Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

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

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

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

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

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

Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.

“TNBC is incredibly heterogeneous, which makes it challenging to treat,” said Rita Nanda, MD, director of the breast oncology program and associate professor of medicine at the University of Chicago. “We have subsets of TNBC that don’t respond to currently available therapies and, as of yet, have no identifiable therapeutic targets.”

Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy – typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.

When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).

Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.

“For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential,” said Kelly McCann, MD, PhD, a hematologist/oncologist in the department of medicine at the University of California, Los Angeles. “Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets.”
 

A targeted strategy

The Food and Drug Administration’s approval of sacituzumab govitecan, the first antibody-drug conjugate to treat metastatic TNBC, marked an important addition to the TNBC drug armamentarium. “Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease,” Dr. Nanda said.

Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells.

In the phase 1/2 ASCENT trial, the median progression-free survival was 5.5 months and overall survival was 13.0 months in 108 patients with metastatic TNBC who had received at least two therapies prior to sacituzumab govitecan.

A subsequent phase 3 trial showed progression-free survival of 5.6 months with sacituzumab govitecan and 1.7 months with physician’s choice of chemotherapy. The median overall survival was 12.1 months and 6.7 months, respectively.

But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given sacituzumab govitecan, compared with chemotherapy alone.

In other words, “patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit,” Dr. Nanda said.

Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.

Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, “trastuzumab deruxtecan represents potential in treating HER2-low TNBC,” said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

Early results from a phase 1b study showed that trastuzumab deruxtecan produced a response rate of 37% in patients with HER2-low breast cancer.

Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
 

Immunotherapy advances

Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing PD-L1. Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.

Yet, data on which patients will benefit are not so clear-cut. “These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker,” Dr. Yuan said.

Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). As with the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs. 17.6 months with nab-paclitaxel alone.

However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs. 6 months, respectively, and overall survival was 28.3 months vs. 22.1 months.

“It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel,” Dr. Nanda said. “Perhaps the negative finding has to do with how the trial was conducted, or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit.”
 

Continued efforts to understand TNBC

Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.

On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received olaparib exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.

When considering signaling pathways, the PI3K/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3K and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival – 19.1 months vs. 12.6 with placebo plus paclitaxel – with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.

But there’s more to learn about treating metastatic TNBC. “Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go,” said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York. “Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail.”

Dr. Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. “For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available,” she said.

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

Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.

“TNBC is incredibly heterogeneous, which makes it challenging to treat,” said Rita Nanda, MD, director of the breast oncology program and associate professor of medicine at the University of Chicago. “We have subsets of TNBC that don’t respond to currently available therapies and, as of yet, have no identifiable therapeutic targets.”

Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy – typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.

When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).

Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.

“For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential,” said Kelly McCann, MD, PhD, a hematologist/oncologist in the department of medicine at the University of California, Los Angeles. “Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets.”
 

A targeted strategy

The Food and Drug Administration’s approval of sacituzumab govitecan, the first antibody-drug conjugate to treat metastatic TNBC, marked an important addition to the TNBC drug armamentarium. “Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease,” Dr. Nanda said.

Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells.

In the phase 1/2 ASCENT trial, the median progression-free survival was 5.5 months and overall survival was 13.0 months in 108 patients with metastatic TNBC who had received at least two therapies prior to sacituzumab govitecan.

A subsequent phase 3 trial showed progression-free survival of 5.6 months with sacituzumab govitecan and 1.7 months with physician’s choice of chemotherapy. The median overall survival was 12.1 months and 6.7 months, respectively.

But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given sacituzumab govitecan, compared with chemotherapy alone.

In other words, “patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit,” Dr. Nanda said.

Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.

Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, “trastuzumab deruxtecan represents potential in treating HER2-low TNBC,” said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

Early results from a phase 1b study showed that trastuzumab deruxtecan produced a response rate of 37% in patients with HER2-low breast cancer.

Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
 

Immunotherapy advances

Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing PD-L1. Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.

Yet, data on which patients will benefit are not so clear-cut. “These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker,” Dr. Yuan said.

Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). As with the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs. 17.6 months with nab-paclitaxel alone.

However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs. 6 months, respectively, and overall survival was 28.3 months vs. 22.1 months.

“It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel,” Dr. Nanda said. “Perhaps the negative finding has to do with how the trial was conducted, or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit.”
 

Continued efforts to understand TNBC

Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.

On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received olaparib exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.

When considering signaling pathways, the PI3K/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3K and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival – 19.1 months vs. 12.6 with placebo plus paclitaxel – with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.

But there’s more to learn about treating metastatic TNBC. “Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go,” said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York. “Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail.”

Dr. Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. “For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available,” she said.

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

Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.

“TNBC is incredibly heterogeneous, which makes it challenging to treat,” said Rita Nanda, MD, director of the breast oncology program and associate professor of medicine at the University of Chicago. “We have subsets of TNBC that don’t respond to currently available therapies and, as of yet, have no identifiable therapeutic targets.”

Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy – typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.

When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).

Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.

“For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential,” said Kelly McCann, MD, PhD, a hematologist/oncologist in the department of medicine at the University of California, Los Angeles. “Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets.”
 

A targeted strategy

The Food and Drug Administration’s approval of sacituzumab govitecan, the first antibody-drug conjugate to treat metastatic TNBC, marked an important addition to the TNBC drug armamentarium. “Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease,” Dr. Nanda said.

Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells.

In the phase 1/2 ASCENT trial, the median progression-free survival was 5.5 months and overall survival was 13.0 months in 108 patients with metastatic TNBC who had received at least two therapies prior to sacituzumab govitecan.

A subsequent phase 3 trial showed progression-free survival of 5.6 months with sacituzumab govitecan and 1.7 months with physician’s choice of chemotherapy. The median overall survival was 12.1 months and 6.7 months, respectively.

But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given sacituzumab govitecan, compared with chemotherapy alone.

In other words, “patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit,” Dr. Nanda said.

Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.

Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, “trastuzumab deruxtecan represents potential in treating HER2-low TNBC,” said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

Early results from a phase 1b study showed that trastuzumab deruxtecan produced a response rate of 37% in patients with HER2-low breast cancer.

Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
 

Immunotherapy advances

Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing PD-L1. Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.

Yet, data on which patients will benefit are not so clear-cut. “These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker,” Dr. Yuan said.

Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). As with the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs. 17.6 months with nab-paclitaxel alone.

However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs. 6 months, respectively, and overall survival was 28.3 months vs. 22.1 months.

“It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel,” Dr. Nanda said. “Perhaps the negative finding has to do with how the trial was conducted, or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit.”
 

Continued efforts to understand TNBC

Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.

On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received olaparib exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.

When considering signaling pathways, the PI3K/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3K and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival – 19.1 months vs. 12.6 with placebo plus paclitaxel – with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.

But there’s more to learn about treating metastatic TNBC. “Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go,” said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York. “Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail.”

Dr. Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. “For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available,” she said.

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

This article has been updated to reflect new US Food and Drug Administration and Centers for Disease Control and Prevention recommendations to pause administration of the Johnson and Johnson Jansen (JNJ-78436735) COVID-19 vaccine.¹

Since the outbreak of the pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),a plethora of studies have been performed to increase our knowledge of its associated illness COVID-19.² There is no cure for COVID-19, which can be lethal. In the absence of a cure, preventive measures are of vital importance. In order to help prevent the spread of the virus, the Centers for Diseases Control and Prevention (CDC) advocates for: (1) the use of a face mask over the mouth and nose; (2) a minimum of 6-foot distance between individuals; and (3) avoidance of gatherings.As of March 2021, the US Food and Drug Administration (FDA) approved 3 vaccines for the prevention of COVID-19, under an emergency use authorization (EUA).^3-5

COVID-19 and Multiple Sclerosis

Since the beginning of the pandemic, neurologists have faced a new challenge—determining whether persons with multiple sclerosis (pwMS) were more at risk than others of becoming ill from COVID-19 or were destined for a worse outcome. The National MS Society has advised a personalized approach in relation to particularly vulnerable persons when needed and has also initiated worldwide registries to collect information regarding incidence and outcome of COVID-19 in pwMS. Accordingly, through the MS Center of Excellence (MSCoE), the Veterans Health Administration (VHA) has established a national registry assembling data regarding COVID-19 in veterans with MS.

A recent descriptive literature review summarized the outcomes of 873 persons with both MS and COVID-19 and reported that about 36% of COVID-19 cases were treated with B-cell depleting therapies (ocrelizumab or rituximab).⁶ This proportion was relatively higher when compared with other disease modifying agents. Of those who became infected with SARS-CoV-2, death from COVID-19 occurred in about 4%, and an additional 3% required assisted invasive or noninvasive ventilation. Persons reported to have passed away from COVID-19 generally were older; had progressive MS; or had associated comorbidities such as obesity, hypertension, heart or lung conditions, or cancers. Of these, 50% were not on any disease modifying agent, 25% were on B-cell depleting therapies (ocrelizumab or rituximab), and the remaining 25% were on various medications for MS. It is important to highlight that no formal statistical analyses were performed in this review. On the contrary, in the recently published Italian report on 844 pwMS who had suspected or confirmed COVID-19, the authors used univariate and multivariate models to analyze their findings and noted that the use of ocrelizumab was significantly associated with a worse clinical outcome.⁷ These authors also identified age, sex, disability score, and recent (within 1 month) use of steroids as risk factors for a severe COVID-19 outcome. The incidence of death from COVID-19 in this cohort was 1.54%.

The recently published data from the North American Registry of the National MS Society based on 1,626 patients reported a 3.3% incidence of death from COVID-19.⁸ The following factors were identified as risks for worse outcome: male sex, nonambulatory status, age, Black race, and cardiovascular disease. The use of rituximab, ocrelizumab, and steroids (the latter medication over the preceding 2 months) increased the risks of hospitalization for COVID-19.

COVID-19 Vaccines

Of the 3 available vaccines, the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine is approved for individuals aged ≥ 16 years, while the Moderna COVID-19 (mRNA-1273) and the Johnson and Johnson/Jannsen COVID-19 (JNJ-78436735) vaccines are approved for individuals aged ≥ 18 years, though the latter vaccine has been temporarily suspended.^1,3-5 The EUAs were released following the disclosure of the results of 3 phase 3 clinical trials and several phase 1 and 2 clinical trials.^9-16

The BNT162b2 vaccine from Pfizer-BioNTech encodes the SARS-CoV-2 full-length spike protein (S) in prefusion conformation locked by the mutation in 2 prolines.⁹ Differently from the BNT162b2 vaccine, the BNT162b1 vaccine encodes a secreted trimerized SARS-CoV-2 receptor–binding domain. The S-glycoprotein is required for viral entry, as implicated in host cell attachment, and is the target of the neutralizing antibodies. In a phase 1 clinical study on 195 volunteers treated with BNT162b1 (10 mg, 20 mg, 30 mg, or 100 mg doses) or BNT162b2 (10 mg, 20 mg, or 30 mg doses) vaccines or placebo 21 days apart, both the binding and neutralizing antibody response was found to be age and “somewhat” dose dependent.⁹

Higher neutralization titers were measured at day 28 and 35 (7 and 14 days after the second dose, respectively) and compared with titers of persons who recovered from a COVID-19 infection.⁹ Serum neutralization was measured using a fluorescence-based high-throughput neutralization assay, while binding activity was assessed using the receptor-binding domain (RBD)–binding or S1-binding IgG direct Luminex immunoassays.

The overall reactogenicity/immunogenicity profile of BNT162b2 administered twice (30 mg each time) led to its selection for the phase 3 clinical trial.^9,10 In a large phase 3 clinical trial on 43,458 participants, the BNT162b2 vaccine given at 30 mg doses 21 days apart conferred 95% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁰ No safety concerns to stop the trial were identified, though related severe and life-threatening events were reported in 0.3% and 0.1% of the volunteers, respectively. We note that these incidence rates were the same for the treated and the placebo group.

The mRNA-1273 vaccine from Moderna also encodes the SARS-CoV-2 S-glycoprotein. In a dose escalation phase 1 trial of 45 participants aged between 18 and 55 years (25 mg, 100 mg or 250 mg, given at days 1 and 29) and 40 participants aged ≥ 57 years (25 mg and 100 mg, given at days 1 and 29), a dose-dependent effect was observed for both binding (receptor-binding domain and S-2p IgG on enzyme-linked immunosorbent assay [ELISA])and neutralizing antibodies (SARS-CoV-2 nanoluciferase high-throughput neutralization assay, focus reduction neutralization test mNeonGreen and SARS-CoV-2 plaque-reduction neutralization testing assay) development.^11,12 The geometric mean of both binding and neutralizing antibodies declined over time but persisted high as late as 119 days after the first burst of 100 mg dose.¹³ The same dose of the vaccine also elicited a strong T helper-1 response with little T helper-2 response across all ages.¹¹ The strength of the memory cellular response remains to be defined and is the subject of ongoing investigations. In a large phase 3 clinical trial with 30,420 participants, the Moderna COVID-19 mRNA-1273 vaccine, given 28 days apart at the dose of 100 mg, met 94.1% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁴

Less than 0.1% of volunteers in both groups withdrew from the trial due to adverse effects (AEs); 0.5% in the placebo group and 0.3% in the treated group had AEs after the first dose, which precluded receiving the second dose.¹⁴

The Johnson and Johnson/Jannsen JNJ-78436735 vaccine is based upon a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector, which encodes the full-length, stabilized S-glycoprotein of SARS-CoV-2. The currently reported results of the phase 1 and 2 clinical study indicated that 805 volunteers (402 participants between ages 18 and 55 years and 403 individuals aged ≥ 65 years) were randomized to receive a single or double dose of either 5 x 10¹⁰ viral particles per 0.5 mL (low dose) or 1 x 10¹¹ viral particles per 0.5 mL (high dose), each compared with a placebo group. Incidence of seroconversion to binding antibodies against the full-length stabilized S-glycoprotein, as measured by ELISA, showed ≥ 96% seroconversion by day 29 after the first dose. The incidence of seroconversion to neutralizing antibodies was ≥ 90% as early as early as 29 days after the first of either dose. In this study, neutralization activity was measured using the wild-type virus microneutralization assay based on the Victoria/1/2020/ SARS-CoV-2 strain.¹⁵ We note that the data related to this study have been partially reported and additional information will be available when each participant will have received the second dose.

In a large phase 3 clinical trial with 40,000 participants aged between 18 and 100 years, the Johnson and Johnson/Jannsen JNJ-78436735 vaccine, given as single dose of 5 x 10¹⁰ viral particles per 0.5 mL, met 65.5% clinical efficacy in the likelihood of being affected by symptomatic COVID-19 ≥ 28 days postimmunization.¹⁶ In this study, the vaccine efficacy was found to have a geographic distribution with highest efficacy in the US (74.4%), followed by Latin America (64.7%) where Brazil showed a predominance of the P2 COVID-19 lineage (64.7%), and Africa (52%) where the B.1.351 lineage was most frequent (94.5%). The vaccine also proved to be effective in reducing the likelihood of asymptomatic seroconversion, as measured by the level of a non-S protein, eg, 0.7% of positive cases in the vaccine group vs 2.8% in the placebo group. Immunological data indicated that the vaccine response was mainly driven by T-helper 1 lymphocytes. As of April 13, 2021 the FDA has recommend suspending the administration of the Johnson and Johnson/Janssen vaccine due to the occurrence of severe blood clots reported in a 6 subjects out of ~6.8 millions administered doses.¹

It is noteworthy to highlight that all vaccines reduced the likelihood of hospitalizations and deaths due to COVID-19.

As of April 17, 2021, the CDC reports that more than 130 million (40%) Americans, nearly 1/3 of the population, have received at least 1 dose of any of the 3 available vaccines, including 4.6 million at the VHA.¹⁷ Using the Vaccine Adverse Event Reporting System and v-safe, the US is conducting what has been defined the most “intense and comprehensive safety monitoring in the US history.”¹⁸ Thus far, data affirm the overall safety of the available vaccines against COVID-19. Individuals should not receive the COVID-19 vaccines if they have had a severe allergic reaction to any ingredient in the vaccine or a severe allergic reaction to a prior dose of the vaccine. Additionally, individuals who have received convalescent plasma should wait 90 days before getting the COVID-19 vaccine.

