be considered in severe cases.

This case is unique as our patient, who had no known risk factors for mpox, presented with mpox and VZV, simultaneously. Although clinical presentation and epidemiological patterns between these diseases differ, there have been a limited number of cases of coinfection reported in the literature, mainly in the DRC where mpox is endemic. Diagnosis must be made by separate laboratory tests and there are differences in presentation between independent and coinfection for these viruses. Notably, patients with mpox/VZV coinfection may be less likely to present with lesions on the face, thorax, arms, palms, and soles than those with only mpox but experience a higher lesion burden than those afflicted by only VZV. Coinfection may be related to reactivation of dormant VZV, or increased susceptibility to secondary infection when infected with one virus.

This case and photo were submitted by Lucas Shapiro, BS, of the Dr. Kiran C. Patel College of Osteopathic Medicine at Nova Southeastern University, Fort Lauderdale, Fla., and Donna Bilu Martin, MD.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Macneil A et al. Clin Infect Dis. 2009 Jan 1;48(1):e6-8.

2. Di Gennaro F et al. Microorganisms. 2022 Aug 12;10(8):1633.

3. Hughes CM et al. Am J Trop Med Hyg. 2020 Dec 7;104(2):604-11.

In this patient, bacterial and viral cultures were taken and varicella zoster virus (VZV) was isolated. Additionally, Orthopox DNA by PCR and Monkeypox (mpox) virus DNA by PCR were detected. Herpes simplex virus and bacterial viral cultures were negative. Valacyclovir was started at the time of presentation and the patient’s lesions resolved without sequelae.

Mpox is a zoonotic double-stranded DNA virus that is part of the Orthopoxvirus family, including the West African and Central African variants. This disease presents similarly to smallpox, so most mpox research was conducted around the time smallpox was eradicated. It was not until 1970, when the disease was isolated from a patient with suspected smallpox in the Democratic Republic of the Congo (DRC), that human mpox was considered a distinct disease. An epidemic outbreak in the United States occurred in 2003 related to infected prairie dogs, and travel-related outbreaks have been more recently reported up until May 2022, in which mpox was reported in nonendemic areas including North America, Europe, and Australia. Most cases in this outbreak occurred in men who have sex with men (MSM), but this is not always the case, and mpox is not necessarily considered a sexually transmitted infection. Mpox presents similarly to smallpox and VZV, so using laboratory tests is important in diagnosing and tracking this disease.

Although it is not easily transmitted, the disease can spread through bodily secretions both directly and indirectly. Mpox typically begins with a prodrome that includes fever, headache, myalgia, and fatigue. This is followed by lymphadenopathy that precedes and coincides with rash development. The lymph nodes are firm, tender, may be painful, and are a defining factor in presentation that differs from smallpox and varicella. The rash typically starts on the face, then presents on the body in a centrifugal distribution. However, cases related to sexual transmission present with anogenital lesions. The lesions are characterized by a progression from maculopapular to vesiculopustular, and can vary widely in quantity.

Notably, individuals are contagious from the onset of the prodrome until the lesions have scabbed over and fallen off. The eruptive nature of the later lesions poses a threat of secondary infection, and is often accompanied by a second febrile period that signifies deterioration of the patient’s condition. Other signs of secondary infection are variable and include pulmonary symptoms, vomiting, diarrhea, ocular infections, and in rare cases, encephalitis. These sequelae are more common in unvaccinated and immunocompromised individuals. Long-term complications of mpox include pitted scarring from cutaneous lesions with children being more susceptible to severe disease. The mortality rate for the disease is very low. (As of May 10, 2023, there have been 30,395 mpox cases reported in the United States, and 42 deaths, according to the Centers for Disease Control and Prevention.)

There are a variety of diagnostic tests that can aid in mpox identification, but they are most strongly supported when combined with clinical and epidemiological data. The best, least invasive method includes collection of lesion exudate or crust on a swab, and viral DNA is best preserved by keeping the specimen in a cool, dry, and dark environment. PCR is considered the standard, and electron microscopy and immunohistochemistry are valid tests, but all modalities require sophisticated technicians with the proper laboratory equipment. This is limiting because many cases present in underserved areas that lack the facilities for proper, real-time analysis. Antigen and antibody-based tests can be used, but cross-reactivity of other orthopoxviridae limits confirmation of mpox infection. Vaccination status, history and location must be considered.

Vaccination is the chief form of prevention for mpox, although it is not considered entirely protective. Smallpox vaccination provides protection, but widespread administration of the vaccine is no longer practiced, and an estimated 70% of the global population is no longer vaccinated. Vaccination is recommended for anyone at risk of exposure, but as this is a live, attenuated vaccine, the immune status of the patient is important to keep in mind. Tecovirimat and other antiviral medications including cidofovir and brincidofovir may be considered in severe cases.

This case is unique as our patient, who had no known risk factors for mpox, presented with mpox and VZV, simultaneously. Although clinical presentation and epidemiological patterns between these diseases differ, there have been a limited number of cases of coinfection reported in the literature, mainly in the DRC where mpox is endemic. Diagnosis must be made by separate laboratory tests and there are differences in presentation between independent and coinfection for these viruses. Notably, patients with mpox/VZV coinfection may be less likely to present with lesions on the face, thorax, arms, palms, and soles than those with only mpox but experience a higher lesion burden than those afflicted by only VZV. Coinfection may be related to reactivation of dormant VZV, or increased susceptibility to secondary infection when infected with one virus.

This case and photo were submitted by Lucas Shapiro, BS, of the Dr. Kiran C. Patel College of Osteopathic Medicine at Nova Southeastern University, Fort Lauderdale, Fla., and Donna Bilu Martin, MD.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Macneil A et al. Clin Infect Dis. 2009 Jan 1;48(1):e6-8.

2. Di Gennaro F et al. Microorganisms. 2022 Aug 12;10(8):1633.

3. Hughes CM et al. Am J Trop Med Hyg. 2020 Dec 7;104(2):604-11.

If you’re looking for it, you’ll find fatigue almost everywhere. It’s so common that it hides in plain sight, never dealt with because it’s present for good reason: the inevitable consequence of age, whatever disease you’re treating, poor lifestyle choices, and the daily grind of twenty-first–century life. Its impact is so ubiquitous and pernicious that it’s considered acceptable.

Is it though? After all, fatigue can be debilitating. Not every symptom is worthy of a chronic syndrome bearing its name. Furthermore, what if its relationship to the disease you’re treating is bidirectional? What if we actually paid attention, asked about it, and expended energy trying to relieve it? Could we improve quality of life and other outcomes too?

Outside of sleep medicine, I see little focus on fatigue among pulmonologists. This despite the existing data on fatigue related to sarcoidosis, chronic obstructive pulmonary disease (COPD), and interstitial lung disease. Even when we do pay it lip service, “addressing” fatigue or sleep is essentially a euphemism for ordering a sleep study.

As with fatigue, if you look for obstructive sleep apnea, it’ll be there, although with OSA, it’s related to the incredibly low, nonevidence-based threshold the American Academy of Sleep Medicine has established for making the diagnosis. With continuous positive airway pressure (CPAP) in hand, the patient has a new disease to worry about and a difficult behavioral change (wearing, cleaning, and resupplying their CPAP equipment) to make. Too often, the CPAP isn’t used – or is – and the fatigue persists. But it’s okay, because we followed somebody’s guideline.

The American Thoracic Society just published a research statement on cancer-related fatigue. It is comprehensive and highlights the high prevalence and poor recognition of cancer-related fatigue. The authors note that among cancers, those of the lung are associated with a higher comorbid disease burden, older age, and cigarette smoking. All these factors make patients with lung cancer particularly prone to fatigue. Interactions between these factors, lung cancer histology, and specific chemotherapy regimens are poorly understood. True to its title, the “research statement” serves more as a call to action than an evidence-based blueprint for diagnosis and management.

The cancer-related fatigue data that does exist suggests treatment starts with recognition followed by a focus on sleep, exercise, and nutrition. This should surprise no one. The data on fatigue in general (not specific to cancer-related fatigue) shows that although fatigue is not synonymous with poor quality or insufficient sleep, sleep is usually a major factor. The cancer-related conditions affecting sleep include anxiety, depression, insufficient sleep, insomnia, medication side effects, and OSA. The intersecting web is complex, but across underlying conditions (cancer or otherwise), the quickest most efficient method for mitigating fatigue is optimizing sleep.

Exercise and nutrition are also important. Again, across disease processes (interstitial lung disease, COPD, lung cancer, and so on), no drug comes close to aerobic exercise for reducing symptoms, including fatigue. If an exercise prescription could be delivered in pill-form, it’d be a blockbuster. But it can’t be, and the ATS lung cancer–related fatigue research statement nicely outlines the evidence for increased activity levels and the barriers to obtaining support and compliance. As is the case with exercise, support for improving nutrition is limited by cost, access, and patient education.

Perhaps most importantly, sleep, exercise, and nutrition require time for counseling and a behavior change for the physician and patient. Both are in short supply, and commitment is always ephemeral. Incentivization could perhaps be re-structured, but the ATS document notes this will be challenging. With respect to pulmonary rehabilitation (about 50% of patients with lung cancer have comorbid COPD), for example, reimbursement is poor, which serves as a disincentive. Their suggestions? Early integration and repeated introduction to rehabilitation and exercise concepts. Sounds great.

In summary, in my opinion, fatigue doesn’t receive the attention level commensurate with its impact. It’s easy to understand why, but I’m glad the ATS is highlighting the problem. Unbeknownst to me, multiple cancer guidelines already recommend screening for fatigue. The recent sarcoidosis treatment guideline published by the European Respiratory Society dedicated a PICO (Patients, Intervention, Comparison, Outcomes) to the topic and recommended exercise (pulmonary rehabilitation). That said, consensus statements on COPD mention it only in passing in relation to severe disease and end-of-life care, and idiopathic pulmonary fibrosis guidelines ignore it entirely. So, recognition is improving, but we’ve got ways to go.

Dr. Holley is professor of medicine at Uniformed Services University, Bethesda, Md., and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington. He disclosed ties with Metapharm, CHEST College, and WebMD.

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

If you’re looking for it, you’ll find fatigue almost everywhere. It’s so common that it hides in plain sight, never dealt with because it’s present for good reason: the inevitable consequence of age, whatever disease you’re treating, poor lifestyle choices, and the daily grind of twenty-first–century life. Its impact is so ubiquitous and pernicious that it’s considered acceptable.

Is it though? After all, fatigue can be debilitating. Not every symptom is worthy of a chronic syndrome bearing its name. Furthermore, what if its relationship to the disease you’re treating is bidirectional? What if we actually paid attention, asked about it, and expended energy trying to relieve it? Could we improve quality of life and other outcomes too?

Outside of sleep medicine, I see little focus on fatigue among pulmonologists. This despite the existing data on fatigue related to sarcoidosis, chronic obstructive pulmonary disease (COPD), and interstitial lung disease. Even when we do pay it lip service, “addressing” fatigue or sleep is essentially a euphemism for ordering a sleep study.

As with fatigue, if you look for obstructive sleep apnea, it’ll be there, although with OSA, it’s related to the incredibly low, nonevidence-based threshold the American Academy of Sleep Medicine has established for making the diagnosis. With continuous positive airway pressure (CPAP) in hand, the patient has a new disease to worry about and a difficult behavioral change (wearing, cleaning, and resupplying their CPAP equipment) to make. Too often, the CPAP isn’t used – or is – and the fatigue persists. But it’s okay, because we followed somebody’s guideline.

The American Thoracic Society just published a research statement on cancer-related fatigue. It is comprehensive and highlights the high prevalence and poor recognition of cancer-related fatigue. The authors note that among cancers, those of the lung are associated with a higher comorbid disease burden, older age, and cigarette smoking. All these factors make patients with lung cancer particularly prone to fatigue. Interactions between these factors, lung cancer histology, and specific chemotherapy regimens are poorly understood. True to its title, the “research statement” serves more as a call to action than an evidence-based blueprint for diagnosis and management.

The cancer-related fatigue data that does exist suggests treatment starts with recognition followed by a focus on sleep, exercise, and nutrition. This should surprise no one. The data on fatigue in general (not specific to cancer-related fatigue) shows that although fatigue is not synonymous with poor quality or insufficient sleep, sleep is usually a major factor. The cancer-related conditions affecting sleep include anxiety, depression, insufficient sleep, insomnia, medication side effects, and OSA. The intersecting web is complex, but across underlying conditions (cancer or otherwise), the quickest most efficient method for mitigating fatigue is optimizing sleep.

Exercise and nutrition are also important. Again, across disease processes (interstitial lung disease, COPD, lung cancer, and so on), no drug comes close to aerobic exercise for reducing symptoms, including fatigue. If an exercise prescription could be delivered in pill-form, it’d be a blockbuster. But it can’t be, and the ATS lung cancer–related fatigue research statement nicely outlines the evidence for increased activity levels and the barriers to obtaining support and compliance. As is the case with exercise, support for improving nutrition is limited by cost, access, and patient education.

Perhaps most importantly, sleep, exercise, and nutrition require time for counseling and a behavior change for the physician and patient. Both are in short supply, and commitment is always ephemeral. Incentivization could perhaps be re-structured, but the ATS document notes this will be challenging. With respect to pulmonary rehabilitation (about 50% of patients with lung cancer have comorbid COPD), for example, reimbursement is poor, which serves as a disincentive. Their suggestions? Early integration and repeated introduction to rehabilitation and exercise concepts. Sounds great.

In summary, in my opinion, fatigue doesn’t receive the attention level commensurate with its impact. It’s easy to understand why, but I’m glad the ATS is highlighting the problem. Unbeknownst to me, multiple cancer guidelines already recommend screening for fatigue. The recent sarcoidosis treatment guideline published by the European Respiratory Society dedicated a PICO (Patients, Intervention, Comparison, Outcomes) to the topic and recommended exercise (pulmonary rehabilitation). That said, consensus statements on COPD mention it only in passing in relation to severe disease and end-of-life care, and idiopathic pulmonary fibrosis guidelines ignore it entirely. So, recognition is improving, but we’ve got ways to go.

Dr. Holley is professor of medicine at Uniformed Services University, Bethesda, Md., and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington. He disclosed ties with Metapharm, CHEST College, and WebMD.

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

If you’re looking for it, you’ll find fatigue almost everywhere. It’s so common that it hides in plain sight, never dealt with because it’s present for good reason: the inevitable consequence of age, whatever disease you’re treating, poor lifestyle choices, and the daily grind of twenty-first–century life. Its impact is so ubiquitous and pernicious that it’s considered acceptable.

Is it though? After all, fatigue can be debilitating. Not every symptom is worthy of a chronic syndrome bearing its name. Furthermore, what if its relationship to the disease you’re treating is bidirectional? What if we actually paid attention, asked about it, and expended energy trying to relieve it? Could we improve quality of life and other outcomes too?

Outside of sleep medicine, I see little focus on fatigue among pulmonologists. This despite the existing data on fatigue related to sarcoidosis, chronic obstructive pulmonary disease (COPD), and interstitial lung disease. Even when we do pay it lip service, “addressing” fatigue or sleep is essentially a euphemism for ordering a sleep study.

As with fatigue, if you look for obstructive sleep apnea, it’ll be there, although with OSA, it’s related to the incredibly low, nonevidence-based threshold the American Academy of Sleep Medicine has established for making the diagnosis. With continuous positive airway pressure (CPAP) in hand, the patient has a new disease to worry about and a difficult behavioral change (wearing, cleaning, and resupplying their CPAP equipment) to make. Too often, the CPAP isn’t used – or is – and the fatigue persists. But it’s okay, because we followed somebody’s guideline.

The American Thoracic Society just published a research statement on cancer-related fatigue. It is comprehensive and highlights the high prevalence and poor recognition of cancer-related fatigue. The authors note that among cancers, those of the lung are associated with a higher comorbid disease burden, older age, and cigarette smoking. All these factors make patients with lung cancer particularly prone to fatigue. Interactions between these factors, lung cancer histology, and specific chemotherapy regimens are poorly understood. True to its title, the “research statement” serves more as a call to action than an evidence-based blueprint for diagnosis and management.

The cancer-related fatigue data that does exist suggests treatment starts with recognition followed by a focus on sleep, exercise, and nutrition. This should surprise no one. The data on fatigue in general (not specific to cancer-related fatigue) shows that although fatigue is not synonymous with poor quality or insufficient sleep, sleep is usually a major factor. The cancer-related conditions affecting sleep include anxiety, depression, insufficient sleep, insomnia, medication side effects, and OSA. The intersecting web is complex, but across underlying conditions (cancer or otherwise), the quickest most efficient method for mitigating fatigue is optimizing sleep.

Exercise and nutrition are also important. Again, across disease processes (interstitial lung disease, COPD, lung cancer, and so on), no drug comes close to aerobic exercise for reducing symptoms, including fatigue. If an exercise prescription could be delivered in pill-form, it’d be a blockbuster. But it can’t be, and the ATS lung cancer–related fatigue research statement nicely outlines the evidence for increased activity levels and the barriers to obtaining support and compliance. As is the case with exercise, support for improving nutrition is limited by cost, access, and patient education.

Perhaps most importantly, sleep, exercise, and nutrition require time for counseling and a behavior change for the physician and patient. Both are in short supply, and commitment is always ephemeral. Incentivization could perhaps be re-structured, but the ATS document notes this will be challenging. With respect to pulmonary rehabilitation (about 50% of patients with lung cancer have comorbid COPD), for example, reimbursement is poor, which serves as a disincentive. Their suggestions? Early integration and repeated introduction to rehabilitation and exercise concepts. Sounds great.