Vaccination for Persons with MS

PwMS or those on immunosuppressive medications were excluded from the clinical trial led by Pfizer-BioNTech. There is no mention of MS as comorbidity in the study from Moderna, although this condition is not listed as an exclusion criterion either. The results of the phase 3 clinical trial for the Johnson and Johnson/Janssen vaccine are not fully public yet, thus this information is not known as well. As a result, the use of this vaccine in pwMS under immunomodulatory agents is based on previous knowledge of other vaccines. Evidence is growing for the safety of the BNT162b2 COVID-19 vaccination in pwMS.¹⁹ Data regarding COVID-19 efficacy and safety are still largely based on previous knowledge on other vaccines.^20,21

Immunization of pwMS is considered safe and should proceed with confidence in those persons who have no other contraindication to receive a vaccine. A fundamental problem for pwMS treated with immunomodulatory or immunosuppressive medications is whether the vaccine will remain safe or be able to solicit an adequate immune response.^20,21 As of the time of publication 2021, there is consensus that mRNA based or inactivated vaccines are also considered safe in pwMS undergoing immunomodulatory or immunosuppressive treatments.^20-23 We advise a one-on-one conversation between each veteran with MS and their primary neurologist to understand the importance of the vaccination, the minimal risks associated with it and if any specific treatment modification should be made.

To provide guidance, the National MS Society released a position statement that is regularly updated.²² Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. In addition, on the basis of available literature and the American Academy of Neurology recommendations on the use of vaccines in general, the following recommendations are proposed.^20-23

Recommendation 1: injections, orals, and natalizumab. Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. Neither delay in start nor adjustments in dosing or timing of administration are advised for pwMS taking currently available either generic or brand formulations of β interferons, glatiramer acetate, teriflunomide, dimethyl or monomethyl fumarate, or natalizumab.²²

Recommendation 2: anti-CD20 monoclonal infusions. As an attenuated humoral response is predicted in pwMS treated with anti-CD20 monoclonal infusions, coordinating the timing of vaccination with treatment schedule may maximize efficacy of the vaccine. Whenever possible, it is advised to be vaccinated ≥ 12 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting anti-CD20 monoclonal infusions are advised to be fully vaccinated first and start these medications ≥ 2 to 4 weeks later.²²

Recommendation 3: alemtuzumab infusion. Given its effect on CD52+ cells, it is advised to be vaccinated ≥ 24 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting alemtuzumab infusions are advised to get fully vaccinated first and start this medication 4 weeks or more after completing the vaccine.²²

Recommendation 4: sphingosine 1 phosphate receptor modulators, oral cladribine, and ofatumumab. PwMS starting any of these medications are advised to be fully vaccinated first and start these medications 2 to 4 weeks after completing the vaccine. PwMS already on those medications are not advised to change the schedule of administration. When possible, though, one should resume the dose of cladribine or ofatumumab 2 to 4 weeks after the last dose of the vaccine. ²⁰

Notably, all these recommendations hold true when there is enough disease stability to allow delaying treatment. We also add that it remains unclear if persons with an overall very low number of lymphocytes will be able to elicit a strong reaction to the vaccine. Blood collection and analysis of white blood cell count and lymphocyte subset estimates should be obtained in those persons with a markedly suppressed immune system. Whenever possible, to maximize outcome, timing the vaccination with treatment should be considered in those persons with a markedly reduced number of T-helper 1 cells.

Vaccination for Veterans

Currently the VHA is offering to veterans the Pfizer and Moderna COVID-19 vaccines with FDA EUAs. In accordance with FDA regulations, the VHA has paused administration of the Johnson and Johnson/Janssen vaccine. The VHA has launched its vaccination program in December 2020 by first providing the vaccine to health care personnel, nursing home patients, spinal cord injury patients, chemotherapy patients, dialysis and transplant patients, as well as homeless veterans. Most VA health care systems have passed this phase and are now able to provide vaccines to veterans with MS.

In December 2020, the MSCoE released a position statement regarding the importance and safety of the COVID-19 vaccine for veterans with MS.²⁴ This statement will be updated on a regular basis as new information becomes available from major organizations like the National MS Society, FDA, CDC, and World Health Organization (WHO) or relevant literature.

Conclusions

Older veterans with progressive MS and associated comorbidities are at higher risk of death should they be infected by COVID-19. Fortunately, we live in a time where vaccines are recognized as a critical tool to prevent this infection and to significantly reduce its morbidity and mortality. Yet, hesitancy to vaccinate has been identified as one of the most important threats to public health by the WHO in 2019.²⁵ Understandably such hesitancy is even more profound for the COVID-19 vaccine, which is being administered under an EUA. In light of this indecision, and given the current state of the pandemic, we urge health care providers to educate every veteran about the benefits of being vaccinated against COVID-19. Within the VHA, a solid campaign of vaccination has been put in place at an unprecedented speed.

Health care providers interacting with veterans with MS are encouraged to use the MSCoE website (www.va.gov/ms) for any questions or concerns, or to reach out to MSCoE staff. It is vitally important that our community of veterans receives appropriate education on the importance of this vaccination for their own safety, for that of their household and society.

This article has been updated to reflect new US Food and Drug Administration and Centers for Disease Control and Prevention recommendations to pause administration of the Johnson and Johnson Jansen (JNJ-78436735) COVID-19 vaccine.¹

Since the outbreak of the pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),a plethora of studies have been performed to increase our knowledge of its associated illness COVID-19.² There is no cure for COVID-19, which can be lethal. In the absence of a cure, preventive measures are of vital importance. In order to help prevent the spread of the virus, the Centers for Diseases Control and Prevention (CDC) advocates for: (1) the use of a face mask over the mouth and nose; (2) a minimum of 6-foot distance between individuals; and (3) avoidance of gatherings.As of March 2021, the US Food and Drug Administration (FDA) approved 3 vaccines for the prevention of COVID-19, under an emergency use authorization (EUA).^3-5

COVID-19 and Multiple Sclerosis

Since the beginning of the pandemic, neurologists have faced a new challenge—determining whether persons with multiple sclerosis (pwMS) were more at risk than others of becoming ill from COVID-19 or were destined for a worse outcome. The National MS Society has advised a personalized approach in relation to particularly vulnerable persons when needed and has also initiated worldwide registries to collect information regarding incidence and outcome of COVID-19 in pwMS. Accordingly, through the MS Center of Excellence (MSCoE), the Veterans Health Administration (VHA) has established a national registry assembling data regarding COVID-19 in veterans with MS.

A recent descriptive literature review summarized the outcomes of 873 persons with both MS and COVID-19 and reported that about 36% of COVID-19 cases were treated with B-cell depleting therapies (ocrelizumab or rituximab).⁶ This proportion was relatively higher when compared with other disease modifying agents. Of those who became infected with SARS-CoV-2, death from COVID-19 occurred in about 4%, and an additional 3% required assisted invasive or noninvasive ventilation. Persons reported to have passed away from COVID-19 generally were older; had progressive MS; or had associated comorbidities such as obesity, hypertension, heart or lung conditions, or cancers. Of these, 50% were not on any disease modifying agent, 25% were on B-cell depleting therapies (ocrelizumab or rituximab), and the remaining 25% were on various medications for MS. It is important to highlight that no formal statistical analyses were performed in this review. On the contrary, in the recently published Italian report on 844 pwMS who had suspected or confirmed COVID-19, the authors used univariate and multivariate models to analyze their findings and noted that the use of ocrelizumab was significantly associated with a worse clinical outcome.⁷ These authors also identified age, sex, disability score, and recent (within 1 month) use of steroids as risk factors for a severe COVID-19 outcome. The incidence of death from COVID-19 in this cohort was 1.54%.

The recently published data from the North American Registry of the National MS Society based on 1,626 patients reported a 3.3% incidence of death from COVID-19.⁸ The following factors were identified as risks for worse outcome: male sex, nonambulatory status, age, Black race, and cardiovascular disease. The use of rituximab, ocrelizumab, and steroids (the latter medication over the preceding 2 months) increased the risks of hospitalization for COVID-19.

COVID-19 Vaccines

Of the 3 available vaccines, the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine is approved for individuals aged ≥ 16 years, while the Moderna COVID-19 (mRNA-1273) and the Johnson and Johnson/Jannsen COVID-19 (JNJ-78436735) vaccines are approved for individuals aged ≥ 18 years, though the latter vaccine has been temporarily suspended.^1,3-5 The EUAs were released following the disclosure of the results of 3 phase 3 clinical trials and several phase 1 and 2 clinical trials.^9-16

The BNT162b2 vaccine from Pfizer-BioNTech encodes the SARS-CoV-2 full-length spike protein (S) in prefusion conformation locked by the mutation in 2 prolines.⁹ Differently from the BNT162b2 vaccine, the BNT162b1 vaccine encodes a secreted trimerized SARS-CoV-2 receptor–binding domain. The S-glycoprotein is required for viral entry, as implicated in host cell attachment, and is the target of the neutralizing antibodies. In a phase 1 clinical study on 195 volunteers treated with BNT162b1 (10 mg, 20 mg, 30 mg, or 100 mg doses) or BNT162b2 (10 mg, 20 mg, or 30 mg doses) vaccines or placebo 21 days apart, both the binding and neutralizing antibody response was found to be age and “somewhat” dose dependent.⁹

Higher neutralization titers were measured at day 28 and 35 (7 and 14 days after the second dose, respectively) and compared with titers of persons who recovered from a COVID-19 infection.⁹ Serum neutralization was measured using a fluorescence-based high-throughput neutralization assay, while binding activity was assessed using the receptor-binding domain (RBD)–binding or S1-binding IgG direct Luminex immunoassays.

The overall reactogenicity/immunogenicity profile of BNT162b2 administered twice (30 mg each time) led to its selection for the phase 3 clinical trial.^9,10 In a large phase 3 clinical trial on 43,458 participants, the BNT162b2 vaccine given at 30 mg doses 21 days apart conferred 95% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁰ No safety concerns to stop the trial were identified, though related severe and life-threatening events were reported in 0.3% and 0.1% of the volunteers, respectively. We note that these incidence rates were the same for the treated and the placebo group.

The mRNA-1273 vaccine from Moderna also encodes the SARS-CoV-2 S-glycoprotein. In a dose escalation phase 1 trial of 45 participants aged between 18 and 55 years (25 mg, 100 mg or 250 mg, given at days 1 and 29) and 40 participants aged ≥ 57 years (25 mg and 100 mg, given at days 1 and 29), a dose-dependent effect was observed for both binding (receptor-binding domain and S-2p IgG on enzyme-linked immunosorbent assay [ELISA])and neutralizing antibodies (SARS-CoV-2 nanoluciferase high-throughput neutralization assay, focus reduction neutralization test mNeonGreen and SARS-CoV-2 plaque-reduction neutralization testing assay) development.^11,12 The geometric mean of both binding and neutralizing antibodies declined over time but persisted high as late as 119 days after the first burst of 100 mg dose.¹³ The same dose of the vaccine also elicited a strong T helper-1 response with little T helper-2 response across all ages.¹¹ The strength of the memory cellular response remains to be defined and is the subject of ongoing investigations. In a large phase 3 clinical trial with 30,420 participants, the Moderna COVID-19 mRNA-1273 vaccine, given 28 days apart at the dose of 100 mg, met 94.1% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁴

Less than 0.1% of volunteers in both groups withdrew from the trial due to adverse effects (AEs); 0.5% in the placebo group and 0.3% in the treated group had AEs after the first dose, which precluded receiving the second dose.¹⁴

The Johnson and Johnson/Jannsen JNJ-78436735 vaccine is based upon a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector, which encodes the full-length, stabilized S-glycoprotein of SARS-CoV-2. The currently reported results of the phase 1 and 2 clinical study indicated that 805 volunteers (402 participants between ages 18 and 55 years and 403 individuals aged ≥ 65 years) were randomized to receive a single or double dose of either 5 x 10¹⁰ viral particles per 0.5 mL (low dose) or 1 x 10¹¹ viral particles per 0.5 mL (high dose), each compared with a placebo group. Incidence of seroconversion to binding antibodies against the full-length stabilized S-glycoprotein, as measured by ELISA, showed ≥ 96% seroconversion by day 29 after the first dose. The incidence of seroconversion to neutralizing antibodies was ≥ 90% as early as early as 29 days after the first of either dose. In this study, neutralization activity was measured using the wild-type virus microneutralization assay based on the Victoria/1/2020/ SARS-CoV-2 strain.¹⁵ We note that the data related to this study have been partially reported and additional information will be available when each participant will have received the second dose.

In a large phase 3 clinical trial with 40,000 participants aged between 18 and 100 years, the Johnson and Johnson/Jannsen JNJ-78436735 vaccine, given as single dose of 5 x 10¹⁰ viral particles per 0.5 mL, met 65.5% clinical efficacy in the likelihood of being affected by symptomatic COVID-19 ≥ 28 days postimmunization.¹⁶ In this study, the vaccine efficacy was found to have a geographic distribution with highest efficacy in the US (74.4%), followed by Latin America (64.7%) where Brazil showed a predominance of the P2 COVID-19 lineage (64.7%), and Africa (52%) where the B.1.351 lineage was most frequent (94.5%). The vaccine also proved to be effective in reducing the likelihood of asymptomatic seroconversion, as measured by the level of a non-S protein, eg, 0.7% of positive cases in the vaccine group vs 2.8% in the placebo group. Immunological data indicated that the vaccine response was mainly driven by T-helper 1 lymphocytes. As of April 13, 2021 the FDA has recommend suspending the administration of the Johnson and Johnson/Janssen vaccine due to the occurrence of severe blood clots reported in a 6 subjects out of ~6.8 millions administered doses.¹

It is noteworthy to highlight that all vaccines reduced the likelihood of hospitalizations and deaths due to COVID-19.

As of April 17, 2021, the CDC reports that more than 130 million (40%) Americans, nearly 1/3 of the population, have received at least 1 dose of any of the 3 available vaccines, including 4.6 million at the VHA.¹⁷ Using the Vaccine Adverse Event Reporting System and v-safe, the US is conducting what has been defined the most “intense and comprehensive safety monitoring in the US history.”¹⁸ Thus far, data affirm the overall safety of the available vaccines against COVID-19. Individuals should not receive the COVID-19 vaccines if they have had a severe allergic reaction to any ingredient in the vaccine or a severe allergic reaction to a prior dose of the vaccine. Additionally, individuals who have received convalescent plasma should wait 90 days before getting the COVID-19 vaccine.

Vaccination for Persons with MS

PwMS or those on immunosuppressive medications were excluded from the clinical trial led by Pfizer-BioNTech. There is no mention of MS as comorbidity in the study from Moderna, although this condition is not listed as an exclusion criterion either. The results of the phase 3 clinical trial for the Johnson and Johnson/Janssen vaccine are not fully public yet, thus this information is not known as well. As a result, the use of this vaccine in pwMS under immunomodulatory agents is based on previous knowledge of other vaccines. Evidence is growing for the safety of the BNT162b2 COVID-19 vaccination in pwMS.¹⁹ Data regarding COVID-19 efficacy and safety are still largely based on previous knowledge on other vaccines.^20,21

Immunization of pwMS is considered safe and should proceed with confidence in those persons who have no other contraindication to receive a vaccine. A fundamental problem for pwMS treated with immunomodulatory or immunosuppressive medications is whether the vaccine will remain safe or be able to solicit an adequate immune response.^20,21 As of the time of publication 2021, there is consensus that mRNA based or inactivated vaccines are also considered safe in pwMS undergoing immunomodulatory or immunosuppressive treatments.^20-23 We advise a one-on-one conversation between each veteran with MS and their primary neurologist to understand the importance of the vaccination, the minimal risks associated with it and if any specific treatment modification should be made.