In summary, in my opinion, fatigue doesn’t receive the attention level commensurate with its impact. It’s easy to understand why, but I’m glad the ATS is highlighting the problem. Unbeknownst to me, multiple cancer guidelines already recommend screening for fatigue. The recent sarcoidosis treatment guideline published by the European Respiratory Society dedicated a PICO (Patients, Intervention, Comparison, Outcomes) to the topic and recommended exercise (pulmonary rehabilitation). That said, consensus statements on COPD mention it only in passing in relation to severe disease and end-of-life care, and idiopathic pulmonary fibrosis guidelines ignore it entirely. So, recognition is improving, but we’ve got ways to go.

Dr. Holley is professor of medicine at Uniformed Services University, Bethesda, Md., and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington. He disclosed ties with Metapharm, CHEST College, and WebMD.

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

Overweight boy, infertile man?

When it comes to causes of infertility, history and science have generally focused on women. A lot of the research overlooks men, but some previous studies have suggested that male infertility contributes to about half of the cases of couple infertility. The reason for much of that male infertility, however, has been a mystery. Until now.

A group of Italian investigators looked at the declining trend in sperm counts over the past 40 years and the increase of childhood obesity. Is there a correlation? The researchers think so. Childhood obesity can be linked to multiple causes, but the researchers zeroed in on the effect that obesity has on metabolic rates and, therefore, testicular growth.

Collecting data on testicular volume, body mass index (BMI), and insulin resistance from 268 boys aged 2-18 years, the researchers discovered that those with normal weight and normal insulin levels had testicular volumes 1.5 times higher than their overweight counterparts and 1.5-2 times higher than those with hyperinsulinemia, building a case for obesity being a factor for infertility later in life.

Since low testicular volume is associated with lower sperm count and production as an adult, putting two and two together makes a compelling argument for childhood obesity being a major male infertility culprit. It also creates even more urgency for the health care industry and community decision makers to focus on childhood obesity.

It sure would be nice to be able to take one of the many risk factors for future human survival off the table. Maybe by taking something, like cake, off the table.

Fecal transplantation moves to the kitchen

Fecal microbiota transplantation is an effective way to treat Clostridioides difficile infection, but, in the end, it’s still a transplantation procedure involving a nasogastric or colorectal tube or rather large oral capsules with a demanding (30-40 capsules over 2 days) dosage. Please, Science, tell us there’s a better way.

CC BY-NC-ND 4.0, Adèle Rakotonirina et Nathalie Boulens

Science, in the form of investigators at the University of Geneva and Lausanne University Hospital in Switzerland, has spoken, and there may be a better way. Presenting fecal beads: All the bacterial goodness of donor stool without the tubal insertions or massive quantities of giant capsules.

We know you’re scoffing out there, but it’s true. All you need is a little alginate, which is a “biocompatible polysaccharide isolated from brown algae” of the Phaeophyceae family. The donor feces is microencapsulated by mixing it with the alginate, dropping that mixture into water containing calcium chloride, turning it into a gel, and then freeze-drying the gel into small (just 2 mm), solid beads.

Sounds plausible enough, but what do you do with them? “These brownish beads can be easily dispersed in a liquid or food that is pleasant to eat. They also have no taste,” senior author Eric Allémann, PhD, said in a statement released by the University of Geneva.

Pleasant to eat? No taste? So which is it? If you really want to know, watch fecal beads week on the new season of “The Great British Baking Show,” when Paul and Prue judge poop baked into crumpets, crepes, and crostatas. Yum.
 

We’re on the low-oxygen diet

Nine out of ten doctors agree: Oxygen is more important to your continued well-being than food. After all, a human can go weeks without food, but just minutes without oxygen. However, ten out of ten doctors agree that the United States has an obesity problem. They all also agree that previous research has shown soldiers who train at high altitudes lose more weight than those training at lower altitudes.

PBRC

So, on the one hand, we have a country full of overweight people, and on the other, we have low oxygen levels causing weight loss. The solution, then, is obvious: Stop breathing.

More specifically (and somewhat less facetiously), researchers from Louisiana have launched the Low Oxygen and Weight Status trial and are currently recruiting individuals with BMIs of 30-40 to, uh, suffocate themselves. No, no, it’s okay, it’s just when they’re sleeping.

Fine, straight face. Participants in the LOWS trial will undergo an 8-week period when they will consume a controlled weight-loss diet and spend their nights in a hypoxic sealed tent, where they will sleep in an environment with an oxygen level equivalent to 8,500 feet above sea level (roughly equivalent to Aspen, Colo.). They will be compared with people on the same diet who sleep in a normal, sea-level oxygen environment.

The study’s goal is to determine whether or not spending time in a low-oxygen environment will suppress appetite, increase energy expenditure, and improve weight loss and insulin sensitivity. Excessive weight loss in high-altitude environments isn’t a good thing for soldiers – they kind of need their muscles and body weight to do the whole soldiering thing – but it could be great for people struggling to lose those last few pounds. And it also may prove LOTME’s previous thesis: Air is not good.

Overweight boy, infertile man?

When it comes to causes of infertility, history and science have generally focused on women. A lot of the research overlooks men, but some previous studies have suggested that male infertility contributes to about half of the cases of couple infertility. The reason for much of that male infertility, however, has been a mystery. Until now.

A group of Italian investigators looked at the declining trend in sperm counts over the past 40 years and the increase of childhood obesity. Is there a correlation? The researchers think so. Childhood obesity can be linked to multiple causes, but the researchers zeroed in on the effect that obesity has on metabolic rates and, therefore, testicular growth.

Collecting data on testicular volume, body mass index (BMI), and insulin resistance from 268 boys aged 2-18 years, the researchers discovered that those with normal weight and normal insulin levels had testicular volumes 1.5 times higher than their overweight counterparts and 1.5-2 times higher than those with hyperinsulinemia, building a case for obesity being a factor for infertility later in life.

Since low testicular volume is associated with lower sperm count and production as an adult, putting two and two together makes a compelling argument for childhood obesity being a major male infertility culprit. It also creates even more urgency for the health care industry and community decision makers to focus on childhood obesity.

It sure would be nice to be able to take one of the many risk factors for future human survival off the table. Maybe by taking something, like cake, off the table.

Fecal transplantation moves to the kitchen

Fecal microbiota transplantation is an effective way to treat Clostridioides difficile infection, but, in the end, it’s still a transplantation procedure involving a nasogastric or colorectal tube or rather large oral capsules with a demanding (30-40 capsules over 2 days) dosage. Please, Science, tell us there’s a better way.

CC BY-NC-ND 4.0, Adèle Rakotonirina et Nathalie Boulens

Science, in the form of investigators at the University of Geneva and Lausanne University Hospital in Switzerland, has spoken, and there may be a better way. Presenting fecal beads: All the bacterial goodness of donor stool without the tubal insertions or massive quantities of giant capsules.

We know you’re scoffing out there, but it’s true. All you need is a little alginate, which is a “biocompatible polysaccharide isolated from brown algae” of the Phaeophyceae family. The donor feces is microencapsulated by mixing it with the alginate, dropping that mixture into water containing calcium chloride, turning it into a gel, and then freeze-drying the gel into small (just 2 mm), solid beads.

Sounds plausible enough, but what do you do with them? “These brownish beads can be easily dispersed in a liquid or food that is pleasant to eat. They also have no taste,” senior author Eric Allémann, PhD, said in a statement released by the University of Geneva.

Pleasant to eat? No taste? So which is it? If you really want to know, watch fecal beads week on the new season of “The Great British Baking Show,” when Paul and Prue judge poop baked into crumpets, crepes, and crostatas. Yum.
 

We’re on the low-oxygen diet

Nine out of ten doctors agree: Oxygen is more important to your continued well-being than food. After all, a human can go weeks without food, but just minutes without oxygen. However, ten out of ten doctors agree that the United States has an obesity problem. They all also agree that previous research has shown soldiers who train at high altitudes lose more weight than those training at lower altitudes.

PBRC

So, on the one hand, we have a country full of overweight people, and on the other, we have low oxygen levels causing weight loss. The solution, then, is obvious: Stop breathing.

More specifically (and somewhat less facetiously), researchers from Louisiana have launched the Low Oxygen and Weight Status trial and are currently recruiting individuals with BMIs of 30-40 to, uh, suffocate themselves. No, no, it’s okay, it’s just when they’re sleeping.

Fine, straight face. Participants in the LOWS trial will undergo an 8-week period when they will consume a controlled weight-loss diet and spend their nights in a hypoxic sealed tent, where they will sleep in an environment with an oxygen level equivalent to 8,500 feet above sea level (roughly equivalent to Aspen, Colo.). They will be compared with people on the same diet who sleep in a normal, sea-level oxygen environment.

The study’s goal is to determine whether or not spending time in a low-oxygen environment will suppress appetite, increase energy expenditure, and improve weight loss and insulin sensitivity. Excessive weight loss in high-altitude environments isn’t a good thing for soldiers – they kind of need their muscles and body weight to do the whole soldiering thing – but it could be great for people struggling to lose those last few pounds. And it also may prove LOTME’s previous thesis: Air is not good.