To provide guidance, the National MS Society released a position statement that is regularly updated.²² Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. In addition, on the basis of available literature and the American Academy of Neurology recommendations on the use of vaccines in general, the following recommendations are proposed.^20-23

Recommendation 1: injections, orals, and natalizumab. Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. Neither delay in start nor adjustments in dosing or timing of administration are advised for pwMS taking currently available either generic or brand formulations of β interferons, glatiramer acetate, teriflunomide, dimethyl or monomethyl fumarate, or natalizumab.²²

Recommendation 2: anti-CD20 monoclonal infusions. As an attenuated humoral response is predicted in pwMS treated with anti-CD20 monoclonal infusions, coordinating the timing of vaccination with treatment schedule may maximize efficacy of the vaccine. Whenever possible, it is advised to be vaccinated ≥ 12 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting anti-CD20 monoclonal infusions are advised to be fully vaccinated first and start these medications ≥ 2 to 4 weeks later.²²

Recommendation 3: alemtuzumab infusion. Given its effect on CD52+ cells, it is advised to be vaccinated ≥ 24 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting alemtuzumab infusions are advised to get fully vaccinated first and start this medication 4 weeks or more after completing the vaccine.²²

Recommendation 4: sphingosine 1 phosphate receptor modulators, oral cladribine, and ofatumumab. PwMS starting any of these medications are advised to be fully vaccinated first and start these medications 2 to 4 weeks after completing the vaccine. PwMS already on those medications are not advised to change the schedule of administration. When possible, though, one should resume the dose of cladribine or ofatumumab 2 to 4 weeks after the last dose of the vaccine. ²⁰

Notably, all these recommendations hold true when there is enough disease stability to allow delaying treatment. We also add that it remains unclear if persons with an overall very low number of lymphocytes will be able to elicit a strong reaction to the vaccine. Blood collection and analysis of white blood cell count and lymphocyte subset estimates should be obtained in those persons with a markedly suppressed immune system. Whenever possible, to maximize outcome, timing the vaccination with treatment should be considered in those persons with a markedly reduced number of T-helper 1 cells.

Vaccination for Veterans

Currently the VHA is offering to veterans the Pfizer and Moderna COVID-19 vaccines with FDA EUAs. In accordance with FDA regulations, the VHA has paused administration of the Johnson and Johnson/Janssen vaccine. The VHA has launched its vaccination program in December 2020 by first providing the vaccine to health care personnel, nursing home patients, spinal cord injury patients, chemotherapy patients, dialysis and transplant patients, as well as homeless veterans. Most VA health care systems have passed this phase and are now able to provide vaccines to veterans with MS.

In December 2020, the MSCoE released a position statement regarding the importance and safety of the COVID-19 vaccine for veterans with MS.²⁴ This statement will be updated on a regular basis as new information becomes available from major organizations like the National MS Society, FDA, CDC, and World Health Organization (WHO) or relevant literature.

Conclusions

Older veterans with progressive MS and associated comorbidities are at higher risk of death should they be infected by COVID-19. Fortunately, we live in a time where vaccines are recognized as a critical tool to prevent this infection and to significantly reduce its morbidity and mortality. Yet, hesitancy to vaccinate has been identified as one of the most important threats to public health by the WHO in 2019.²⁵ Understandably such hesitancy is even more profound for the COVID-19 vaccine, which is being administered under an EUA. In light of this indecision, and given the current state of the pandemic, we urge health care providers to educate every veteran about the benefits of being vaccinated against COVID-19. Within the VHA, a solid campaign of vaccination has been put in place at an unprecedented speed.

Health care providers interacting with veterans with MS are encouraged to use the MSCoE website (www.va.gov/ms) for any questions or concerns, or to reach out to MSCoE staff. It is vitally important that our community of veterans receives appropriate education on the importance of this vaccination for their own safety, for that of their household and society.

This article has been updated to reflect new US Food and Drug Administration and Centers for Disease Control and Prevention recommendations to pause administration of the Johnson and Johnson Jansen (JNJ-78436735) COVID-19 vaccine.¹

Since the outbreak of the pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),a plethora of studies have been performed to increase our knowledge of its associated illness COVID-19.² There is no cure for COVID-19, which can be lethal. In the absence of a cure, preventive measures are of vital importance. In order to help prevent the spread of the virus, the Centers for Diseases Control and Prevention (CDC) advocates for: (1) the use of a face mask over the mouth and nose; (2) a minimum of 6-foot distance between individuals; and (3) avoidance of gatherings.As of March 2021, the US Food and Drug Administration (FDA) approved 3 vaccines for the prevention of COVID-19, under an emergency use authorization (EUA).^3-5

COVID-19 and Multiple Sclerosis

Since the beginning of the pandemic, neurologists have faced a new challenge—determining whether persons with multiple sclerosis (pwMS) were more at risk than others of becoming ill from COVID-19 or were destined for a worse outcome. The National MS Society has advised a personalized approach in relation to particularly vulnerable persons when needed and has also initiated worldwide registries to collect information regarding incidence and outcome of COVID-19 in pwMS. Accordingly, through the MS Center of Excellence (MSCoE), the Veterans Health Administration (VHA) has established a national registry assembling data regarding COVID-19 in veterans with MS.

A recent descriptive literature review summarized the outcomes of 873 persons with both MS and COVID-19 and reported that about 36% of COVID-19 cases were treated with B-cell depleting therapies (ocrelizumab or rituximab).⁶ This proportion was relatively higher when compared with other disease modifying agents. Of those who became infected with SARS-CoV-2, death from COVID-19 occurred in about 4%, and an additional 3% required assisted invasive or noninvasive ventilation. Persons reported to have passed away from COVID-19 generally were older; had progressive MS; or had associated comorbidities such as obesity, hypertension, heart or lung conditions, or cancers. Of these, 50% were not on any disease modifying agent, 25% were on B-cell depleting therapies (ocrelizumab or rituximab), and the remaining 25% were on various medications for MS. It is important to highlight that no formal statistical analyses were performed in this review. On the contrary, in the recently published Italian report on 844 pwMS who had suspected or confirmed COVID-19, the authors used univariate and multivariate models to analyze their findings and noted that the use of ocrelizumab was significantly associated with a worse clinical outcome.⁷ These authors also identified age, sex, disability score, and recent (within 1 month) use of steroids as risk factors for a severe COVID-19 outcome. The incidence of death from COVID-19 in this cohort was 1.54%.

The recently published data from the North American Registry of the National MS Society based on 1,626 patients reported a 3.3% incidence of death from COVID-19.⁸ The following factors were identified as risks for worse outcome: male sex, nonambulatory status, age, Black race, and cardiovascular disease. The use of rituximab, ocrelizumab, and steroids (the latter medication over the preceding 2 months) increased the risks of hospitalization for COVID-19.

COVID-19 Vaccines

Of the 3 available vaccines, the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine is approved for individuals aged ≥ 16 years, while the Moderna COVID-19 (mRNA-1273) and the Johnson and Johnson/Jannsen COVID-19 (JNJ-78436735) vaccines are approved for individuals aged ≥ 18 years, though the latter vaccine has been temporarily suspended.^1,3-5 The EUAs were released following the disclosure of the results of 3 phase 3 clinical trials and several phase 1 and 2 clinical trials.^9-16

The BNT162b2 vaccine from Pfizer-BioNTech encodes the SARS-CoV-2 full-length spike protein (S) in prefusion conformation locked by the mutation in 2 prolines.⁹ Differently from the BNT162b2 vaccine, the BNT162b1 vaccine encodes a secreted trimerized SARS-CoV-2 receptor–binding domain. The S-glycoprotein is required for viral entry, as implicated in host cell attachment, and is the target of the neutralizing antibodies. In a phase 1 clinical study on 195 volunteers treated with BNT162b1 (10 mg, 20 mg, 30 mg, or 100 mg doses) or BNT162b2 (10 mg, 20 mg, or 30 mg doses) vaccines or placebo 21 days apart, both the binding and neutralizing antibody response was found to be age and “somewhat” dose dependent.⁹

Higher neutralization titers were measured at day 28 and 35 (7 and 14 days after the second dose, respectively) and compared with titers of persons who recovered from a COVID-19 infection.⁹ Serum neutralization was measured using a fluorescence-based high-throughput neutralization assay, while binding activity was assessed using the receptor-binding domain (RBD)–binding or S1-binding IgG direct Luminex immunoassays.

The overall reactogenicity/immunogenicity profile of BNT162b2 administered twice (30 mg each time) led to its selection for the phase 3 clinical trial.^9,10 In a large phase 3 clinical trial on 43,458 participants, the BNT162b2 vaccine given at 30 mg doses 21 days apart conferred 95% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁰ No safety concerns to stop the trial were identified, though related severe and life-threatening events were reported in 0.3% and 0.1% of the volunteers, respectively. We note that these incidence rates were the same for the treated and the placebo group.

The mRNA-1273 vaccine from Moderna also encodes the SARS-CoV-2 S-glycoprotein. In a dose escalation phase 1 trial of 45 participants aged between 18 and 55 years (25 mg, 100 mg or 250 mg, given at days 1 and 29) and 40 participants aged ≥ 57 years (25 mg and 100 mg, given at days 1 and 29), a dose-dependent effect was observed for both binding (receptor-binding domain and S-2p IgG on enzyme-linked immunosorbent assay [ELISA])and neutralizing antibodies (SARS-CoV-2 nanoluciferase high-throughput neutralization assay, focus reduction neutralization test mNeonGreen and SARS-CoV-2 plaque-reduction neutralization testing assay) development.^11,12 The geometric mean of both binding and neutralizing antibodies declined over time but persisted high as late as 119 days after the first burst of 100 mg dose.¹³ The same dose of the vaccine also elicited a strong T helper-1 response with little T helper-2 response across all ages.¹¹ The strength of the memory cellular response remains to be defined and is the subject of ongoing investigations. In a large phase 3 clinical trial with 30,420 participants, the Moderna COVID-19 mRNA-1273 vaccine, given 28 days apart at the dose of 100 mg, met 94.1% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁴

Less than 0.1% of volunteers in both groups withdrew from the trial due to adverse effects (AEs); 0.5% in the placebo group and 0.3% in the treated group had AEs after the first dose, which precluded receiving the second dose.¹⁴

The Johnson and Johnson/Jannsen JNJ-78436735 vaccine is based upon a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector, which encodes the full-length, stabilized S-glycoprotein of SARS-CoV-2. The currently reported results of the phase 1 and 2 clinical study indicated that 805 volunteers (402 participants between ages 18 and 55 years and 403 individuals aged ≥ 65 years) were randomized to receive a single or double dose of either 5 x 10¹⁰ viral particles per 0.5 mL (low dose) or 1 x 10¹¹ viral particles per 0.5 mL (high dose), each compared with a placebo group. Incidence of seroconversion to binding antibodies against the full-length stabilized S-glycoprotein, as measured by ELISA, showed ≥ 96% seroconversion by day 29 after the first dose. The incidence of seroconversion to neutralizing antibodies was ≥ 90% as early as early as 29 days after the first of either dose. In this study, neutralization activity was measured using the wild-type virus microneutralization assay based on the Victoria/1/2020/ SARS-CoV-2 strain.¹⁵ We note that the data related to this study have been partially reported and additional information will be available when each participant will have received the second dose.

In a large phase 3 clinical trial with 40,000 participants aged between 18 and 100 years, the Johnson and Johnson/Jannsen JNJ-78436735 vaccine, given as single dose of 5 x 10¹⁰ viral particles per 0.5 mL, met 65.5% clinical efficacy in the likelihood of being affected by symptomatic COVID-19 ≥ 28 days postimmunization.¹⁶ In this study, the vaccine efficacy was found to have a geographic distribution with highest efficacy in the US (74.4%), followed by Latin America (64.7%) where Brazil showed a predominance of the P2 COVID-19 lineage (64.7%), and Africa (52%) where the B.1.351 lineage was most frequent (94.5%). The vaccine also proved to be effective in reducing the likelihood of asymptomatic seroconversion, as measured by the level of a non-S protein, eg, 0.7% of positive cases in the vaccine group vs 2.8% in the placebo group. Immunological data indicated that the vaccine response was mainly driven by T-helper 1 lymphocytes. As of April 13, 2021 the FDA has recommend suspending the administration of the Johnson and Johnson/Janssen vaccine due to the occurrence of severe blood clots reported in a 6 subjects out of ~6.8 millions administered doses.¹

It is noteworthy to highlight that all vaccines reduced the likelihood of hospitalizations and deaths due to COVID-19.

As of April 17, 2021, the CDC reports that more than 130 million (40%) Americans, nearly 1/3 of the population, have received at least 1 dose of any of the 3 available vaccines, including 4.6 million at the VHA.¹⁷ Using the Vaccine Adverse Event Reporting System and v-safe, the US is conducting what has been defined the most “intense and comprehensive safety monitoring in the US history.”¹⁸ Thus far, data affirm the overall safety of the available vaccines against COVID-19. Individuals should not receive the COVID-19 vaccines if they have had a severe allergic reaction to any ingredient in the vaccine or a severe allergic reaction to a prior dose of the vaccine. Additionally, individuals who have received convalescent plasma should wait 90 days before getting the COVID-19 vaccine.

Vaccination for Persons with MS

PwMS or those on immunosuppressive medications were excluded from the clinical trial led by Pfizer-BioNTech. There is no mention of MS as comorbidity in the study from Moderna, although this condition is not listed as an exclusion criterion either. The results of the phase 3 clinical trial for the Johnson and Johnson/Janssen vaccine are not fully public yet, thus this information is not known as well. As a result, the use of this vaccine in pwMS under immunomodulatory agents is based on previous knowledge of other vaccines. Evidence is growing for the safety of the BNT162b2 COVID-19 vaccination in pwMS.¹⁹ Data regarding COVID-19 efficacy and safety are still largely based on previous knowledge on other vaccines.^20,21

Immunization of pwMS is considered safe and should proceed with confidence in those persons who have no other contraindication to receive a vaccine. A fundamental problem for pwMS treated with immunomodulatory or immunosuppressive medications is whether the vaccine will remain safe or be able to solicit an adequate immune response.^20,21 As of the time of publication 2021, there is consensus that mRNA based or inactivated vaccines are also considered safe in pwMS undergoing immunomodulatory or immunosuppressive treatments.^20-23 We advise a one-on-one conversation between each veteran with MS and their primary neurologist to understand the importance of the vaccination, the minimal risks associated with it and if any specific treatment modification should be made.

To provide guidance, the National MS Society released a position statement that is regularly updated.²² Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. In addition, on the basis of available literature and the American Academy of Neurology recommendations on the use of vaccines in general, the following recommendations are proposed.^20-23

Recommendation 1: injections, orals, and natalizumab. Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. Neither delay in start nor adjustments in dosing or timing of administration are advised for pwMS taking currently available either generic or brand formulations of β interferons, glatiramer acetate, teriflunomide, dimethyl or monomethyl fumarate, or natalizumab.²²

Recommendation 2: anti-CD20 monoclonal infusions. As an attenuated humoral response is predicted in pwMS treated with anti-CD20 monoclonal infusions, coordinating the timing of vaccination with treatment schedule may maximize efficacy of the vaccine. Whenever possible, it is advised to be vaccinated ≥ 12 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting anti-CD20 monoclonal infusions are advised to be fully vaccinated first and start these medications ≥ 2 to 4 weeks later.²²

Recommendation 3: alemtuzumab infusion. Given its effect on CD52+ cells, it is advised to be vaccinated ≥ 24 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting alemtuzumab infusions are advised to get fully vaccinated first and start this medication 4 weeks or more after completing the vaccine.²²

Recommendation 4: sphingosine 1 phosphate receptor modulators, oral cladribine, and ofatumumab. PwMS starting any of these medications are advised to be fully vaccinated first and start these medications 2 to 4 weeks after completing the vaccine. PwMS already on those medications are not advised to change the schedule of administration. When possible, though, one should resume the dose of cladribine or ofatumumab 2 to 4 weeks after the last dose of the vaccine. ²⁰

Notably, all these recommendations hold true when there is enough disease stability to allow delaying treatment. We also add that it remains unclear if persons with an overall very low number of lymphocytes will be able to elicit a strong reaction to the vaccine. Blood collection and analysis of white blood cell count and lymphocyte subset estimates should be obtained in those persons with a markedly suppressed immune system. Whenever possible, to maximize outcome, timing the vaccination with treatment should be considered in those persons with a markedly reduced number of T-helper 1 cells.

Vaccination for Veterans

Currently the VHA is offering to veterans the Pfizer and Moderna COVID-19 vaccines with FDA EUAs. In accordance with FDA regulations, the VHA has paused administration of the Johnson and Johnson/Janssen vaccine. The VHA has launched its vaccination program in December 2020 by first providing the vaccine to health care personnel, nursing home patients, spinal cord injury patients, chemotherapy patients, dialysis and transplant patients, as well as homeless veterans. Most VA health care systems have passed this phase and are now able to provide vaccines to veterans with MS.