Overweight boy, infertile man?

When it comes to causes of infertility, history and science have generally focused on women. A lot of the research overlooks men, but some previous studies have suggested that male infertility contributes to about half of the cases of couple infertility. The reason for much of that male infertility, however, has been a mystery. Until now.

A group of Italian investigators looked at the declining trend in sperm counts over the past 40 years and the increase of childhood obesity. Is there a correlation? The researchers think so. Childhood obesity can be linked to multiple causes, but the researchers zeroed in on the effect that obesity has on metabolic rates and, therefore, testicular growth.

Collecting data on testicular volume, body mass index (BMI), and insulin resistance from 268 boys aged 2-18 years, the researchers discovered that those with normal weight and normal insulin levels had testicular volumes 1.5 times higher than their overweight counterparts and 1.5-2 times higher than those with hyperinsulinemia, building a case for obesity being a factor for infertility later in life.

Since low testicular volume is associated with lower sperm count and production as an adult, putting two and two together makes a compelling argument for childhood obesity being a major male infertility culprit. It also creates even more urgency for the health care industry and community decision makers to focus on childhood obesity.

It sure would be nice to be able to take one of the many risk factors for future human survival off the table. Maybe by taking something, like cake, off the table.

Fecal transplantation moves to the kitchen

Fecal microbiota transplantation is an effective way to treat Clostridioides difficile infection, but, in the end, it’s still a transplantation procedure involving a nasogastric or colorectal tube or rather large oral capsules with a demanding (30-40 capsules over 2 days) dosage. Please, Science, tell us there’s a better way.

CC BY-NC-ND 4.0, Adèle Rakotonirina et Nathalie Boulens

Science, in the form of investigators at the University of Geneva and Lausanne University Hospital in Switzerland, has spoken, and there may be a better way. Presenting fecal beads: All the bacterial goodness of donor stool without the tubal insertions or massive quantities of giant capsules.

We know you’re scoffing out there, but it’s true. All you need is a little alginate, which is a “biocompatible polysaccharide isolated from brown algae” of the Phaeophyceae family. The donor feces is microencapsulated by mixing it with the alginate, dropping that mixture into water containing calcium chloride, turning it into a gel, and then freeze-drying the gel into small (just 2 mm), solid beads.

Sounds plausible enough, but what do you do with them? “These brownish beads can be easily dispersed in a liquid or food that is pleasant to eat. They also have no taste,” senior author Eric Allémann, PhD, said in a statement released by the University of Geneva.

Pleasant to eat? No taste? So which is it? If you really want to know, watch fecal beads week on the new season of “The Great British Baking Show,” when Paul and Prue judge poop baked into crumpets, crepes, and crostatas. Yum.
 

We’re on the low-oxygen diet

Nine out of ten doctors agree: Oxygen is more important to your continued well-being than food. After all, a human can go weeks without food, but just minutes without oxygen. However, ten out of ten doctors agree that the United States has an obesity problem. They all also agree that previous research has shown soldiers who train at high altitudes lose more weight than those training at lower altitudes.

PBRC

So, on the one hand, we have a country full of overweight people, and on the other, we have low oxygen levels causing weight loss. The solution, then, is obvious: Stop breathing.

More specifically (and somewhat less facetiously), researchers from Louisiana have launched the Low Oxygen and Weight Status trial and are currently recruiting individuals with BMIs of 30-40 to, uh, suffocate themselves. No, no, it’s okay, it’s just when they’re sleeping.

Fine, straight face. Participants in the LOWS trial will undergo an 8-week period when they will consume a controlled weight-loss diet and spend their nights in a hypoxic sealed tent, where they will sleep in an environment with an oxygen level equivalent to 8,500 feet above sea level (roughly equivalent to Aspen, Colo.). They will be compared with people on the same diet who sleep in a normal, sea-level oxygen environment.

The study’s goal is to determine whether or not spending time in a low-oxygen environment will suppress appetite, increase energy expenditure, and improve weight loss and insulin sensitivity. Excessive weight loss in high-altitude environments isn’t a good thing for soldiers – they kind of need their muscles and body weight to do the whole soldiering thing – but it could be great for people struggling to lose those last few pounds. And it also may prove LOTME’s previous thesis: Air is not good.

The Centers for Disease Control and Prevention and the U.S. Census Bureau estimate that 6.1% of the U.S. adult population is living with long COVID, with millions more debilitated worldwide. The demand for substantial treatment is enormous, but the urgency to fund and begin the necessary range of clinical trials has not met the severity of the problem.
 

While trials are slowly beginning to happen, the treatment choices and trial design require crucial nuances and understanding of viral-onset illnesses, and few research groups are creating strong trials that fully reflect the complexities of this landscape.

This article aims to share key considerations and best practices that are essential to the success of these trials. These recommendations recognize that roughly half of long COVID patients have new-onset myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia from COVID, which must be at the forefront of how trials are designed and conducted, and are additionally based on the current hypotheses about long COVID’s pathophysiologies. 
 

1: Drugs proposed by experts in postviral fields should be prioritized

Upward of 50 drugs for viral-onset conditions like ME/CFS, dysautonomia, AIDS, and others have been waiting for years to go to trial, but have not had the funding to do so. 

Treatments proposed by experts in viral-onset illnesses (such as ME/CFS and dysautonomia) should be prioritized (PM R. 2022 Oct;14[10]:1270-91), as outside researchers are not familiar with these fields and their potential treatment options.
 

2: Drugs targeting a wide range of mechanisms should be trialed

Treatments that should be trialed include anticoagulants/antiplatelets for clotting and vascular functioning, immunomodulators including JAK-STAT inhibitors, COVID-specific antivirals and antivirals against reactivated herpesviruses (Valcyte, Valacyclovir, EBV vaccine). 

Other options include prescription mast cell stabilizers (ketotifen, cromolyn sodium), drugs that regulate microglial activation (low-dose naltrexone, low-dose aripiprazole), anti-CGRP medications, beta-blockers, and intravenous immunoglobulin.

Others include medications that target mitochondrial dysfunction; ivabradine; pyridostigmine;, DRP1 inhibitors; supplements showing success in patient communities including lactoferrin, ubiquinone, and nattokinase; and therapies targeting glymphatic/lymphatic dysfunction, microbiome therapies, and therapeutic peptides. 
 

3: Use appropriate long COVID subtypes 

Long COVID is an umbrella term that encompasses multiple new-onset and worsened conditions and symptoms after COVID. Roughly half of long COVID patients likely meet the criteria for ME/CFS and/or dysautonomia. Others may have new-onset diabetes, major clotting events, lung damage, neurological disorders, loss of smell or taste, and other manifestations. 

Patients in different categories likely have different responses to treatments. It’s critical to identify appropriate subtypes for each trial, ideally performing detailed analyses to identify the treatments that work best, and don’t, for each subtype. 
 

4: Behavioral treatments, especially those that have harmed similar populations, should not be trialed

Behavioral treatments including exercise, graded exercise therapy (GET), and cognitive-behavioral therapy (CBT) should not be trialed, let alone prioritized, for long COVID. 

In patients with postexertional malaise (PEM), one of the most common long COVID symptoms, exercise is actively harmful and causes dysfunctional metabolic patterns, cardiac preload failure, impaired systemic oxygen extraction, and more. GET and CBT have failed similar populations , and exercise is explicitly contraindicated by the World Health Organization, the British National Institute for Health and Care Excellence, the CDC, and other organizations. 

Resources should instead be put toward the wide range of medications that have not yet adequately undergone clinical trials.  
 

5: PCR and antibody tests should not be used as inclusion criteria for trial participants

Only an estimated 1%-3% of cases in the first wave of COVID were documented, and the CDC estimates that only 25% of cases through September 2021 were documented. Similarly, antibody tests are unreliable to determine past infection, as roughly a third of patients don’t seroconvert, and a similar proportion serorevert within a few months. Using polymerase chain reaction (PCR) and antibody testing to determine who should be included in clinical trials limits who is eligible to participate in research, particularly those who have been ill for longer. Additionally, the majority of those who serorevert are women, so using antibody tests for inclusion introduces a selection bias and may miss mechanisms of immune system functioning that are part of long COVID.

PCR tests also have high false-negative rates and requiring them in research excludes people with lower viral loads with long COVID, which would confound findings. 

These issues with testing also lead to COVID-infected people accidentally being included in control groups, which ruins the credibility of the research findings completely.
 

6: Include comparator groups

There are several common diagnoses that occur in people with long COVID, including ME/CFS, postural orthostatic tachycardia syndrome, small-fiber neuropathy, mast cell activation syndrome, and Ehlers-Danlos syndrome.

Identifying people with these conditions within the trial cohort improves research across all fields, benefiting all groups, and helps clarify what types of patients benefit most from certain medications. 
 

7: Identify the right endpoints; avoid the wrong ones

Even though our understanding of the pathophysiology of long COVID is still evolving, it’s still possible to do clinical trials by identifying strong endpoints and outcome measures. 

Several tools have been designed for viral-onset conditions and should be used alongside other endpoints. Postexertional malaise and autonomic symptoms, which are some of the most common symptoms of long COVID, can be measured with the validated DSQ-PEM and COMPASS-31, respectively. Tools for cognitive dysfunction trials should capture specific and common types of impairment, like processing speed. 

Endpoints should be high-impact and aim for large improvements that have clinical significance over small improvements that do not have clinical significance. 

Objective tests should be incorporated where possible; some to consider include natural killer cell functioning, cerebral blood flow, T-cell functioning, levels of reactivated herpesviruses, blood lactate levels, and microclots, as testing becomes available. 

Mental health outcomes shouldn’t be primary endpoints, except where a trial is targeting a specific mental health condition because of COVID (for example, premenstrual dysphoric disorder). 

If mental health conditions are tracked secondarily, it’s vital not to use questionnaires that include physical symptoms like fatigue, difficulty concentrating, difficulty sleeping, or palpitations, as these artificially increase depression and anxiety scores in chronically ill respondents. Tools that include physical symptoms (Patient Health Questionnaire–9, Beck Anxiety Inventory, Beck Depression Inventory) can be replaced with scales like the PHQ-2, General Anxiety Disorder–7, Hospital Anxiety and Depression Scale, or PROMIS-29 subscales.

Because certain cytokines and other inflammatory markers may naturally decrease over time without corresponding improvement in the ME/CFS subtype, caution should be taken when using cytokines as endpoints.
 

8: Consider enrollment and objectives carefully

A proportion of people with long COVID will recover in the early months after infection. Ideally, clinical trials will primarily study treatments in patients who have been ill 6 months or longer, as some natural recovery will happen before that can bias studies.

But where resources are abundant, it is ideal for trials to additionally look at whether the treatments can help patients in the early months recover and prevent progression to the later stage.
 

9: Tracking illness duration is crucial

Research from ME/CFS shows that there may be an immune change in the first few years of the illness, where cytokines decrease without any corresponding change in symptom improvement. 

Because of this and the possibility that other markers follow the same pattern, disease duration should be a core feature of all analyses and trial designs. Trial outcomes should be designed to answer the question of whether the medication helps patients at different durations of illness. 
 

10: Prioritize patient populations less likely to recover without intervention

Some long COVID phenotypes seem less likely to recover without intervention. Trials should take care to focus on these patient populations, which include those with neurologic symptoms and those meeting ME/CFS criteria.

 

11: Account for the relapsing/remitting nature

Outcome measures need to be assessed in a way that can distinguish a temporary remission, which is part of the natural course of the disease, from a permanent cure. 

Factors that can contribute to the relapsing/remitting nature include physical and cognitive postexertional malaise, menstrual cycle changes, and seasonal changes.
 

12: Trial participants should reflect the diversity of the long COVID population

Certain demographics are more likely to be affected by acute and long COVID and need to be appropriately recruited and reflected in research, including in patient engagement. 

Trials must include high numbers of Hispanic/Latinx, Black, and indigenous communities, queer and transgender populations, and women. Trial materials and design need to incorporate linguistic diversity in addition to racial/ethnic diversity.

Upward of 75% of long COVID cases happen after mild acute cases; clinical researchers should ensure that nonhospitalized patients make up the bulk of trial participants. 
 

13: Utilize meaningful engagement of patients, especially in treatment selection and study design

Meaningful patient engagement means engaging multiple patients at every step of the trial process, from treatment selection to study design to analysis to communication of the results. 

Patient experiences are extremely valuable and contain information that researchers may not be familiar with, including the nature and patterns of the illness, insights into possible treatments, and barriers to documentation and care that may also impact research. Tapping into those patient experiences will make trials stronger.

Overall, the landscape of long COVID clinical trials is ripe for discovery, and researchers choosing to go down this path will be deeply appreciated by the patient community. 

Hannah Davis is a long COVID patient-researcher and cofounder of the Patient-Led Research Collaborative, an organization studying the long-term effects of COVID.

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

The Centers for Disease Control and Prevention and the U.S. Census Bureau estimate that 6.1% of the U.S. adult population is living with long COVID, with millions more debilitated worldwide. The demand for substantial treatment is enormous, but the urgency to fund and begin the necessary range of clinical trials has not met the severity of the problem.
 

While trials are slowly beginning to happen, the treatment choices and trial design require crucial nuances and understanding of viral-onset illnesses, and few research groups are creating strong trials that fully reflect the complexities of this landscape.

This article aims to share key considerations and best practices that are essential to the success of these trials. These recommendations recognize that roughly half of long COVID patients have new-onset myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia from COVID, which must be at the forefront of how trials are designed and conducted, and are additionally based on the current hypotheses about long COVID’s pathophysiologies. 
 

1: Drugs proposed by experts in postviral fields should be prioritized

Upward of 50 drugs for viral-onset conditions like ME/CFS, dysautonomia, AIDS, and others have been waiting for years to go to trial, but have not had the funding to do so. 

Treatments proposed by experts in viral-onset illnesses (such as ME/CFS and dysautonomia) should be prioritized (PM R. 2022 Oct;14[10]:1270-91), as outside researchers are not familiar with these fields and their potential treatment options.
 

2: Drugs targeting a wide range of mechanisms should be trialed

Treatments that should be trialed include anticoagulants/antiplatelets for clotting and vascular functioning, immunomodulators including JAK-STAT inhibitors, COVID-specific antivirals and antivirals against reactivated herpesviruses (Valcyte, Valacyclovir, EBV vaccine). 

Other options include prescription mast cell stabilizers (ketotifen, cromolyn sodium), drugs that regulate microglial activation (low-dose naltrexone, low-dose aripiprazole), anti-CGRP medications, beta-blockers, and intravenous immunoglobulin.

Others include medications that target mitochondrial dysfunction; ivabradine; pyridostigmine;, DRP1 inhibitors; supplements showing success in patient communities including lactoferrin, ubiquinone, and nattokinase; and therapies targeting glymphatic/lymphatic dysfunction, microbiome therapies, and therapeutic peptides. 
 

3: Use appropriate long COVID subtypes 

Long COVID is an umbrella term that encompasses multiple new-onset and worsened conditions and symptoms after COVID. Roughly half of long COVID patients likely meet the criteria for ME/CFS and/or dysautonomia. Others may have new-onset diabetes, major clotting events, lung damage, neurological disorders, loss of smell or taste, and other manifestations. 

Patients in different categories likely have different responses to treatments. It’s critical to identify appropriate subtypes for each trial, ideally performing detailed analyses to identify the treatments that work best, and don’t, for each subtype. 
 

4: Behavioral treatments, especially those that have harmed similar populations, should not be trialed

Behavioral treatments including exercise, graded exercise therapy (GET), and cognitive-behavioral therapy (CBT) should not be trialed, let alone prioritized, for long COVID. 

In patients with postexertional malaise (PEM), one of the most common long COVID symptoms, exercise is actively harmful and causes dysfunctional metabolic patterns, cardiac preload failure, impaired systemic oxygen extraction, and more. GET and CBT have failed similar populations , and exercise is explicitly contraindicated by the World Health Organization, the British National Institute for Health and Care Excellence, the CDC, and other organizations. 

Resources should instead be put toward the wide range of medications that have not yet adequately undergone clinical trials.  
 

5: PCR and antibody tests should not be used as inclusion criteria for trial participants

Only an estimated 1%-3% of cases in the first wave of COVID were documented, and the CDC estimates that only 25% of cases through September 2021 were documented. Similarly, antibody tests are unreliable to determine past infection, as roughly a third of patients don’t seroconvert, and a similar proportion serorevert within a few months. Using polymerase chain reaction (PCR) and antibody testing to determine who should be included in clinical trials limits who is eligible to participate in research, particularly those who have been ill for longer. Additionally, the majority of those who serorevert are women, so using antibody tests for inclusion introduces a selection bias and may miss mechanisms of immune system functioning that are part of long COVID.

PCR tests also have high false-negative rates and requiring them in research excludes people with lower viral loads with long COVID, which would confound findings. 

These issues with testing also lead to COVID-infected people accidentally being included in control groups, which ruins the credibility of the research findings completely.
 

6: Include comparator groups

There are several common diagnoses that occur in people with long COVID, including ME/CFS, postural orthostatic tachycardia syndrome, small-fiber neuropathy, mast cell activation syndrome, and Ehlers-Danlos syndrome.

Identifying people with these conditions within the trial cohort improves research across all fields, benefiting all groups, and helps clarify what types of patients benefit most from certain medications. 
 

7: Identify the right endpoints; avoid the wrong ones

Even though our understanding of the pathophysiology of long COVID is still evolving, it’s still possible to do clinical trials by identifying strong endpoints and outcome measures. 

Several tools have been designed for viral-onset conditions and should be used alongside other endpoints. Postexertional malaise and autonomic symptoms, which are some of the most common symptoms of long COVID, can be measured with the validated DSQ-PEM and COMPASS-31, respectively. Tools for cognitive dysfunction trials should capture specific and common types of impairment, like processing speed. 