In December 2020, the MSCoE released a position statement regarding the importance and safety of the COVID-19 vaccine for veterans with MS.²⁴ This statement will be updated on a regular basis as new information becomes available from major organizations like the National MS Society, FDA, CDC, and World Health Organization (WHO) or relevant literature.

Conclusions

Older veterans with progressive MS and associated comorbidities are at higher risk of death should they be infected by COVID-19. Fortunately, we live in a time where vaccines are recognized as a critical tool to prevent this infection and to significantly reduce its morbidity and mortality. Yet, hesitancy to vaccinate has been identified as one of the most important threats to public health by the WHO in 2019.²⁵ Understandably such hesitancy is even more profound for the COVID-19 vaccine, which is being administered under an EUA. In light of this indecision, and given the current state of the pandemic, we urge health care providers to educate every veteran about the benefits of being vaccinated against COVID-19. Within the VHA, a solid campaign of vaccination has been put in place at an unprecedented speed.

Health care providers interacting with veterans with MS are encouraged to use the MSCoE website (www.va.gov/ms) for any questions or concerns, or to reach out to MSCoE staff. It is vitally important that our community of veterans receives appropriate education on the importance of this vaccination for their own safety, for that of their household and society.

Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.

Sean Warren/iStockphoto.com

Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.

It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.

“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.

Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.

“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”

Novavax deliberately sought an HBCU to work with on this trial to help people of color feel more at ease and increase minority participation. Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.

“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
 

Building more representative clinical trials

For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.

Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.

Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.

“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”

Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
 

A trial designed to engender trust

Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.

“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”

Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.

“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”

There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.

Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.

From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.

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

Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.

Sean Warren/iStockphoto.com

Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.

It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.

“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.

Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.

“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”

Novavax deliberately sought an HBCU to work with on this trial to help people of color feel more at ease and increase minority participation. Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.

“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
 

Building more representative clinical trials

For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.

Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.

Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.

“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”

Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
 

A trial designed to engender trust

Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.

“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”

Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.

“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”

There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.

Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.

From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.

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

Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.

Sean Warren/iStockphoto.com

Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.

It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.

“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.

Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.

“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”

Novavax deliberately sought an HBCU to work with on this trial to help people of color feel more at ease and increase minority participation. Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.

“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
 

Building more representative clinical trials

For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.

Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.

Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.

“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”

Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
 

A trial designed to engender trust

Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.

“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”

Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.

“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”

There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.

Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.

From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.

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

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹ The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

• The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
• Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
• Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
• Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-­related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰ Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

• 46% expressed a lack of knowledge of the hazards of sun exposure
• 44% did not recall ever receiving medical advice regarding sun protection
• 89% did not wear sun-protective clothing
• 86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-­determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

• annually—when there is no history of skin cancer
• every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
• every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
• every 1 to 3 months—when there is a history of metastatic disease.

Continue to: Other risk factors...

Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following^{1,20,21,24-26}:

• male gender, fair skin, history of childhood sunburn, history of smoking
• lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
• immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
• immunosuppression with cyclosporine, compared to tacrolimus
• an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
• antithymocyte globulin within the first year posttransplantation.

Regular screening of skin is important in the solid organ transplant population.

Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.¹⁵ AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.²² Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.²²

Sun-protective measures (TABLE 1^{1,11,12,15,19-23}). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include

• daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions²³
• sun-protective clothing (pants, long sleeves, hat, sunglasses)²³
• avoidance of tanning salons.¹⁵

SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.¹⁵

Recommendations for treatment

Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.

Continue to: Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-­specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac

Diclofenac is a nonsteroidal anti-­inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and ­cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

Continue to: Pregnancy must be avoided...

Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.²⁷

Capecitabine is typically initiated with the help of Medical Oncology.^27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.³⁹ Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.²⁷

HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.^4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.^51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.¹⁹

The role of immunosuppression reduction and immunosuppressive replacement

Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.²⁷ In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.⁵³ Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.^1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.

Recommendations: Treating cSCC

Risk should guide strategy

Consider chemoprophylactic therapy for solid organ transplant recipients who have had multiple prior cutaneous malignancies or multiple AKs.

Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.^3,58,59

Continue to: Risk factors for invasive growth...

Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.⁶⁰ The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework⁶⁰:

• any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
• ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
• > 1 cm on cheeks, forehead, neck, and scalp
• > 2 cm on the trunk and extremities.

In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:

• poor differentiation
• deep extension of the tumor into subcutaneous fat
• perineural invasion or inflammation
• perivascular or intravascular invasion.

Treatment modalities

Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue^3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.^3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.³

Pregnancy must be avoided while taking an oral retinoid; because of its persistence, acitretin should generally be avoided in patients of childbearing potential.

Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.^3,7,58-61)

Recommendations: Treating BCC

BCC in SOTRs is treated similarly (TABLE 3^3,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.³ Standard management after biopsy is either^3,61:

• Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
• excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).

Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.³

CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; [email protected]

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹ The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

• The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
• Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
• Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
• Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-­related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰ Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

• 46% expressed a lack of knowledge of the hazards of sun exposure
• 44% did not recall ever receiving medical advice regarding sun protection
• 89% did not wear sun-protective clothing
• 86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-­determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

• annually—when there is no history of skin cancer
• every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
• every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
• every 1 to 3 months—when there is a history of metastatic disease.

Continue to: Other risk factors...

Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following^{1,20,21,24-26}:

• male gender, fair skin, history of childhood sunburn, history of smoking
• lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
• immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
• immunosuppression with cyclosporine, compared to tacrolimus
• an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
• antithymocyte globulin within the first year posttransplantation.

Regular screening of skin is important in the solid organ transplant population.

Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.¹⁵ AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.²² Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.²²

Sun-protective measures (TABLE 1^{1,11,12,15,19-23}). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include

• daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions²³
• sun-protective clothing (pants, long sleeves, hat, sunglasses)²³
• avoidance of tanning salons.¹⁵

SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.¹⁵

Recommendations for treatment

Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.

Continue to: Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-­specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac

Diclofenac is a nonsteroidal anti-­inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and ­cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

Continue to: Pregnancy must be avoided...

Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.²⁷

Capecitabine is typically initiated with the help of Medical Oncology.^27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.³⁹ Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.²⁷

HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.^4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.^51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.¹⁹

The role of immunosuppression reduction and immunosuppressive replacement

Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.²⁷ In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.⁵³ Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.^1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.

Recommendations: Treating cSCC

Risk should guide strategy

Consider chemoprophylactic therapy for solid organ transplant recipients who have had multiple prior cutaneous malignancies or multiple AKs.

Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.^3,58,59

Continue to: Risk factors for invasive growth...

Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.⁶⁰ The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework⁶⁰:

• any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
• ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
• > 1 cm on cheeks, forehead, neck, and scalp
• > 2 cm on the trunk and extremities.

In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:

• poor differentiation
• deep extension of the tumor into subcutaneous fat
• perineural invasion or inflammation
• perivascular or intravascular invasion.

Treatment modalities

Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue^3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.^3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.³

Pregnancy must be avoided while taking an oral retinoid; because of its persistence, acitretin should generally be avoided in patients of childbearing potential.

Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.^3,7,58-61)

Recommendations: Treating BCC

BCC in SOTRs is treated similarly (TABLE 3^3,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.³ Standard management after biopsy is either^3,61:

• Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
• excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).

Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.³

CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; [email protected]

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹ The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

• The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
• Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
• Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
• Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-­related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰ Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

• 46% expressed a lack of knowledge of the hazards of sun exposure
• 44% did not recall ever receiving medical advice regarding sun protection
• 89% did not wear sun-protective clothing
• 86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-­determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

• annually—when there is no history of skin cancer
• every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
• every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
• every 1 to 3 months—when there is a history of metastatic disease.

Continue to: Other risk factors...

Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following^{1,20,21,24-26}:

• male gender, fair skin, history of childhood sunburn, history of smoking
• lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
• immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
• immunosuppression with cyclosporine, compared to tacrolimus
• an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
• antithymocyte globulin within the first year posttransplantation.

Regular screening of skin is important in the solid organ transplant population.

Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.¹⁵ AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.²² Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.²²

Sun-protective measures (TABLE 1^{1,11,12,15,19-23}). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include

• daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions²³
• sun-protective clothing (pants, long sleeves, hat, sunglasses)²³
• avoidance of tanning salons.¹⁵

SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.¹⁵

Recommendations for treatment

Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.

Continue to: Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-­specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac

Diclofenac is a nonsteroidal anti-­inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and ­cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

Continue to: Pregnancy must be avoided...

Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.²⁷

Capecitabine is typically initiated with the help of Medical Oncology.^27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.³⁹ Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.²⁷

HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.^4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.^51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.¹⁹

The role of immunosuppression reduction and immunosuppressive replacement

Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.²⁷ In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.⁵³ Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.^1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.

Recommendations: Treating cSCC

Risk should guide strategy

Consider chemoprophylactic therapy for solid organ transplant recipients who have had multiple prior cutaneous malignancies or multiple AKs.

Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.^3,58,59

Continue to: Risk factors for invasive growth...

Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.⁶⁰ The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework⁶⁰:

• any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
• ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
• > 1 cm on cheeks, forehead, neck, and scalp
• > 2 cm on the trunk and extremities.

In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:

• poor differentiation
• deep extension of the tumor into subcutaneous fat
• perineural invasion or inflammation
• perivascular or intravascular invasion.

Treatment modalities

Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue^3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.^3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.³

Pregnancy must be avoided while taking an oral retinoid; because of its persistence, acitretin should generally be avoided in patients of childbearing potential.

Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.^3,7,58-61)

Recommendations: Treating BCC

BCC in SOTRs is treated similarly (TABLE 3^3,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.³ Standard management after biopsy is either^3,61:

• Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
• excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).

Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.³

CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; [email protected]

An estimated 20 million patients in the United States have a substance use disorder (SUD), with hundreds of millions of prescriptions for controlled substances written annually. Consequently, urine drug screening (UDS) has become widely utilized to evaluate and treat patients with an SUD or on chronic opioid or benzodiazepine therapy.¹

Used appropriately, UDS can be a valuable tool; there is ample evidence, however, that it has been misused, by some physicians, to stigmatize patients who use drugs of abuse,² profile patients racially,² profit from excessive testing,³ and inappropriately discontinue treatment.⁴

A patient-centered approach. We have extensive clinical experience in the use and interpretation of urine toxicology, serving as clinical leads in busy family medicine residency practices that care for patients with SUDs, and are often consulted regarding patients on chronic opioid or benzodiazepine therapy. We have encountered countless situations in which the correct interpretation of UDS is critical to providing care.

Over time, and after considerable trial and error, we developed the patient-centered approach to urine toxicology described in this article. We believe that the medical evidence strongly supports our approach to the appropriate use and interpretation of urine toxicology in clinical practice. Our review here is intended as a resource when you consider implementing a UDS protocol or are struggling with the management of unexpected results.

Urine toxicology for therapeutic drug monitoring

Prescribing a controlled substance carries inherent risks, including diversion, nonmedical use, and development of an SUD. Prescribed medications, particularly opioids and benzodiazepines, have been linked to a large increase in overdose deaths over the past decade.⁵ Several strategies have been investigated to mitigate risk (see “How frequently should a patient be tested?,” later in the article).

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed a substance use disorder—has been shown to be highly inaccurate.

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed an SUD—has been shown to be highly inaccurate. Implicit racial bias might affect the physician’s judgment, leading to changes in testing and test interpretation. For example, Black patients were found to be 10% more likely to have drug screening ordered while being treated with long-term opioid therapy and 2 to 3 times more likely to have their medication discontinued as a result of a marijuana- or cocaine-positive test.²

Other studies have shown that testing patients for “bad behavior,” so to speak—reporting a prescription lost or stolen, consuming more than the prescribed dosage, visiting the office without an appointment, having multiple drug intolerances and allergies, and making frequent telephone calls to the practice—is ineffective.⁶ Patients with these behaviors were slightly more likely to unexpectedly test positive, or negative, on their UDS; however, many patients without suspect behavior also were found to have abnormal toxicology results.⁶ Data do not support therapeutic drug monitoring only of patients selected on the basis of aberrant behavior.⁶

Continue to: Questions and concerns about urine drug screening

Why not just ask the patient? Studies have evaluated whether patient self-reporting of adherence is a feasible alternative to laboratory drug screening. Regrettably, patients have repeatedly been shown to underreport their use of both prescribed and illicit drugs.^7,8

That question leads to another: Why do patients lie to their physician? It is easy to assume malicious intent, but a variety of obstacles might dissuade a patient from being fully truthful with their physician:

• Monetary gain. A small, but real, percentage of medications are diverted by patients for this reason.⁹
• Addiction, pseudo-addiction due to tolerance, and self-medication for psychological symptoms are clinically treatable syndromes that can lead to underreporting of prescribed and nonprescribed drug and alcohol use.
• Shame. Addiction is a highly stigmatized disease, and patients might simply be ashamed to admit that they need treatment: 13% to 38% of patients receiving chronic opioid therapy in a pain management or primary care setting have a clinically diagnosable SUD.^10,11

Is consent needed to test or to share test results? Historically, UDS has been performed on patients without their consent or knowledge.¹² Patients give a urine specimen to their physician for a variety of reasons; it seems easy to “add on” UDS. Evidence is clear, however, that confronting a patient about an unexpected test result can make the clinical outcome worse—often resulting in irreparable damage to the patient–­physician relationship.^12,13 Unless the patient is experiencing a medical emergency, guidelines unanimously recommend obtaining consent prior to testing.^1,5,14

Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months.

Federal law requires written permission from the patient for the physician to disclose information about alcohol or substance use, unless the information is expressly needed to provide care during a medical emergency. Substance use is highly stigmatized, and patients might—legitimately—fear that sharing their history could undermine their care.^1,12,14

How frequently should a patient be tested? Experts recommend utilizing a risk-based strategy to determine the frequency of UDS.^1,5,15 Validated risk-assessment questionnaires include:

• Opioid Risk Tool for Opioid Use Disorder (ORT-OUD)^a
• Screener and Opioid Assessment for Patients With Pain–Revised (SOAPP-R)^b
• Diagnosis, Intractability, Risk and Efficacy (DIRE)^c
• Addiction Behaviors Checklist (ABC).^d

Continue to: Each of these tools...

Each of these tools takes less than 5 minutes to administer and can be used by a primary care physician to objectively quantify the risk of prescribing; there is no evidence for the use of 1 of these screeners over the others.¹⁵ It is recommended that you choose a questionnaire that works for you and incorporate the risk assessment into prescribing any high-risk medication.^1,5,15

Once you have completed an initial risk assessment, the frequency of UDS can be based on ongoing assessment that incorporates baseline testing, patient self-reporting, toxicology results, behavioral monitoring, and state database monitoring through a prescription drug monitoring program. Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months (FIGURE).¹⁵

Many state and federal agencies, health systems, employers, and insurers mandate the frequency of testing through guidelines or legislation. These regulations often are inconsistent with the newest medical evidence.¹⁵ Consult local guidelines and review the medical evidence and consensus recommendations on UDS.

What are the cost considerations in providing UDS? Insurers have been billed as much as $4000 for definitive chromatography testing (described later).³ This has led to insurance fraud, when drug-testing practices with a financial interest routinely use large and expensive test panels, test too frequently, or unnecessarily send for confirmatory or quantitative analysis of all positive tests.^3,14 Often, insurers refuse to pay for unnecessary testing, leaving patients with significant indebtedness.^3,14 Take time to review the evidence and consensus recommendations on UDS to avoid waste, potential accusations of fraud, and financial burden on your patients.

Urine toxicology for addiction treatment

UDS protocols in addiction settings are often different from those in which a controlled substance is being prescribed.

Continue to: Routine and random testing

Routine and random testing. Two common practices when treating addiction are to perform UDS on all patients, at every visit, or to test randomly.¹ These practices can be problematic, however. Routine testing at every visit can make urine-tampering more likely and is often unnecessary for stable patients. Random testing can reduce the risk of urine-tampering, but it is often difficult for primary care clinics to institute such a protocol. Some clinics have patients provide a urine specimen at every visit and then only send tests to the lab based on randomization.¹

Contingency management—a behavioral intervention in which a patient is rewarded, or their performance is reinforced, when they display evidence of positive change—is the most effective strategy used in addiction medicine to determine the frequency of patient visits and UDS.^14,16 High-risk patients with self-reported active substance use or UDS results consistent with substance use, or both, are seen more often; as their addiction behavior diminishes, visits and UDS become less frequent. If addiction behavior increases, the patient is seen more often. Keep in mind that addiction behavior decreases over months of treatment, not immediately upon initiation.^14,17 For contingency management to be successful, patient-centered interviewing and UDS will need to be employed frequently as the patient works toward meaningful change.¹⁴

The technology of urine drug screening

Two general techniques are used for UDS: immunoassay and chromatography. Each plays an important role in clinical practice; physicians must therefore maintain a basic understanding of the mechanism of each technique and their comparable advantages and disadvantages. Such an understanding allows for (1) matching the appropriate technique to the individual clinical scenario and (2) correctly interpreting results.