Endpoints should be high-impact and aim for large improvements that have clinical significance over small improvements that do not have clinical significance. 

Objective tests should be incorporated where possible; some to consider include natural killer cell functioning, cerebral blood flow, T-cell functioning, levels of reactivated herpesviruses, blood lactate levels, and microclots, as testing becomes available. 

Mental health outcomes shouldn’t be primary endpoints, except where a trial is targeting a specific mental health condition because of COVID (for example, premenstrual dysphoric disorder). 

If mental health conditions are tracked secondarily, it’s vital not to use questionnaires that include physical symptoms like fatigue, difficulty concentrating, difficulty sleeping, or palpitations, as these artificially increase depression and anxiety scores in chronically ill respondents. Tools that include physical symptoms (Patient Health Questionnaire–9, Beck Anxiety Inventory, Beck Depression Inventory) can be replaced with scales like the PHQ-2, General Anxiety Disorder–7, Hospital Anxiety and Depression Scale, or PROMIS-29 subscales.

Because certain cytokines and other inflammatory markers may naturally decrease over time without corresponding improvement in the ME/CFS subtype, caution should be taken when using cytokines as endpoints.
 

8: Consider enrollment and objectives carefully

A proportion of people with long COVID will recover in the early months after infection. Ideally, clinical trials will primarily study treatments in patients who have been ill 6 months or longer, as some natural recovery will happen before that can bias studies.

But where resources are abundant, it is ideal for trials to additionally look at whether the treatments can help patients in the early months recover and prevent progression to the later stage.
 

9: Tracking illness duration is crucial

Research from ME/CFS shows that there may be an immune change in the first few years of the illness, where cytokines decrease without any corresponding change in symptom improvement. 

Because of this and the possibility that other markers follow the same pattern, disease duration should be a core feature of all analyses and trial designs. Trial outcomes should be designed to answer the question of whether the medication helps patients at different durations of illness. 
 

10: Prioritize patient populations less likely to recover without intervention

Some long COVID phenotypes seem less likely to recover without intervention. Trials should take care to focus on these patient populations, which include those with neurologic symptoms and those meeting ME/CFS criteria.

 

11: Account for the relapsing/remitting nature

Outcome measures need to be assessed in a way that can distinguish a temporary remission, which is part of the natural course of the disease, from a permanent cure. 

Factors that can contribute to the relapsing/remitting nature include physical and cognitive postexertional malaise, menstrual cycle changes, and seasonal changes.
 

12: Trial participants should reflect the diversity of the long COVID population

Certain demographics are more likely to be affected by acute and long COVID and need to be appropriately recruited and reflected in research, including in patient engagement. 

Trials must include high numbers of Hispanic/Latinx, Black, and indigenous communities, queer and transgender populations, and women. Trial materials and design need to incorporate linguistic diversity in addition to racial/ethnic diversity.

Upward of 75% of long COVID cases happen after mild acute cases; clinical researchers should ensure that nonhospitalized patients make up the bulk of trial participants. 
 

13: Utilize meaningful engagement of patients, especially in treatment selection and study design

Meaningful patient engagement means engaging multiple patients at every step of the trial process, from treatment selection to study design to analysis to communication of the results. 

Patient experiences are extremely valuable and contain information that researchers may not be familiar with, including the nature and patterns of the illness, insights into possible treatments, and barriers to documentation and care that may also impact research. Tapping into those patient experiences will make trials stronger.

Overall, the landscape of long COVID clinical trials is ripe for discovery, and researchers choosing to go down this path will be deeply appreciated by the patient community. 

Hannah Davis is a long COVID patient-researcher and cofounder of the Patient-Led Research Collaborative, an organization studying the long-term effects of COVID.

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

The Centers for Disease Control and Prevention and the U.S. Census Bureau estimate that 6.1% of the U.S. adult population is living with long COVID, with millions more debilitated worldwide. The demand for substantial treatment is enormous, but the urgency to fund and begin the necessary range of clinical trials has not met the severity of the problem.
 

While trials are slowly beginning to happen, the treatment choices and trial design require crucial nuances and understanding of viral-onset illnesses, and few research groups are creating strong trials that fully reflect the complexities of this landscape.

This article aims to share key considerations and best practices that are essential to the success of these trials. These recommendations recognize that roughly half of long COVID patients have new-onset myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia from COVID, which must be at the forefront of how trials are designed and conducted, and are additionally based on the current hypotheses about long COVID’s pathophysiologies. 
 

1: Drugs proposed by experts in postviral fields should be prioritized

Upward of 50 drugs for viral-onset conditions like ME/CFS, dysautonomia, AIDS, and others have been waiting for years to go to trial, but have not had the funding to do so. 

Treatments proposed by experts in viral-onset illnesses (such as ME/CFS and dysautonomia) should be prioritized (PM R. 2022 Oct;14[10]:1270-91), as outside researchers are not familiar with these fields and their potential treatment options.
 

2: Drugs targeting a wide range of mechanisms should be trialed

Treatments that should be trialed include anticoagulants/antiplatelets for clotting and vascular functioning, immunomodulators including JAK-STAT inhibitors, COVID-specific antivirals and antivirals against reactivated herpesviruses (Valcyte, Valacyclovir, EBV vaccine). 

Other options include prescription mast cell stabilizers (ketotifen, cromolyn sodium), drugs that regulate microglial activation (low-dose naltrexone, low-dose aripiprazole), anti-CGRP medications, beta-blockers, and intravenous immunoglobulin.

Others include medications that target mitochondrial dysfunction; ivabradine; pyridostigmine;, DRP1 inhibitors; supplements showing success in patient communities including lactoferrin, ubiquinone, and nattokinase; and therapies targeting glymphatic/lymphatic dysfunction, microbiome therapies, and therapeutic peptides. 
 

3: Use appropriate long COVID subtypes 

Long COVID is an umbrella term that encompasses multiple new-onset and worsened conditions and symptoms after COVID. Roughly half of long COVID patients likely meet the criteria for ME/CFS and/or dysautonomia. Others may have new-onset diabetes, major clotting events, lung damage, neurological disorders, loss of smell or taste, and other manifestations. 

Patients in different categories likely have different responses to treatments. It’s critical to identify appropriate subtypes for each trial, ideally performing detailed analyses to identify the treatments that work best, and don’t, for each subtype. 
 

4: Behavioral treatments, especially those that have harmed similar populations, should not be trialed

Behavioral treatments including exercise, graded exercise therapy (GET), and cognitive-behavioral therapy (CBT) should not be trialed, let alone prioritized, for long COVID. 

In patients with postexertional malaise (PEM), one of the most common long COVID symptoms, exercise is actively harmful and causes dysfunctional metabolic patterns, cardiac preload failure, impaired systemic oxygen extraction, and more. GET and CBT have failed similar populations , and exercise is explicitly contraindicated by the World Health Organization, the British National Institute for Health and Care Excellence, the CDC, and other organizations. 

Resources should instead be put toward the wide range of medications that have not yet adequately undergone clinical trials.  
 

5: PCR and antibody tests should not be used as inclusion criteria for trial participants

Only an estimated 1%-3% of cases in the first wave of COVID were documented, and the CDC estimates that only 25% of cases through September 2021 were documented. Similarly, antibody tests are unreliable to determine past infection, as roughly a third of patients don’t seroconvert, and a similar proportion serorevert within a few months. Using polymerase chain reaction (PCR) and antibody testing to determine who should be included in clinical trials limits who is eligible to participate in research, particularly those who have been ill for longer. Additionally, the majority of those who serorevert are women, so using antibody tests for inclusion introduces a selection bias and may miss mechanisms of immune system functioning that are part of long COVID.

PCR tests also have high false-negative rates and requiring them in research excludes people with lower viral loads with long COVID, which would confound findings. 

These issues with testing also lead to COVID-infected people accidentally being included in control groups, which ruins the credibility of the research findings completely.
 

6: Include comparator groups

There are several common diagnoses that occur in people with long COVID, including ME/CFS, postural orthostatic tachycardia syndrome, small-fiber neuropathy, mast cell activation syndrome, and Ehlers-Danlos syndrome.

Identifying people with these conditions within the trial cohort improves research across all fields, benefiting all groups, and helps clarify what types of patients benefit most from certain medications. 
 

7: Identify the right endpoints; avoid the wrong ones

Even though our understanding of the pathophysiology of long COVID is still evolving, it’s still possible to do clinical trials by identifying strong endpoints and outcome measures. 

Several tools have been designed for viral-onset conditions and should be used alongside other endpoints. Postexertional malaise and autonomic symptoms, which are some of the most common symptoms of long COVID, can be measured with the validated DSQ-PEM and COMPASS-31, respectively. Tools for cognitive dysfunction trials should capture specific and common types of impairment, like processing speed. 

Endpoints should be high-impact and aim for large improvements that have clinical significance over small improvements that do not have clinical significance. 

Objective tests should be incorporated where possible; some to consider include natural killer cell functioning, cerebral blood flow, T-cell functioning, levels of reactivated herpesviruses, blood lactate levels, and microclots, as testing becomes available. 

Mental health outcomes shouldn’t be primary endpoints, except where a trial is targeting a specific mental health condition because of COVID (for example, premenstrual dysphoric disorder). 

If mental health conditions are tracked secondarily, it’s vital not to use questionnaires that include physical symptoms like fatigue, difficulty concentrating, difficulty sleeping, or palpitations, as these artificially increase depression and anxiety scores in chronically ill respondents. Tools that include physical symptoms (Patient Health Questionnaire–9, Beck Anxiety Inventory, Beck Depression Inventory) can be replaced with scales like the PHQ-2, General Anxiety Disorder–7, Hospital Anxiety and Depression Scale, or PROMIS-29 subscales.

Because certain cytokines and other inflammatory markers may naturally decrease over time without corresponding improvement in the ME/CFS subtype, caution should be taken when using cytokines as endpoints.
 

8: Consider enrollment and objectives carefully

A proportion of people with long COVID will recover in the early months after infection. Ideally, clinical trials will primarily study treatments in patients who have been ill 6 months or longer, as some natural recovery will happen before that can bias studies.

But where resources are abundant, it is ideal for trials to additionally look at whether the treatments can help patients in the early months recover and prevent progression to the later stage.
 

9: Tracking illness duration is crucial

Research from ME/CFS shows that there may be an immune change in the first few years of the illness, where cytokines decrease without any corresponding change in symptom improvement. 

Because of this and the possibility that other markers follow the same pattern, disease duration should be a core feature of all analyses and trial designs. Trial outcomes should be designed to answer the question of whether the medication helps patients at different durations of illness. 
 

10: Prioritize patient populations less likely to recover without intervention

Some long COVID phenotypes seem less likely to recover without intervention. Trials should take care to focus on these patient populations, which include those with neurologic symptoms and those meeting ME/CFS criteria.

 

11: Account for the relapsing/remitting nature

Outcome measures need to be assessed in a way that can distinguish a temporary remission, which is part of the natural course of the disease, from a permanent cure. 

Factors that can contribute to the relapsing/remitting nature include physical and cognitive postexertional malaise, menstrual cycle changes, and seasonal changes.
 

12: Trial participants should reflect the diversity of the long COVID population

Certain demographics are more likely to be affected by acute and long COVID and need to be appropriately recruited and reflected in research, including in patient engagement. 

Trials must include high numbers of Hispanic/Latinx, Black, and indigenous communities, queer and transgender populations, and women. Trial materials and design need to incorporate linguistic diversity in addition to racial/ethnic diversity.

Upward of 75% of long COVID cases happen after mild acute cases; clinical researchers should ensure that nonhospitalized patients make up the bulk of trial participants. 
 

13: Utilize meaningful engagement of patients, especially in treatment selection and study design

Meaningful patient engagement means engaging multiple patients at every step of the trial process, from treatment selection to study design to analysis to communication of the results. 

Patient experiences are extremely valuable and contain information that researchers may not be familiar with, including the nature and patterns of the illness, insights into possible treatments, and barriers to documentation and care that may also impact research. Tapping into those patient experiences will make trials stronger.

Overall, the landscape of long COVID clinical trials is ripe for discovery, and researchers choosing to go down this path will be deeply appreciated by the patient community. 

Hannah Davis is a long COVID patient-researcher and cofounder of the Patient-Led Research Collaborative, an organization studying the long-term effects of COVID.

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

Cholangiocarcinoma is a heterogeneous, highly aggressive cancer of the biliary tract epithelium with an overall 5-year relative survival rate of only 9%.^1,2 Although surgical resection of localized, intrahepatic cholangiocarcinoma is associated with improved overall survival, most patients present with advanced disease not amenable to surgery due to a late onset of symptoms.² Recently, an increased incidence of cholangiocarcinoma has been reported in the United States.³ Although relatively rare in the US, cholangiocarcinoma is prevalent across large parts of Asia, including China, Vietnam, Thailand, South Korea, and Taiwan.²

Risk Factors

To date, risk factors for developing cholangiocarcinoma have not been elucidated. ^4,5 However, a growing body of literature suggests that chronic infection of genetically susceptible human subjects with Clonorchis sinensis ( C sinensis ) and Opisthorchis viverrini ( O viverrini ) plays a role. ^6,7 The life cycle of these food-borne zoonotic trematodes involves eggs discharged in the stool of infected humans, the definitive host. ^6,7 In nature, these eggs are ingested by freshwater snails, the intermediate host, where they undergo several developmental stages to form cercariae. Once released from snails into the water, free-swimming cercariae come in contact and penetrate freshwater fish where they encyst as metacercariae. Infection of humans occurs by ingesting undercooked, salted, pickled, or smoked freshwater fish infested with metacercariae. After ingestion, metacercariae excyst in the duodenum and ascend the biliary tract through the ampulla of Vater. They then mature into adult flukes that reside in small- and medium-sized intrahepatic biliary ducts. ^6,7

Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for as long as 30 years, which is the lifespan of the trematodes.^6,7 During this prolonged period, C sinensis and O viverrini feeding activities and their excretory-secretory products may damage bile duct epithelium and promote intense local inflammation.^6,7 Conceivably, these pathological processes could then provoke the epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to initiation and progression of cholangiocarcinoma in genetically susceptible people.⁸ Accordingly, the International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of chronic infections with C sinensis and O viverrini in humans and that chronic infections with these trematodes cause cholangiocarcinoma.⁹ The IARC concluded that chronic infections with C sinensis and O viverrini are carcinogenic to humans (Group 1).⁹

Diagnosis

Presently, the diagnosis of C sinensis and O viverrini infection is based on microscopic identification and enumeration of the parasites’ eggs in weighted stool specimens using a formalin-ethyl acetate sedimentation concentration technique. ^6,7 This approach requires a labor-intensive test that is conducted by an experienced technician. The test has low specificity and sensitivity because eggs could be confused with those of nonpathogenic intestinal flukes that are morphologically similar and because eggs are not present in feces during all stages of the infection. Although diffuse dilatation of intrahepatic bile ducts by screening sonography is used to diagnose clonorchiasis in endemic areas, it has low sensitivity, particularly in patients with low-level C sinensis and O viverrin i infections. ¹⁰

To address the current diagnostic gap, several enzyme-linked immunosorbent assays (ELISA) have been developed for the diagnosis of C sinensis, including monoclonal antibody-based (mAb) ELISA and indirect antibody ELISA.^11,12 However, both have important limitations. The mAb ELISA detects only active infections while indirect antibody ELISA cross-reacts with other liver flukes.^11,12 Taken together, these data illustrate the difficulties in diagnosing asymptomatic individuals with low-burden C sinensis or O viverrini infections by existing laboratory methods.

Timely serodiagnosis of indolent C sinensis and O viverrini infections is important because these parasites have recently been raised as a risk factor for cholangiocarcinoma in veterans who served in Vietnam.¹³ The American War Library estimates that as of February 28, 2019, about 610,000 Americans who served on land in Vietnam or in the air over Vietnam between 1954 and 1975 are alive, and about 164,000 Americans who served at sea in Vietnam waters are alive.¹⁴ To that end, Psevdos and colleagues screened 97 US veterans who served in Vietnam and identified 50 who reported exposure to raw or undercooked fish while there.¹³ None had evidence of active C sinensis or O viverrini infection. Blood samples obtained from these veterans were analyzed for circulating C sinensis and O viverrini antibodies using an ELISA developed in South Korea and 12 blood samples tested positive for the trematodes. Imaging of extrahepatic and intrahepatic bile ducts was unyielding in all cases. One veteran diagnosed with cholangiocarcinoma had repeated negative tests. However, the results of this study were challenged by several experts in this field because the authors did not report the sensitivity and specificity of the ELISA assay used.¹⁵

Serologic testing of US veterans who served in C sinensis and O viverrini–endemic countries for indolent infections with these parasites is not recommended at present.¹⁵ Nevertheless, there is an urgent need to develop sensitive and specific serologic assays, such as ELISA tests with recombinant antigens, to detect both acute and indolent infections caused by each biliary liver fluke in the US, including in patients diagnosed with cholangiocarcinoma. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival in the population at risk.