Immunoassay technology is used for point-of-care and rapid laboratory UDS, using antibodies to detect the drug or drug metabolite of interest. Antibodies utilized in immunoassays are designed to selectively bind a specific antigen—ie, a unique chemical structure within the drug of choice. Once bound, the antigen–antibody complex can be exploited for detection through various methods.

Chromatography–mass ­spectrometry is considered the gold standard for UDS, yielding confirmatory results. This is a 2-step process: Chromatography separates components within a specimen; mass spectrometry then identifies those components. Most laboratories employ liquid, rather than gas, chromatography. The specificity of the liquid chromatography–mass spectrometry method is such that a false-positive result is, essentially, impossible.¹⁸

Continue to: How is the appropriate tests elected for urine drug screening?

Variables that influence your choice of the proper test method include the clinical question at hand; cost; the urgency of obtaining results; and the stakes in that decision (ie, will the results be used to simply change the dosage of a medication or, of greater consequence, to determine fitness for employment or inform criminal justice decisions?). Each method of UDS has advantages that can be utilized and disadvantages that must be considered to obtain an accurate and useful result.

Immunoassay provides rapid results, is relatively easy to perform, and is, comparatively, inexpensive.^1,14 The speed of results makes this method particularly useful in settings such as the emergency department, where rapid results are crucial. Ease of use makes immunoassay ideal for the office, where non-laboratory staff can be trained to properly administer the test.

A major disadvantage of immunoassay technology, however, is interference resulting in both false-positive and false-negative results, which is discussed in detail in the next section. Immunoassay should be considered a screening test that yields presumptive results.

Liquid chromatography–mass spectrometry is exquisitely specific and provides confirmatory test results—major advantages of the method. However, specificity comes at a price: significantly increased cost and longer wait time for results (typically days, if specimens are sent out to a laboratory). These barriers can make it impractical to employ this method in routine practice.

Interpretation of results: Not so fast

Interpreting UDS results is not as simple as noting a positive or negative result. Physicians must understand the concept of interference, so that results can be appropriately interpreted and confirmed. This is crucial when results influence clinical decisions; inappropriate action, taken on the basis of presumptive results, can have severe consequences for the patient–provider relationship and the treatment plan.^1,14

Continue to: Interference falls into 2 categories...

Interference falls into 2 categories: variables inherent in the testing process and patient variables.

Obtain consent prior to performing urine drug screening, even if you are already collecting a specimen for other testing.

Antibody cross-reactivity. A major disadvantage of immunoassay technology is interference that results in false-positive and false-negative results.^19,20 The source of this interference is antibody cross-­reactivity—the degree to which an antibody binds to structurally similar compounds. Antibody–­antigen interactions are incredibly complex; although assay antibodies are engineered to specifically detect a drug class of interest, reactivity with other, structurally similar compounds is unavoidable.

Nevertheless, cross-reactivity is a useful phenomenon that allows broad testing for multiple drugs within a class. For example, most point-of-care tests for benzodiazepines reliably detect diazepam and chlordiazepoxide. Likewise, opiate tests reliably detect natural opiates, such as morphine and codeine. Cross-reactivity is not limitless, however; most benzodiazepine immunoassays have poor reactivity to clonazepam and lorazepam, making it possible that a patient taking clonazepam tests negative for benzodiazepine on an immunoassay.^14,20 Similarly, standard opioid tests have only moderate cross-reactivity for semisynthetic opioids, such as hydrocodone and hydromorphone; poor cross-r­eactivity for oxycodone and oxymorphone; and essentially no cross-­reactivity for full synthetics, such as fentanyl and methadone.¹⁴

It is the responsibility of the ordering physician to understand cross-reactivity to various drugs within a testing class.

Routine urine drug screening at every visit can make urine tampering more likely and is often unnecessary for stable patients.

Whereas weak cross-reactivity to drugs within a class can be a source of false-negative results, cross-reactivity to drugs outside the class of interest is a source of false-positive results. An extensive review of drugs that cause false-positive immunoassay screening tests is outside the scope of this article; commonly prescribed medications implicated in false-positive results are listed in TABLE 1.¹⁹

Continue to: In general...

In general, amphetamine immunoassays produce frequent false-positive results, whereas cocaine and cannabinoid assays are more specific.^1,18 Common over-the-counter medications, including nonsteroidal anti-inflammatory drugs, decongestants, and antacids, can yield false-positive results, highlighting the need to obtain a comprehensive medication list from patients, including over-the-counter and herbal medications, before ordering UDS. Because of the complexity of cross-reactivity, it might not be possible to identify the source of a false-positive result.¹⁴

Patient variables. Intentional effort to skew results is another source of interference. The frequency of this effort varies by setting and the potential consequences of results—eg, employment testing or substance use treatment—and a range of attempts have been reported in the literature.^21,22 Common practices are dilution, adulteration, and substitution.^20,23

• Dilution lowers the concentration of the drug of interest below the detection limit of the assay by directly adding water to the urine specimen, drinking copious amounts of fluid, taking a diuretic, or a combination of these practices.
• Adulteration involves adding a substance to urine that interferes with the testing mechanism: for example, bleach, household cleaners, eye drops, and even commercially available products expressly marketed to interfere with UDS.²⁴
• Substitution involves providing urine or a urine-like substance for testing that did not originate from the patient.

Methods to minimize patient-related interference include observed collection and specimen validity testing for pH, creatinine, and adulterants (TABLE 2).^1,15 Efforts to detect patient interference must be balanced against concerns about privacy, personnel resources, and the cost of expanded testing.^14,19,20

Additional aspects inherent to the testing process, such as cutoff concentrations and detection windows, can lead to interference. Laboratories must set reporting cutoffs, and specimens with a drug concentration present but below the cutoff value are reported as a negative result. Detection windows are complex and are influenced by inherent properties of the drug, including metabolic pathway and route and frequency of use.¹ A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported (TABLE 3^1,23).

Managing test results

Appropriate management of UDS results is built on the foundation of understanding the testing mechanism, selecting the correct test, and properly interpreting results. Drug testing is, ultimately, a therapeutic tool used to monitor treatment, provide reinforcement, and explore substance use behavior; results of testing should be employed to achieve those objectives.^1,4,14 A negative or expected UDS result can be utilized as positive reinforcement for a patient who is adherent to the treatment plan—much the way objective weight loss in an obese patient can provide encouragement to continue lifestyle changes.

Continue to: Test results should be presented...

Test results should be presented in an objective, nonconfrontational, and compassionate manner, not with stigmatizing language, such as “clean” or “dirty.”^1,13,14 Using stigmatizing terms such as “substance abuser” instead of “person with a substance use disorder” has been shown, even among highly trained health care professionals, to have a negative effect on patient care.¹³

A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported.

Inevitably, you will encounter an unexpected result, and therefore must develop a rational, systematic, and compassionate management approach. “Unexpected result” is a broad term that includes results that conflict with

• a patient’s self-report
• your understanding of what the patient is taking (using)
• prescribed medications
• a patient’s typical substance use pattern.

When faced with an unexpected test result, first, ensure that the result in question is reliable. If a screening test yields an unanticipated finding—especially if it conflicts with the patient’s self-reporting—make every effort to seek confirmation if you are going to be making a significant clinical decision because of the result.^1,14

Second, use your understanding of interference to consider the result in a broader context. If confirmatory results are inconsistent with a patient’s self-report, discuss whether there has been a break in the ­ph­ysician–patient relationship and emphasize that recurrent use or failure to adhere to a treatment plan has clear consequences.^1,14 Modify the treatment plan to address the inconsistent finding by escalating care, adjusting medications, and connecting the patient to additional resources.

Third, keep in mind that a positive urine test is not diagnostic of an SUD. Occasional drug use is extremely common¹⁷ and should not categorically lead to a change in the treatment plan. Addiction is, fundamentally, a disease of disordered reward, motivation, and behavior that is defined by the consequences of substance use, not substance use per se,²⁵ and an SUD diagnosis is complex, based on clinical history, physical examination, and laboratory testing. Similarly, a negative UDS result does not rule out an SUD.^4,10

Continue to: Fourth, patient dismissal...

Fourth, patient dismissal is rarely an appropriate initial response to UDS results. Regrettably, some physicians misinterpret urine toxicology results and inappropriately discharge patients on that basis.

In general, amphetamine immunoassays produce frequent falsepositive results, whereas cocaine and cannabinoid assays are more specific.

The Centers for Disease Control and Prevention guideline for prescribing opioids has increased utilization of UDS in primary care settings but does not provide the necessary education on proper use of the tool, which has resulted in a rise in misinterpretation and inappropriate discharge.^13,26

If recurrent aberrant behavior is detected (by history or urine toxicology), do not abruptly discontinue the patient’s medication(s). Inform the patient of your concern, taper medication, and refer the patient to addiction treatment. Abrupt discontinuation of an opioid or benzodiazepine can lead to significant harm.^1,14

CORRESPONDENCE
John Hayes, DO, Department of Family and Community Medicine, Medical College of Wisconsin, 1121 E North Avenue, Milwaukee, WI, 53212; [email protected]

An estimated 20 million patients in the United States have a substance use disorder (SUD), with hundreds of millions of prescriptions for controlled substances written annually. Consequently, urine drug screening (UDS) has become widely utilized to evaluate and treat patients with an SUD or on chronic opioid or benzodiazepine therapy.¹

Used appropriately, UDS can be a valuable tool; there is ample evidence, however, that it has been misused, by some physicians, to stigmatize patients who use drugs of abuse,² profile patients racially,² profit from excessive testing,³ and inappropriately discontinue treatment.⁴

A patient-centered approach. We have extensive clinical experience in the use and interpretation of urine toxicology, serving as clinical leads in busy family medicine residency practices that care for patients with SUDs, and are often consulted regarding patients on chronic opioid or benzodiazepine therapy. We have encountered countless situations in which the correct interpretation of UDS is critical to providing care.

Over time, and after considerable trial and error, we developed the patient-centered approach to urine toxicology described in this article. We believe that the medical evidence strongly supports our approach to the appropriate use and interpretation of urine toxicology in clinical practice. Our review here is intended as a resource when you consider implementing a UDS protocol or are struggling with the management of unexpected results.

Urine toxicology for therapeutic drug monitoring

Prescribing a controlled substance carries inherent risks, including diversion, nonmedical use, and development of an SUD. Prescribed medications, particularly opioids and benzodiazepines, have been linked to a large increase in overdose deaths over the past decade.⁵ Several strategies have been investigated to mitigate risk (see “How frequently should a patient be tested?,” later in the article).

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed a substance use disorder—has been shown to be highly inaccurate.

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed an SUD—has been shown to be highly inaccurate. Implicit racial bias might affect the physician’s judgment, leading to changes in testing and test interpretation. For example, Black patients were found to be 10% more likely to have drug screening ordered while being treated with long-term opioid therapy and 2 to 3 times more likely to have their medication discontinued as a result of a marijuana- or cocaine-positive test.²

Other studies have shown that testing patients for “bad behavior,” so to speak—reporting a prescription lost or stolen, consuming more than the prescribed dosage, visiting the office without an appointment, having multiple drug intolerances and allergies, and making frequent telephone calls to the practice—is ineffective.⁶ Patients with these behaviors were slightly more likely to unexpectedly test positive, or negative, on their UDS; however, many patients without suspect behavior also were found to have abnormal toxicology results.⁶ Data do not support therapeutic drug monitoring only of patients selected on the basis of aberrant behavior.⁶

Continue to: Questions and concerns about urine drug screening

Why not just ask the patient? Studies have evaluated whether patient self-reporting of adherence is a feasible alternative to laboratory drug screening. Regrettably, patients have repeatedly been shown to underreport their use of both prescribed and illicit drugs.^7,8

That question leads to another: Why do patients lie to their physician? It is easy to assume malicious intent, but a variety of obstacles might dissuade a patient from being fully truthful with their physician:

• Monetary gain. A small, but real, percentage of medications are diverted by patients for this reason.⁹
• Addiction, pseudo-addiction due to tolerance, and self-medication for psychological symptoms are clinically treatable syndromes that can lead to underreporting of prescribed and nonprescribed drug and alcohol use.
• Shame. Addiction is a highly stigmatized disease, and patients might simply be ashamed to admit that they need treatment: 13% to 38% of patients receiving chronic opioid therapy in a pain management or primary care setting have a clinically diagnosable SUD.^10,11

Is consent needed to test or to share test results? Historically, UDS has been performed on patients without their consent or knowledge.¹² Patients give a urine specimen to their physician for a variety of reasons; it seems easy to “add on” UDS. Evidence is clear, however, that confronting a patient about an unexpected test result can make the clinical outcome worse—often resulting in irreparable damage to the patient–­physician relationship.^12,13 Unless the patient is experiencing a medical emergency, guidelines unanimously recommend obtaining consent prior to testing.^1,5,14

Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months.

Federal law requires written permission from the patient for the physician to disclose information about alcohol or substance use, unless the information is expressly needed to provide care during a medical emergency. Substance use is highly stigmatized, and patients might—legitimately—fear that sharing their history could undermine their care.^1,12,14

How frequently should a patient be tested? Experts recommend utilizing a risk-based strategy to determine the frequency of UDS.^1,5,15 Validated risk-assessment questionnaires include:

• Opioid Risk Tool for Opioid Use Disorder (ORT-OUD)^a
• Screener and Opioid Assessment for Patients With Pain–Revised (SOAPP-R)^b
• Diagnosis, Intractability, Risk and Efficacy (DIRE)^c
• Addiction Behaviors Checklist (ABC).^d

Continue to: Each of these tools...

Each of these tools takes less than 5 minutes to administer and can be used by a primary care physician to objectively quantify the risk of prescribing; there is no evidence for the use of 1 of these screeners over the others.¹⁵ It is recommended that you choose a questionnaire that works for you and incorporate the risk assessment into prescribing any high-risk medication.^1,5,15

Once you have completed an initial risk assessment, the frequency of UDS can be based on ongoing assessment that incorporates baseline testing, patient self-reporting, toxicology results, behavioral monitoring, and state database monitoring through a prescription drug monitoring program. Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months (FIGURE).¹⁵

Many state and federal agencies, health systems, employers, and insurers mandate the frequency of testing through guidelines or legislation. These regulations often are inconsistent with the newest medical evidence.¹⁵ Consult local guidelines and review the medical evidence and consensus recommendations on UDS.

What are the cost considerations in providing UDS? Insurers have been billed as much as $4000 for definitive chromatography testing (described later).³ This has led to insurance fraud, when drug-testing practices with a financial interest routinely use large and expensive test panels, test too frequently, or unnecessarily send for confirmatory or quantitative analysis of all positive tests.^3,14 Often, insurers refuse to pay for unnecessary testing, leaving patients with significant indebtedness.^3,14 Take time to review the evidence and consensus recommendations on UDS to avoid waste, potential accusations of fraud, and financial burden on your patients.

Urine toxicology for addiction treatment

UDS protocols in addiction settings are often different from those in which a controlled substance is being prescribed.