Cholangiocarcinoma is a heterogeneous, highly aggressive cancer of the biliary tract epithelium with an overall 5-year relative survival rate of only 9%.^1,2 Although surgical resection of localized, intrahepatic cholangiocarcinoma is associated with improved overall survival, most patients present with advanced disease not amenable to surgery due to a late onset of symptoms.² Recently, an increased incidence of cholangiocarcinoma has been reported in the United States.³ Although relatively rare in the US, cholangiocarcinoma is prevalent across large parts of Asia, including China, Vietnam, Thailand, South Korea, and Taiwan.²

Risk Factors

To date, risk factors for developing cholangiocarcinoma have not been elucidated. ^4,5 However, a growing body of literature suggests that chronic infection of genetically susceptible human subjects with Clonorchis sinensis ( C sinensis ) and Opisthorchis viverrini ( O viverrini ) plays a role. ^6,7 The life cycle of these food-borne zoonotic trematodes involves eggs discharged in the stool of infected humans, the definitive host. ^6,7 In nature, these eggs are ingested by freshwater snails, the intermediate host, where they undergo several developmental stages to form cercariae. Once released from snails into the water, free-swimming cercariae come in contact and penetrate freshwater fish where they encyst as metacercariae. Infection of humans occurs by ingesting undercooked, salted, pickled, or smoked freshwater fish infested with metacercariae. After ingestion, metacercariae excyst in the duodenum and ascend the biliary tract through the ampulla of Vater. They then mature into adult flukes that reside in small- and medium-sized intrahepatic biliary ducts. ^6,7

Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for as long as 30 years, which is the lifespan of the trematodes.^6,7 During this prolonged period, C sinensis and O viverrini feeding activities and their excretory-secretory products may damage bile duct epithelium and promote intense local inflammation.^6,7 Conceivably, these pathological processes could then provoke the epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to initiation and progression of cholangiocarcinoma in genetically susceptible people.⁸ Accordingly, the International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of chronic infections with C sinensis and O viverrini in humans and that chronic infections with these trematodes cause cholangiocarcinoma.⁹ The IARC concluded that chronic infections with C sinensis and O viverrini are carcinogenic to humans (Group 1).⁹

Diagnosis

Presently, the diagnosis of C sinensis and O viverrini infection is based on microscopic identification and enumeration of the parasites’ eggs in weighted stool specimens using a formalin-ethyl acetate sedimentation concentration technique. ^6,7 This approach requires a labor-intensive test that is conducted by an experienced technician. The test has low specificity and sensitivity because eggs could be confused with those of nonpathogenic intestinal flukes that are morphologically similar and because eggs are not present in feces during all stages of the infection. Although diffuse dilatation of intrahepatic bile ducts by screening sonography is used to diagnose clonorchiasis in endemic areas, it has low sensitivity, particularly in patients with low-level C sinensis and O viverrin i infections. ¹⁰

To address the current diagnostic gap, several enzyme-linked immunosorbent assays (ELISA) have been developed for the diagnosis of C sinensis, including monoclonal antibody-based (mAb) ELISA and indirect antibody ELISA.^11,12 However, both have important limitations. The mAb ELISA detects only active infections while indirect antibody ELISA cross-reacts with other liver flukes.^11,12 Taken together, these data illustrate the difficulties in diagnosing asymptomatic individuals with low-burden C sinensis or O viverrini infections by existing laboratory methods.

Timely serodiagnosis of indolent C sinensis and O viverrini infections is important because these parasites have recently been raised as a risk factor for cholangiocarcinoma in veterans who served in Vietnam.¹³ The American War Library estimates that as of February 28, 2019, about 610,000 Americans who served on land in Vietnam or in the air over Vietnam between 1954 and 1975 are alive, and about 164,000 Americans who served at sea in Vietnam waters are alive.¹⁴ To that end, Psevdos and colleagues screened 97 US veterans who served in Vietnam and identified 50 who reported exposure to raw or undercooked fish while there.¹³ None had evidence of active C sinensis or O viverrini infection. Blood samples obtained from these veterans were analyzed for circulating C sinensis and O viverrini antibodies using an ELISA developed in South Korea and 12 blood samples tested positive for the trematodes. Imaging of extrahepatic and intrahepatic bile ducts was unyielding in all cases. One veteran diagnosed with cholangiocarcinoma had repeated negative tests. However, the results of this study were challenged by several experts in this field because the authors did not report the sensitivity and specificity of the ELISA assay used.¹⁵

Serologic testing of US veterans who served in C sinensis and O viverrini–endemic countries for indolent infections with these parasites is not recommended at present.¹⁵ Nevertheless, there is an urgent need to develop sensitive and specific serologic assays, such as ELISA tests with recombinant antigens, to detect both acute and indolent infections caused by each biliary liver fluke in the US, including in patients diagnosed with cholangiocarcinoma. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival in the population at risk.

Cholangiocarcinoma is a heterogeneous, highly aggressive cancer of the biliary tract epithelium with an overall 5-year relative survival rate of only 9%.^1,2 Although surgical resection of localized, intrahepatic cholangiocarcinoma is associated with improved overall survival, most patients present with advanced disease not amenable to surgery due to a late onset of symptoms.² Recently, an increased incidence of cholangiocarcinoma has been reported in the United States.³ Although relatively rare in the US, cholangiocarcinoma is prevalent across large parts of Asia, including China, Vietnam, Thailand, South Korea, and Taiwan.²

Risk Factors

To date, risk factors for developing cholangiocarcinoma have not been elucidated. ^4,5 However, a growing body of literature suggests that chronic infection of genetically susceptible human subjects with Clonorchis sinensis ( C sinensis ) and Opisthorchis viverrini ( O viverrini ) plays a role. ^6,7 The life cycle of these food-borne zoonotic trematodes involves eggs discharged in the stool of infected humans, the definitive host. ^6,7 In nature, these eggs are ingested by freshwater snails, the intermediate host, where they undergo several developmental stages to form cercariae. Once released from snails into the water, free-swimming cercariae come in contact and penetrate freshwater fish where they encyst as metacercariae. Infection of humans occurs by ingesting undercooked, salted, pickled, or smoked freshwater fish infested with metacercariae. After ingestion, metacercariae excyst in the duodenum and ascend the biliary tract through the ampulla of Vater. They then mature into adult flukes that reside in small- and medium-sized intrahepatic biliary ducts. ^6,7

Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for as long as 30 years, which is the lifespan of the trematodes.^6,7 During this prolonged period, C sinensis and O viverrini feeding activities and their excretory-secretory products may damage bile duct epithelium and promote intense local inflammation.^6,7 Conceivably, these pathological processes could then provoke the epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to initiation and progression of cholangiocarcinoma in genetically susceptible people.⁸ Accordingly, the International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of chronic infections with C sinensis and O viverrini in humans and that chronic infections with these trematodes cause cholangiocarcinoma.⁹ The IARC concluded that chronic infections with C sinensis and O viverrini are carcinogenic to humans (Group 1).⁹

Diagnosis

Presently, the diagnosis of C sinensis and O viverrini infection is based on microscopic identification and enumeration of the parasites’ eggs in weighted stool specimens using a formalin-ethyl acetate sedimentation concentration technique. ^6,7 This approach requires a labor-intensive test that is conducted by an experienced technician. The test has low specificity and sensitivity because eggs could be confused with those of nonpathogenic intestinal flukes that are morphologically similar and because eggs are not present in feces during all stages of the infection. Although diffuse dilatation of intrahepatic bile ducts by screening sonography is used to diagnose clonorchiasis in endemic areas, it has low sensitivity, particularly in patients with low-level C sinensis and O viverrin i infections. ¹⁰

To address the current diagnostic gap, several enzyme-linked immunosorbent assays (ELISA) have been developed for the diagnosis of C sinensis, including monoclonal antibody-based (mAb) ELISA and indirect antibody ELISA.^11,12 However, both have important limitations. The mAb ELISA detects only active infections while indirect antibody ELISA cross-reacts with other liver flukes.^11,12 Taken together, these data illustrate the difficulties in diagnosing asymptomatic individuals with low-burden C sinensis or O viverrini infections by existing laboratory methods.

Timely serodiagnosis of indolent C sinensis and O viverrini infections is important because these parasites have recently been raised as a risk factor for cholangiocarcinoma in veterans who served in Vietnam.¹³ The American War Library estimates that as of February 28, 2019, about 610,000 Americans who served on land in Vietnam or in the air over Vietnam between 1954 and 1975 are alive, and about 164,000 Americans who served at sea in Vietnam waters are alive.¹⁴ To that end, Psevdos and colleagues screened 97 US veterans who served in Vietnam and identified 50 who reported exposure to raw or undercooked fish while there.¹³ None had evidence of active C sinensis or O viverrini infection. Blood samples obtained from these veterans were analyzed for circulating C sinensis and O viverrini antibodies using an ELISA developed in South Korea and 12 blood samples tested positive for the trematodes. Imaging of extrahepatic and intrahepatic bile ducts was unyielding in all cases. One veteran diagnosed with cholangiocarcinoma had repeated negative tests. However, the results of this study were challenged by several experts in this field because the authors did not report the sensitivity and specificity of the ELISA assay used.¹⁵

Serologic testing of US veterans who served in C sinensis and O viverrini–endemic countries for indolent infections with these parasites is not recommended at present.¹⁵ Nevertheless, there is an urgent need to develop sensitive and specific serologic assays, such as ELISA tests with recombinant antigens, to detect both acute and indolent infections caused by each biliary liver fluke in the US, including in patients diagnosed with cholangiocarcinoma. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival in the population at risk.