Continue to: Routine and random testing

Routine and random testing. Two common practices when treating addiction are to perform UDS on all patients, at every visit, or to test randomly.¹ These practices can be problematic, however. Routine testing at every visit can make urine-tampering more likely and is often unnecessary for stable patients. Random testing can reduce the risk of urine-tampering, but it is often difficult for primary care clinics to institute such a protocol. Some clinics have patients provide a urine specimen at every visit and then only send tests to the lab based on randomization.¹

Contingency management—a behavioral intervention in which a patient is rewarded, or their performance is reinforced, when they display evidence of positive change—is the most effective strategy used in addiction medicine to determine the frequency of patient visits and UDS.^14,16 High-risk patients with self-reported active substance use or UDS results consistent with substance use, or both, are seen more often; as their addiction behavior diminishes, visits and UDS become less frequent. If addiction behavior increases, the patient is seen more often. Keep in mind that addiction behavior decreases over months of treatment, not immediately upon initiation.^14,17 For contingency management to be successful, patient-centered interviewing and UDS will need to be employed frequently as the patient works toward meaningful change.¹⁴

The technology of urine drug screening

Two general techniques are used for UDS: immunoassay and chromatography. Each plays an important role in clinical practice; physicians must therefore maintain a basic understanding of the mechanism of each technique and their comparable advantages and disadvantages. Such an understanding allows for (1) matching the appropriate technique to the individual clinical scenario and (2) correctly interpreting results.

Immunoassay technology is used for point-of-care and rapid laboratory UDS, using antibodies to detect the drug or drug metabolite of interest. Antibodies utilized in immunoassays are designed to selectively bind a specific antigen—ie, a unique chemical structure within the drug of choice. Once bound, the antigen–antibody complex can be exploited for detection through various methods.

Chromatography–mass ­spectrometry is considered the gold standard for UDS, yielding confirmatory results. This is a 2-step process: Chromatography separates components within a specimen; mass spectrometry then identifies those components. Most laboratories employ liquid, rather than gas, chromatography. The specificity of the liquid chromatography–mass spectrometry method is such that a false-positive result is, essentially, impossible.¹⁸

Continue to: How is the appropriate tests elected for urine drug screening?

Variables that influence your choice of the proper test method include the clinical question at hand; cost; the urgency of obtaining results; and the stakes in that decision (ie, will the results be used to simply change the dosage of a medication or, of greater consequence, to determine fitness for employment or inform criminal justice decisions?). Each method of UDS has advantages that can be utilized and disadvantages that must be considered to obtain an accurate and useful result.

Immunoassay provides rapid results, is relatively easy to perform, and is, comparatively, inexpensive.^1,14 The speed of results makes this method particularly useful in settings such as the emergency department, where rapid results are crucial. Ease of use makes immunoassay ideal for the office, where non-laboratory staff can be trained to properly administer the test.

A major disadvantage of immunoassay technology, however, is interference resulting in both false-positive and false-negative results, which is discussed in detail in the next section. Immunoassay should be considered a screening test that yields presumptive results.

Liquid chromatography–mass spectrometry is exquisitely specific and provides confirmatory test results—major advantages of the method. However, specificity comes at a price: significantly increased cost and longer wait time for results (typically days, if specimens are sent out to a laboratory). These barriers can make it impractical to employ this method in routine practice.

Interpretation of results: Not so fast

Interpreting UDS results is not as simple as noting a positive or negative result. Physicians must understand the concept of interference, so that results can be appropriately interpreted and confirmed. This is crucial when results influence clinical decisions; inappropriate action, taken on the basis of presumptive results, can have severe consequences for the patient–provider relationship and the treatment plan.^1,14

Continue to: Interference falls into 2 categories...

Interference falls into 2 categories: variables inherent in the testing process and patient variables.

Obtain consent prior to performing urine drug screening, even if you are already collecting a specimen for other testing.

Antibody cross-reactivity. A major disadvantage of immunoassay technology is interference that results in false-positive and false-negative results.^19,20 The source of this interference is antibody cross-­reactivity—the degree to which an antibody binds to structurally similar compounds. Antibody–­antigen interactions are incredibly complex; although assay antibodies are engineered to specifically detect a drug class of interest, reactivity with other, structurally similar compounds is unavoidable.

Nevertheless, cross-reactivity is a useful phenomenon that allows broad testing for multiple drugs within a class. For example, most point-of-care tests for benzodiazepines reliably detect diazepam and chlordiazepoxide. Likewise, opiate tests reliably detect natural opiates, such as morphine and codeine. Cross-reactivity is not limitless, however; most benzodiazepine immunoassays have poor reactivity to clonazepam and lorazepam, making it possible that a patient taking clonazepam tests negative for benzodiazepine on an immunoassay.^14,20 Similarly, standard opioid tests have only moderate cross-reactivity for semisynthetic opioids, such as hydrocodone and hydromorphone; poor cross-r­eactivity for oxycodone and oxymorphone; and essentially no cross-­reactivity for full synthetics, such as fentanyl and methadone.¹⁴

It is the responsibility of the ordering physician to understand cross-reactivity to various drugs within a testing class.

Routine urine drug screening at every visit can make urine tampering more likely and is often unnecessary for stable patients.

Whereas weak cross-reactivity to drugs within a class can be a source of false-negative results, cross-reactivity to drugs outside the class of interest is a source of false-positive results. An extensive review of drugs that cause false-positive immunoassay screening tests is outside the scope of this article; commonly prescribed medications implicated in false-positive results are listed in TABLE 1.¹⁹

Continue to: In general...

In general, amphetamine immunoassays produce frequent false-positive results, whereas cocaine and cannabinoid assays are more specific.^1,18 Common over-the-counter medications, including nonsteroidal anti-inflammatory drugs, decongestants, and antacids, can yield false-positive results, highlighting the need to obtain a comprehensive medication list from patients, including over-the-counter and herbal medications, before ordering UDS. Because of the complexity of cross-reactivity, it might not be possible to identify the source of a false-positive result.¹⁴

Patient variables. Intentional effort to skew results is another source of interference. The frequency of this effort varies by setting and the potential consequences of results—eg, employment testing or substance use treatment—and a range of attempts have been reported in the literature.^21,22 Common practices are dilution, adulteration, and substitution.^20,23

• Dilution lowers the concentration of the drug of interest below the detection limit of the assay by directly adding water to the urine specimen, drinking copious amounts of fluid, taking a diuretic, or a combination of these practices.
• Adulteration involves adding a substance to urine that interferes with the testing mechanism: for example, bleach, household cleaners, eye drops, and even commercially available products expressly marketed to interfere with UDS.²⁴
• Substitution involves providing urine or a urine-like substance for testing that did not originate from the patient.

Methods to minimize patient-related interference include observed collection and specimen validity testing for pH, creatinine, and adulterants (TABLE 2).^1,15 Efforts to detect patient interference must be balanced against concerns about privacy, personnel resources, and the cost of expanded testing.^14,19,20

Additional aspects inherent to the testing process, such as cutoff concentrations and detection windows, can lead to interference. Laboratories must set reporting cutoffs, and specimens with a drug concentration present but below the cutoff value are reported as a negative result. Detection windows are complex and are influenced by inherent properties of the drug, including metabolic pathway and route and frequency of use.¹ A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported (TABLE 3^1,23).

Managing test results

Appropriate management of UDS results is built on the foundation of understanding the testing mechanism, selecting the correct test, and properly interpreting results. Drug testing is, ultimately, a therapeutic tool used to monitor treatment, provide reinforcement, and explore substance use behavior; results of testing should be employed to achieve those objectives.^1,4,14 A negative or expected UDS result can be utilized as positive reinforcement for a patient who is adherent to the treatment plan—much the way objective weight loss in an obese patient can provide encouragement to continue lifestyle changes.

Continue to: Test results should be presented...

Test results should be presented in an objective, nonconfrontational, and compassionate manner, not with stigmatizing language, such as “clean” or “dirty.”^1,13,14 Using stigmatizing terms such as “substance abuser” instead of “person with a substance use disorder” has been shown, even among highly trained health care professionals, to have a negative effect on patient care.¹³

A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported.

Inevitably, you will encounter an unexpected result, and therefore must develop a rational, systematic, and compassionate management approach. “Unexpected result” is a broad term that includes results that conflict with

• a patient’s self-report
• your understanding of what the patient is taking (using)
• prescribed medications
• a patient’s typical substance use pattern.

When faced with an unexpected test result, first, ensure that the result in question is reliable. If a screening test yields an unanticipated finding—especially if it conflicts with the patient’s self-reporting—make every effort to seek confirmation if you are going to be making a significant clinical decision because of the result.^1,14

Second, use your understanding of interference to consider the result in a broader context. If confirmatory results are inconsistent with a patient’s self-report, discuss whether there has been a break in the ­ph­ysician–patient relationship and emphasize that recurrent use or failure to adhere to a treatment plan has clear consequences.^1,14 Modify the treatment plan to address the inconsistent finding by escalating care, adjusting medications, and connecting the patient to additional resources.

Third, keep in mind that a positive urine test is not diagnostic of an SUD. Occasional drug use is extremely common¹⁷ and should not categorically lead to a change in the treatment plan. Addiction is, fundamentally, a disease of disordered reward, motivation, and behavior that is defined by the consequences of substance use, not substance use per se,²⁵ and an SUD diagnosis is complex, based on clinical history, physical examination, and laboratory testing. Similarly, a negative UDS result does not rule out an SUD.^4,10

Continue to: Fourth, patient dismissal...

Fourth, patient dismissal is rarely an appropriate initial response to UDS results. Regrettably, some physicians misinterpret urine toxicology results and inappropriately discharge patients on that basis.

In general, amphetamine immunoassays produce frequent falsepositive results, whereas cocaine and cannabinoid assays are more specific.

The Centers for Disease Control and Prevention guideline for prescribing opioids has increased utilization of UDS in primary care settings but does not provide the necessary education on proper use of the tool, which has resulted in a rise in misinterpretation and inappropriate discharge.^13,26

If recurrent aberrant behavior is detected (by history or urine toxicology), do not abruptly discontinue the patient’s medication(s). Inform the patient of your concern, taper medication, and refer the patient to addiction treatment. Abrupt discontinuation of an opioid or benzodiazepine can lead to significant harm.^1,14

CORRESPONDENCE
John Hayes, DO, Department of Family and Community Medicine, Medical College of Wisconsin, 1121 E North Avenue, Milwaukee, WI, 53212; [email protected]

An estimated 20 million patients in the United States have a substance use disorder (SUD), with hundreds of millions of prescriptions for controlled substances written annually. Consequently, urine drug screening (UDS) has become widely utilized to evaluate and treat patients with an SUD or on chronic opioid or benzodiazepine therapy.¹

Used appropriately, UDS can be a valuable tool; there is ample evidence, however, that it has been misused, by some physicians, to stigmatize patients who use drugs of abuse,² profile patients racially,² profit from excessive testing,³ and inappropriately discontinue treatment.⁴

A patient-centered approach. We have extensive clinical experience in the use and interpretation of urine toxicology, serving as clinical leads in busy family medicine residency practices that care for patients with SUDs, and are often consulted regarding patients on chronic opioid or benzodiazepine therapy. We have encountered countless situations in which the correct interpretation of UDS is critical to providing care.

Over time, and after considerable trial and error, we developed the patient-centered approach to urine toxicology described in this article. We believe that the medical evidence strongly supports our approach to the appropriate use and interpretation of urine toxicology in clinical practice. Our review here is intended as a resource when you consider implementing a UDS protocol or are struggling with the management of unexpected results.

Urine toxicology for therapeutic drug monitoring

Prescribing a controlled substance carries inherent risks, including diversion, nonmedical use, and development of an SUD. Prescribed medications, particularly opioids and benzodiazepines, have been linked to a large increase in overdose deaths over the past decade.⁵ Several strategies have been investigated to mitigate risk (see “How frequently should a patient be tested?,” later in the article).

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed a substance use disorder—has been shown to be highly inaccurate.

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed an SUD—has been shown to be highly inaccurate. Implicit racial bias might affect the physician’s judgment, leading to changes in testing and test interpretation. For example, Black patients were found to be 10% more likely to have drug screening ordered while being treated with long-term opioid therapy and 2 to 3 times more likely to have their medication discontinued as a result of a marijuana- or cocaine-positive test.²

Other studies have shown that testing patients for “bad behavior,” so to speak—reporting a prescription lost or stolen, consuming more than the prescribed dosage, visiting the office without an appointment, having multiple drug intolerances and allergies, and making frequent telephone calls to the practice—is ineffective.⁶ Patients with these behaviors were slightly more likely to unexpectedly test positive, or negative, on their UDS; however, many patients without suspect behavior also were found to have abnormal toxicology results.⁶ Data do not support therapeutic drug monitoring only of patients selected on the basis of aberrant behavior.⁶

Continue to: Questions and concerns about urine drug screening

Why not just ask the patient? Studies have evaluated whether patient self-reporting of adherence is a feasible alternative to laboratory drug screening. Regrettably, patients have repeatedly been shown to underreport their use of both prescribed and illicit drugs.^7,8

That question leads to another: Why do patients lie to their physician? It is easy to assume malicious intent, but a variety of obstacles might dissuade a patient from being fully truthful with their physician:

• Monetary gain. A small, but real, percentage of medications are diverted by patients for this reason.⁹
• Addiction, pseudo-addiction due to tolerance, and self-medication for psychological symptoms are clinically treatable syndromes that can lead to underreporting of prescribed and nonprescribed drug and alcohol use.
• Shame. Addiction is a highly stigmatized disease, and patients might simply be ashamed to admit that they need treatment: 13% to 38% of patients receiving chronic opioid therapy in a pain management or primary care setting have a clinically diagnosable SUD.^10,11

Is consent needed to test or to share test results? Historically, UDS has been performed on patients without their consent or knowledge.¹² Patients give a urine specimen to their physician for a variety of reasons; it seems easy to “add on” UDS. Evidence is clear, however, that confronting a patient about an unexpected test result can make the clinical outcome worse—often resulting in irreparable damage to the patient–­physician relationship.^12,13 Unless the patient is experiencing a medical emergency, guidelines unanimously recommend obtaining consent prior to testing.^1,5,14

Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months.

Federal law requires written permission from the patient for the physician to disclose information about alcohol or substance use, unless the information is expressly needed to provide care during a medical emergency. Substance use is highly stigmatized, and patients might—legitimately—fear that sharing their history could undermine their care.^1,12,14

How frequently should a patient be tested? Experts recommend utilizing a risk-based strategy to determine the frequency of UDS.^1,5,15 Validated risk-assessment questionnaires include:

• Opioid Risk Tool for Opioid Use Disorder (ORT-OUD)^a
• Screener and Opioid Assessment for Patients With Pain–Revised (SOAPP-R)^b
• Diagnosis, Intractability, Risk and Efficacy (DIRE)^c
• Addiction Behaviors Checklist (ABC).^d

Continue to: Each of these tools...

Each of these tools takes less than 5 minutes to administer and can be used by a primary care physician to objectively quantify the risk of prescribing; there is no evidence for the use of 1 of these screeners over the others.¹⁵ It is recommended that you choose a questionnaire that works for you and incorporate the risk assessment into prescribing any high-risk medication.^1,5,15

Once you have completed an initial risk assessment, the frequency of UDS can be based on ongoing assessment that incorporates baseline testing, patient self-reporting, toxicology results, behavioral monitoring, and state database monitoring through a prescription drug monitoring program. Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months (FIGURE).¹⁵

Many state and federal agencies, health systems, employers, and insurers mandate the frequency of testing through guidelines or legislation. These regulations often are inconsistent with the newest medical evidence.¹⁵ Consult local guidelines and review the medical evidence and consensus recommendations on UDS.

What are the cost considerations in providing UDS? Insurers have been billed as much as $4000 for definitive chromatography testing (described later).³ This has led to insurance fraud, when drug-testing practices with a financial interest routinely use large and expensive test panels, test too frequently, or unnecessarily send for confirmatory or quantitative analysis of all positive tests.^3,14 Often, insurers refuse to pay for unnecessary testing, leaving patients with significant indebtedness.^3,14 Take time to review the evidence and consensus recommendations on UDS to avoid waste, potential accusations of fraud, and financial burden on your patients.

Urine toxicology for addiction treatment

UDS protocols in addiction settings are often different from those in which a controlled substance is being prescribed.

Continue to: Routine and random testing

Routine and random testing. Two common practices when treating addiction are to perform UDS on all patients, at every visit, or to test randomly.¹ These practices can be problematic, however. Routine testing at every visit can make urine-tampering more likely and is often unnecessary for stable patients. Random testing can reduce the risk of urine-tampering, but it is often difficult for primary care clinics to institute such a protocol. Some clinics have patients provide a urine specimen at every visit and then only send tests to the lab based on randomization.¹

Contingency management—a behavioral intervention in which a patient is rewarded, or their performance is reinforced, when they display evidence of positive change—is the most effective strategy used in addiction medicine to determine the frequency of patient visits and UDS.^14,16 High-risk patients with self-reported active substance use or UDS results consistent with substance use, or both, are seen more often; as their addiction behavior diminishes, visits and UDS become less frequent. If addiction behavior increases, the patient is seen more often. Keep in mind that addiction behavior decreases over months of treatment, not immediately upon initiation.^14,17 For contingency management to be successful, patient-centered interviewing and UDS will need to be employed frequently as the patient works toward meaningful change.¹⁴

The technology of urine drug screening

Two general techniques are used for UDS: immunoassay and chromatography. Each plays an important role in clinical practice; physicians must therefore maintain a basic understanding of the mechanism of each technique and their comparable advantages and disadvantages. Such an understanding allows for (1) matching the appropriate technique to the individual clinical scenario and (2) correctly interpreting results.

Immunoassay technology is used for point-of-care and rapid laboratory UDS, using antibodies to detect the drug or drug metabolite of interest. Antibodies utilized in immunoassays are designed to selectively bind a specific antigen—ie, a unique chemical structure within the drug of choice. Once bound, the antigen–antibody complex can be exploited for detection through various methods.

Chromatography–mass ­spectrometry is considered the gold standard for UDS, yielding confirmatory results. This is a 2-step process: Chromatography separates components within a specimen; mass spectrometry then identifies those components. Most laboratories employ liquid, rather than gas, chromatography. The specificity of the liquid chromatography–mass spectrometry method is such that a false-positive result is, essentially, impossible.¹⁸

Continue to: How is the appropriate tests elected for urine drug screening?

Variables that influence your choice of the proper test method include the clinical question at hand; cost; the urgency of obtaining results; and the stakes in that decision (ie, will the results be used to simply change the dosage of a medication or, of greater consequence, to determine fitness for employment or inform criminal justice decisions?). Each method of UDS has advantages that can be utilized and disadvantages that must be considered to obtain an accurate and useful result.

Immunoassay provides rapid results, is relatively easy to perform, and is, comparatively, inexpensive.^1,14 The speed of results makes this method particularly useful in settings such as the emergency department, where rapid results are crucial. Ease of use makes immunoassay ideal for the office, where non-laboratory staff can be trained to properly administer the test.

A major disadvantage of immunoassay technology, however, is interference resulting in both false-positive and false-negative results, which is discussed in detail in the next section. Immunoassay should be considered a screening test that yields presumptive results.

Liquid chromatography–mass spectrometry is exquisitely specific and provides confirmatory test results—major advantages of the method. However, specificity comes at a price: significantly increased cost and longer wait time for results (typically days, if specimens are sent out to a laboratory). These barriers can make it impractical to employ this method in routine practice.

Interpretation of results: Not so fast

Interpreting UDS results is not as simple as noting a positive or negative result. Physicians must understand the concept of interference, so that results can be appropriately interpreted and confirmed. This is crucial when results influence clinical decisions; inappropriate action, taken on the basis of presumptive results, can have severe consequences for the patient–provider relationship and the treatment plan.^1,14

Continue to: Interference falls into 2 categories...

Interference falls into 2 categories: variables inherent in the testing process and patient variables.

Obtain consent prior to performing urine drug screening, even if you are already collecting a specimen for other testing.

Antibody cross-reactivity. A major disadvantage of immunoassay technology is interference that results in false-positive and false-negative results.^19,20 The source of this interference is antibody cross-­reactivity—the degree to which an antibody binds to structurally similar compounds. Antibody–­antigen interactions are incredibly complex; although assay antibodies are engineered to specifically detect a drug class of interest, reactivity with other, structurally similar compounds is unavoidable.

Nevertheless, cross-reactivity is a useful phenomenon that allows broad testing for multiple drugs within a class. For example, most point-of-care tests for benzodiazepines reliably detect diazepam and chlordiazepoxide. Likewise, opiate tests reliably detect natural opiates, such as morphine and codeine. Cross-reactivity is not limitless, however; most benzodiazepine immunoassays have poor reactivity to clonazepam and lorazepam, making it possible that a patient taking clonazepam tests negative for benzodiazepine on an immunoassay.^14,20 Similarly, standard opioid tests have only moderate cross-reactivity for semisynthetic opioids, such as hydrocodone and hydromorphone; poor cross-r­eactivity for oxycodone and oxymorphone; and essentially no cross-­reactivity for full synthetics, such as fentanyl and methadone.¹⁴

It is the responsibility of the ordering physician to understand cross-reactivity to various drugs within a testing class.

Routine urine drug screening at every visit can make urine tampering more likely and is often unnecessary for stable patients.

Whereas weak cross-reactivity to drugs within a class can be a source of false-negative results, cross-reactivity to drugs outside the class of interest is a source of false-positive results. An extensive review of drugs that cause false-positive immunoassay screening tests is outside the scope of this article; commonly prescribed medications implicated in false-positive results are listed in TABLE 1.¹⁹

Continue to: In general...

In general, amphetamine immunoassays produce frequent false-positive results, whereas cocaine and cannabinoid assays are more specific.^1,18 Common over-the-counter medications, including nonsteroidal anti-inflammatory drugs, decongestants, and antacids, can yield false-positive results, highlighting the need to obtain a comprehensive medication list from patients, including over-the-counter and herbal medications, before ordering UDS. Because of the complexity of cross-reactivity, it might not be possible to identify the source of a false-positive result.¹⁴

Patient variables. Intentional effort to skew results is another source of interference. The frequency of this effort varies by setting and the potential consequences of results—eg, employment testing or substance use treatment—and a range of attempts have been reported in the literature.^21,22 Common practices are dilution, adulteration, and substitution.^20,23

• Dilution lowers the concentration of the drug of interest below the detection limit of the assay by directly adding water to the urine specimen, drinking copious amounts of fluid, taking a diuretic, or a combination of these practices.
• Adulteration involves adding a substance to urine that interferes with the testing mechanism: for example, bleach, household cleaners, eye drops, and even commercially available products expressly marketed to interfere with UDS.²⁴
• Substitution involves providing urine or a urine-like substance for testing that did not originate from the patient.

Methods to minimize patient-related interference include observed collection and specimen validity testing for pH, creatinine, and adulterants (TABLE 2).^1,15 Efforts to detect patient interference must be balanced against concerns about privacy, personnel resources, and the cost of expanded testing.^14,19,20

Additional aspects inherent to the testing process, such as cutoff concentrations and detection windows, can lead to interference. Laboratories must set reporting cutoffs, and specimens with a drug concentration present but below the cutoff value are reported as a negative result. Detection windows are complex and are influenced by inherent properties of the drug, including metabolic pathway and route and frequency of use.¹ A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported (TABLE 3^1,23).

Managing test results

Appropriate management of UDS results is built on the foundation of understanding the testing mechanism, selecting the correct test, and properly interpreting results. Drug testing is, ultimately, a therapeutic tool used to monitor treatment, provide reinforcement, and explore substance use behavior; results of testing should be employed to achieve those objectives.^1,4,14 A negative or expected UDS result can be utilized as positive reinforcement for a patient who is adherent to the treatment plan—much the way objective weight loss in an obese patient can provide encouragement to continue lifestyle changes.

Continue to: Test results should be presented...

Test results should be presented in an objective, nonconfrontational, and compassionate manner, not with stigmatizing language, such as “clean” or “dirty.”^1,13,14 Using stigmatizing terms such as “substance abuser” instead of “person with a substance use disorder” has been shown, even among highly trained health care professionals, to have a negative effect on patient care.¹³

A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported.

Inevitably, you will encounter an unexpected result, and therefore must develop a rational, systematic, and compassionate management approach. “Unexpected result” is a broad term that includes results that conflict with

• a patient’s self-report
• your understanding of what the patient is taking (using)
• prescribed medications
• a patient’s typical substance use pattern.

When faced with an unexpected test result, first, ensure that the result in question is reliable. If a screening test yields an unanticipated finding—especially if it conflicts with the patient’s self-reporting—make every effort to seek confirmation if you are going to be making a significant clinical decision because of the result.^1,14

Second, use your understanding of interference to consider the result in a broader context. If confirmatory results are inconsistent with a patient’s self-report, discuss whether there has been a break in the ­ph­ysician–patient relationship and emphasize that recurrent use or failure to adhere to a treatment plan has clear consequences.^1,14 Modify the treatment plan to address the inconsistent finding by escalating care, adjusting medications, and connecting the patient to additional resources.

Third, keep in mind that a positive urine test is not diagnostic of an SUD. Occasional drug use is extremely common¹⁷ and should not categorically lead to a change in the treatment plan. Addiction is, fundamentally, a disease of disordered reward, motivation, and behavior that is defined by the consequences of substance use, not substance use per se,²⁵ and an SUD diagnosis is complex, based on clinical history, physical examination, and laboratory testing. Similarly, a negative UDS result does not rule out an SUD.^4,10

Continue to: Fourth, patient dismissal...

Fourth, patient dismissal is rarely an appropriate initial response to UDS results. Regrettably, some physicians misinterpret urine toxicology results and inappropriately discharge patients on that basis.

In general, amphetamine immunoassays produce frequent falsepositive results, whereas cocaine and cannabinoid assays are more specific.

The Centers for Disease Control and Prevention guideline for prescribing opioids has increased utilization of UDS in primary care settings but does not provide the necessary education on proper use of the tool, which has resulted in a rise in misinterpretation and inappropriate discharge.^13,26

If recurrent aberrant behavior is detected (by history or urine toxicology), do not abruptly discontinue the patient’s medication(s). Inform the patient of your concern, taper medication, and refer the patient to addiction treatment. Abrupt discontinuation of an opioid or benzodiazepine can lead to significant harm.^1,14

CORRESPONDENCE
John Hayes, DO, Department of Family and Community Medicine, Medical College of Wisconsin, 1121 E North Avenue, Milwaukee, WI, 53212; [email protected]

It’s alive!!!

Calling all “The Walking Dead” fans! Did you know that, after death, certain cells in the brain can stay active and even become colossal?

inhauscreative/Getty Images

Researchers evaluated brain tissue to feign the gene expression during autopsy and death. By doing this, they found that these inflammatory cells, called glial cells, can increase gene expression and “grow and sprout long arm-like appendages for many hours after death.”

According to Dr. Jeffrey Loeb, the study’s senior author, the continued growth after death doesn’t come as a shock since these are the cells that do damage control after certain brain injuries, such as stroke.

Maybe those mindless zombies aren’t so mindless after all. We’re not sure if we should be more scared of a zombie that can think, or a zombie that can’t. We’re sensing a spin-off!
 

Beam me up, Doc!

In the realm of Star Trek, Dr. Leonard “Bones” McCoy isn’t the only physician who seems to find merit in the adventures of the starship Enterprise.

@stefanbc/Unsplash

Pediatric cardiologist Victor Grech, it was reported, has been so influenced by the generational hit that the show made special guest appearances in his medical writing.

The alarm was sounded by a student at Oxford University who had suspicions about more than 100 articles published in Early Human Development. Of the articles eventually withdrawn by the journal’s publisher, Elsevier, 26 were on COVID-19 alone.

Just like a Romulan cloaking device, where the stories once stood Elsevier has left a “withdrawn” statement, making the articles vanish out of thin air.

Along with articles on COVID-19, Dr. Grech’s 48-article series with coauthors on how to write a scientific paper rightfully came into question. Elsevier’s statement on the incident says that the journal’s editorial work flow has been redesigned “to ensure that this will not happen again in the future.”

The number of retracted articles boldly puts Dr. Grech in a lane where few men have gone before.
 

Something’s wrong, but I can’t put my finger on it

Mixed martial arts is not a sport for the faint of heart. However, we doubt fans who were watching the Khetag Pliev/Devin Goodale fight on April 1 were prepared for the announcement that a search was commencing for a missing finger. Not broken, in case you think that was a misprint. Completely 100% removed from the rest of the hand.

GeorgeRudy/iStock/via Getty Images

One would think that pinpointing the exact moment when the finger, belonging to Mr. Pliev, was severed would be easy, but the video evidence is unclear, with the best guess being that a kick in the first round broke the finger and a grapple in the second severed it completely. Mr. Pliev was not helpful in clearing up the matter; not only did he fail to immediately notice the fact that his finger had broken or severed, he tried to keep the fight going after the second round when the referee noticed some blood where his left ring finger should have been. He thought he was winning. Unfortunately, the doctor on hand, who was clearly a complete drag, felt differently, ending the fight and awarding it to Mr. Goodale in a technical knockout.

Rest assured, there is a happy ending to this gruesome story. After a frantic search, the missing finger was found deep within Mr. Pliev’s glove and was successfully reattached in a Philadelphia emergency room.

The LOTME team commends Mr. Pliev’s commitment to his craft by wanting to continue the fight, but we respectfully disagree with his assertion that he was winning. We’re fairly confident that body part removal is an automatic loss (pun intended), unless you’re the Black Knight from “Monty Python and the Holy Grail.” Then it’s a draw.
 

Take two cookies and call me in the morning

The placebo effect is a well-known phenomenon. A pharmacologically inactive treatment can help people if they don’t know it’s pharmacologically inactive. But what if they did know? Would it still work?

©Purestock/thinkstockphotos.com

That’s what researchers at Beth Israel Deaconess Medical Center in Boston wanted to find out. They divided a cohort of patients with irritable bowel syndrome into three groups. One group got pill bottles containing “open-label placebo,” so the subjects knew they were getting a placebo. The second received bottles labeled “double-blind placebo or peppermint oil.” The third got no pills but followed the rest of the study protocol.

Can you see where this is going? Two-thirds of the open-label placebo group had meaningful improvement of their symptoms, there was no difference in improvement between the two placebo groups, and both did significantly better than the no-pill group.

“If the presumption that deception is necessary for placebos to be effective is false, then many theories about the mechanisms that drive placebo effects may need modification,” investigator Ted J. Kaptchuk said in a written statement.

In other words, this changes everything. Who needs real drugs when anything that a doctor gives to a patient will help? Someone who has trouble swallowing pills can get a milkshake instead. Kid doesn’t like the taste of amoxicillin? Prescribe a slice of therapeutic pizza. Vaccine deniers can get a shot of vitamin C … or bourbon. And just imagine all the good that can be done in this crazy, mixed up world with a batch of chocolate chip cookies.

It’s alive!!!

Calling all “The Walking Dead” fans! Did you know that, after death, certain cells in the brain can stay active and even become colossal?

inhauscreative/Getty Images

Researchers evaluated brain tissue to feign the gene expression during autopsy and death. By doing this, they found that these inflammatory cells, called glial cells, can increase gene expression and “grow and sprout long arm-like appendages for many hours after death.”

According to Dr. Jeffrey Loeb, the study’s senior author, the continued growth after death doesn’t come as a shock since these are the cells that do damage control after certain brain injuries, such as stroke.

Maybe those mindless zombies aren’t so mindless after all. We’re not sure if we should be more scared of a zombie that can think, or a zombie that can’t. We’re sensing a spin-off!
 

Beam me up, Doc!

In the realm of Star Trek, Dr. Leonard “Bones” McCoy isn’t the only physician who seems to find merit in the adventures of the starship Enterprise.

@stefanbc/Unsplash

Pediatric cardiologist Victor Grech, it was reported, has been so influenced by the generational hit that the show made special guest appearances in his medical writing.

The alarm was sounded by a student at Oxford University who had suspicions about more than 100 articles published in Early Human Development. Of the articles eventually withdrawn by the journal’s publisher, Elsevier, 26 were on COVID-19 alone.

Just like a Romulan cloaking device, where the stories once stood Elsevier has left a “withdrawn” statement, making the articles vanish out of thin air.

Along with articles on COVID-19, Dr. Grech’s 48-article series with coauthors on how to write a scientific paper rightfully came into question. Elsevier’s statement on the incident says that the journal’s editorial work flow has been redesigned “to ensure that this will not happen again in the future.”

The number of retracted articles boldly puts Dr. Grech in a lane where few men have gone before.
 

Something’s wrong, but I can’t put my finger on it

Mixed martial arts is not a sport for the faint of heart. However, we doubt fans who were watching the Khetag Pliev/Devin Goodale fight on April 1 were prepared for the announcement that a search was commencing for a missing finger. Not broken, in case you think that was a misprint. Completely 100% removed from the rest of the hand.

GeorgeRudy/iStock/via Getty Images

One would think that pinpointing the exact moment when the finger, belonging to Mr. Pliev, was severed would be easy, but the video evidence is unclear, with the best guess being that a kick in the first round broke the finger and a grapple in the second severed it completely. Mr. Pliev was not helpful in clearing up the matter; not only did he fail to immediately notice the fact that his finger had broken or severed, he tried to keep the fight going after the second round when the referee noticed some blood where his left ring finger should have been. He thought he was winning. Unfortunately, the doctor on hand, who was clearly a complete drag, felt differently, ending the fight and awarding it to Mr. Goodale in a technical knockout.

Rest assured, there is a happy ending to this gruesome story. After a frantic search, the missing finger was found deep within Mr. Pliev’s glove and was successfully reattached in a Philadelphia emergency room.

The LOTME team commends Mr. Pliev’s commitment to his craft by wanting to continue the fight, but we respectfully disagree with his assertion that he was winning. We’re fairly confident that body part removal is an automatic loss (pun intended), unless you’re the Black Knight from “Monty Python and the Holy Grail.” Then it’s a draw.
 

Take two cookies and call me in the morning

The placebo effect is a well-known phenomenon. A pharmacologically inactive treatment can help people if they don’t know it’s pharmacologically inactive. But what if they did know? Would it still work?

©Purestock/thinkstockphotos.com

That’s what researchers at Beth Israel Deaconess Medical Center in Boston wanted to find out. They divided a cohort of patients with irritable bowel syndrome into three groups. One group got pill bottles containing “open-label placebo,” so the subjects knew they were getting a placebo. The second received bottles labeled “double-blind placebo or peppermint oil.” The third got no pills but followed the rest of the study protocol.

Can you see where this is going? Two-thirds of the open-label placebo group had meaningful improvement of their symptoms, there was no difference in improvement between the two placebo groups, and both did significantly better than the no-pill group.

“If the presumption that deception is necessary for placebos to be effective is false, then many theories about the mechanisms that drive placebo effects may need modification,” investigator Ted J. Kaptchuk said in a written statement.

In other words, this changes everything. Who needs real drugs when anything that a doctor gives to a patient will help? Someone who has trouble swallowing pills can get a milkshake instead. Kid doesn’t like the taste of amoxicillin? Prescribe a slice of therapeutic pizza. Vaccine deniers can get a shot of vitamin C … or bourbon. And just imagine all the good that can be done in this crazy, mixed up world with a batch of chocolate chip cookies.

It’s alive!!!

Calling all “The Walking Dead” fans! Did you know that, after death, certain cells in the brain can stay active and even become colossal?

inhauscreative/Getty Images

Researchers evaluated brain tissue to feign the gene expression during autopsy and death. By doing this, they found that these inflammatory cells, called glial cells, can increase gene expression and “grow and sprout long arm-like appendages for many hours after death.”

According to Dr. Jeffrey Loeb, the study’s senior author, the continued growth after death doesn’t come as a shock since these are the cells that do damage control after certain brain injuries, such as stroke.

Maybe those mindless zombies aren’t so mindless after all. We’re not sure if we should be more scared of a zombie that can think, or a zombie that can’t. We’re sensing a spin-off!
 

Beam me up, Doc!

In the realm of Star Trek, Dr. Leonard “Bones” McCoy isn’t the only physician who seems to find merit in the adventures of the starship Enterprise.

@stefanbc/Unsplash

Pediatric cardiologist Victor Grech, it was reported, has been so influenced by the generational hit that the show made special guest appearances in his medical writing.

The alarm was sounded by a student at Oxford University who had suspicions about more than 100 articles published in Early Human Development. Of the articles eventually withdrawn by the journal’s publisher, Elsevier, 26 were on COVID-19 alone.

Just like a Romulan cloaking device, where the stories once stood Elsevier has left a “withdrawn” statement, making the articles vanish out of thin air.

Along with articles on COVID-19, Dr. Grech’s 48-article series with coauthors on how to write a scientific paper rightfully came into question. Elsevier’s statement on the incident says that the journal’s editorial work flow has been redesigned “to ensure that this will not happen again in the future.”

The number of retracted articles boldly puts Dr. Grech in a lane where few men have gone before.
 

Something’s wrong, but I can’t put my finger on it

Mixed martial arts is not a sport for the faint of heart. However, we doubt fans who were watching the Khetag Pliev/Devin Goodale fight on April 1 were prepared for the announcement that a search was commencing for a missing finger. Not broken, in case you think that was a misprint. Completely 100% removed from the rest of the hand.

GeorgeRudy/iStock/via Getty Images

One would think that pinpointing the exact moment when the finger, belonging to Mr. Pliev, was severed would be easy, but the video evidence is unclear, with the best guess being that a kick in the first round broke the finger and a grapple in the second severed it completely. Mr. Pliev was not helpful in clearing up the matter; not only did he fail to immediately notice the fact that his finger had broken or severed, he tried to keep the fight going after the second round when the referee noticed some blood where his left ring finger should have been. He thought he was winning. Unfortunately, the doctor on hand, who was clearly a complete drag, felt differently, ending the fight and awarding it to Mr. Goodale in a technical knockout.

Rest assured, there is a happy ending to this gruesome story. After a frantic search, the missing finger was found deep within Mr. Pliev’s glove and was successfully reattached in a Philadelphia emergency room.

The LOTME team commends Mr. Pliev’s commitment to his craft by wanting to continue the fight, but we respectfully disagree with his assertion that he was winning. We’re fairly confident that body part removal is an automatic loss (pun intended), unless you’re the Black Knight from “Monty Python and the Holy Grail.” Then it’s a draw.
 

Take two cookies and call me in the morning

The placebo effect is a well-known phenomenon. A pharmacologically inactive treatment can help people if they don’t know it’s pharmacologically inactive. But what if they did know? Would it still work?

©Purestock/thinkstockphotos.com

That’s what researchers at Beth Israel Deaconess Medical Center in Boston wanted to find out. They divided a cohort of patients with irritable bowel syndrome into three groups. One group got pill bottles containing “open-label placebo,” so the subjects knew they were getting a placebo. The second received bottles labeled “double-blind placebo or peppermint oil.” The third got no pills but followed the rest of the study protocol.

Can you see where this is going? Two-thirds of the open-label placebo group had meaningful improvement of their symptoms, there was no difference in improvement between the two placebo groups, and both did significantly better than the no-pill group.

“If the presumption that deception is necessary for placebos to be effective is false, then many theories about the mechanisms that drive placebo effects may need modification,” investigator Ted J. Kaptchuk said in a written statement.

In other words, this changes everything. Who needs real drugs when anything that a doctor gives to a patient will help? Someone who has trouble swallowing pills can get a milkshake instead. Kid doesn’t like the taste of amoxicillin? Prescribe a slice of therapeutic pizza. Vaccine deniers can get a shot of vitamin C … or bourbon. And just imagine all the good that can be done in this crazy, mixed up world with a batch of chocolate chip cookies.

The Atlanta spa massacre, the commencement of the George Floyd trial, and COVID-19 highlight societal inequalities and health disparities among minority groups. We can only hope that we have arrived at the tipping point to address historical institutional racism and structural violence in this country.

Admittedly, we, as health care professionals, have been at best apathetic and at worst complicit with this tragedy. Dr. James Sims, the father of gynecology, perfected his surgical techniques of vaginal fistula on slaves. Starting in 1845, he performed over thirty surgeries without anesthesia on Anarcha Westcott.¹ Moreover, the past century was dotted with similar transgressions such as the Tuskegee Untreated Syphilis Experiment from 1932 to 1972, the use of the cells of Henrietta Lack in 1951, and the disproportionate lack of funding of sickle cell research.² We must move from complicit/apathetic to being part of the discourse and solution. 

The juxtaposition of George Floyd’s cry of “I can’t breathe” and the disproportionate way in which COVID-19 has affected Black communities and people of color highlights how deeply entrenched the problem of systemic racism is in this country. The innumerable reported hate crimes against Asian Americans stemming from xenophobia linked to the COVID-19 pandemic and the stereotyping of Hispanic Americans as criminals during the last U.S. administration demonstrate that all minority racial/ethnic groups are affected. As clinicians who care for the health of our communities and strive to reduce suffering, we have a responsibility to identify discrimination that exists in the health care system – ranging from subtle implicit bias to overt discrimination.³

Unconscious bias and its effect on diversity and inclusion has only recently been recognized and addressed in the realm of health care as applied to clinicians. This is key to structural racism as providers inadvertently use unconscious bias every day to make their medical decisions quick and efficient. As Dayna Bowen Matthews points out in her book, “Just Medicine,” “where health and health care are concerned, even when implicit biases are based on seemingly benign distinctions, or supported by apparently rational or widely held observations, these biases can cause grave individual, group, and societal harm that is commensurate to and even exceeds the harm caused by outright racism.” To deny the prejudices that providers have when making decisions for patients will perpetuate the racism and hinder our ability to overcome health inequity. Americans of racial and ethnic minorities have a higher incidence of chronic diseases and premature death when compared to white Americans.⁴ These disparities exist even when controlling for individual variations such as availability of health insurance, education, and socioeconomic status.⁵ Social determinants of health because of racial differences is often talked about as a cause of health care inequity, but given the evidence that providers play a much more active role in this, we need to become more comfortable with the discomfort of using the word “racism” if we intend to bring awareness and create change. 

In order to tackle structural racism in health care, organizations must take a multifaceted approach. Evidence-based strategies include: creation of an inclusive workforce, diversification of the workforce to better represent patient populations, and education/training on the effect of implicit bias on equitable health care.⁶ These aspirations can provide a framework for interventions at all levels of health care organizations.

The JEDI (justice, equity, diversity, and inclusion) committee of the section of hospital medicine at Wake Forest Baptist Health System came into existence in November 2019. The objective for JEDI was to use evidence-based methods to help create an environment that would lead to the creation of a diverse and inclusive hospital medicine group. Prior to establishing our committee, we interviewed providers from traditional minority groups who were part of our practice to bring clarity to the discrimination faced by our providers from colleagues, staff, and patients. The discrimination varied from microaggressions caused by implicit biases to macroaggression from overt discrimination. We initiated our work on this burning platform by following the evidence-based methods mentioned earlier.
 

Creation of an inclusive workforce. Our working committee included members of varied backgrounds and experiences who were passionate about enhancing equity while focusing on inclusion and wellness. The committee brainstormed ideas for interventions that could make a positive impact for our teammates. Individual providers voted to choose the interventions that would positively impact their inclusion and health. Using a validated survey,⁷ we were able to measure the degree of inclusion of our work group based on multiple demographics including age, gender, race/ethnicity, training (physician vs. APP), etc. Our intention is to complete the proposed interventions before remeasuring inclusion to understand the effect of our work.

Diversifying the workforce. Although our section of hospital medicine at Wake Forest Baptist Health System consists of providers self-identifying as people of color, we do not adequately mirror the racial composition of the population we serve. To achieve the desired result, we have made changes to our recruiting program. The section of hospital medicine visibly demonstrates our commitment to diversity and displays our values on our website. We intend for this to attract diverse individuals who would intend to be part of our group.

Education and training on impact of implicit bias on equitable health care. Implicit bias training will have to consist of actions that would help our clinicians recognize their own prejudices and find means to mitigate them. We have committed to bystander education that would give practice and words to our providers to speak up in situations where they see discrimination in the workplace that is directed against patients, staff, and colleagues. A series of open and honest conversations about racial and gender discrimination in health care that involves inviting accomplished speakers from around the country has been planned. Continued attention to opportunities to further awareness on this subject is vital.
 

On Jan. 6, 2021, a day that should have filled citizens with pride and hope with the election of the first Black minister and the first Jewish man to the U.S. Senate in a historically conservative state, as well as the confirmation of the election of a president who pledged to address racial disparities, we instead saw another stark reminder of where we came from and just how far we have to go. White supremacists incited by their perceived threat to a legacy of centuries of suppression transformed into a mob of insurrectionists, blatantly bearing Confederate and Nazi flags, and seemingly easily invaded and desecrated the U.S. Capitol. On March 16, 2021, a white male who was “having a bad day” ended the lives of eight individuals, including six Asian Americans.

These instances have brought forth the reality that many of our interventions have been directed towards subtle prejudices and microaggressions alone. We have skirted around calling out overt discrimination of minority groups and failed to openly acknowledge our own contribution to the problem. This newly found awareness has created an opportunity for more impactful work. The equitable delivery of health care is dependent on creating a patient-provider relationship based on trust; addressing overt discrimination respectfully; and overcoming unconscious bias.

While we have made the commitment to confront structural racism in our workplace and taken important steps to work towards this goal with the initiatives set forth by our JEDI committee, we certainly have a long way to go. George Floyd spent the last 8 minutes and 46 seconds of his life struggling to breathe and asking for his mother. Let’s not waste another second and instead be the change that we seek in health care.
 

Dr. Nagaraj is medical director, Hospital Medicine, at Lexington (N.C.) Medical Center, assistant professor at Wake Forest School of Medicine, and cochair, JEDI committee for diversity and inclusion, hospital medicine, at Wake Forest Baptist Health, Winston-Salem, NC. Ms. Haller is cochair, JEDI committee for diversity and inclusion, hospital medicine, Wake Forest Baptist Health. Dr. Huang is the executive medical director and service line director of general medicine and hospital medicine within the Wake Forest Baptist Health System and associate professor at Wake Forest School of Medicine. The authors would like to acknowledge Dr. Julie Freischlag, Dr. Kevin High, and Dr. David McIntosh at Wake Forest Baptist Health System for the support of the JEDI committee and the section on hospital medicine.

References

1. Holland B. The “father of modern gynecology” performed shocking experiments on enslaved women. History. 2017 Aug 29. www.history.com/news/the-father-of-modern-gynecology-performed-shocking-experiments-on-slaves.

2. Buseh AG et al. Community leaders’ perspectives on engaging African Americans in biobanks and other human genetics initiatives. J Community Genet. 2013 Oct;4(4):483-94. doi: 10.1007/s12687-013-0155-z.

3. National Center for Health Statistics. Health, United States, 2015: With special feature on racial and ethnic health disparities. 2016 May. www.cdc.gov/nchs/data/hus/hus15.pdf.

4. Bailey ZD et al. Structural racism and health inequities in the USA: evidence and interventions. Lancet. 2017 Apr 8;389(10077):1453-63. doi: 10.1016/S0140-6736(17)30569-X.

5. Arvizo C and Garrison E. Diversity and inclusion: the role of unconscious bias on patient care, health outcomes and the workforce in obstetrics and gynaecology. Curr Opin Obstet Gynecol. 2019 Oct;31(5):356-62. doi: 10.1097/GCO.0000000000000566.

6. Chung BG et al. Work group inclusion: test of a scale and model. Group & Organization Management. 2020;45(1):75-102. doi: 10.1177/1059601119839858.

The Atlanta spa massacre, the commencement of the George Floyd trial, and COVID-19 highlight societal inequalities and health disparities among minority groups. We can only hope that we have arrived at the tipping point to address historical institutional racism and structural violence in this country.

Admittedly, we, as health care professionals, have been at best apathetic and at worst complicit with this tragedy. Dr. James Sims, the father of gynecology, perfected his surgical techniques of vaginal fistula on slaves. Starting in 1845, he performed over thirty surgeries without anesthesia on Anarcha Westcott.¹ Moreover, the past century was dotted with similar transgressions such as the Tuskegee Untreated Syphilis Experiment from 1932 to 1972, the use of the cells of Henrietta Lack in 1951, and the disproportionate lack of funding of sickle cell research.² We must move from complicit/apathetic to being part of the discourse and solution. 

The juxtaposition of George Floyd’s cry of “I can’t breathe” and the disproportionate way in which COVID-19 has affected Black communities and people of color highlights how deeply entrenched the problem of systemic racism is in this country. The innumerable reported hate crimes against Asian Americans stemming from xenophobia linked to the COVID-19 pandemic and the stereotyping of Hispanic Americans as criminals during the last U.S. administration demonstrate that all minority racial/ethnic groups are affected. As clinicians who care for the health of our communities and strive to reduce suffering, we have a responsibility to identify discrimination that exists in the health care system – ranging from subtle implicit bias to overt discrimination.³

Unconscious bias and its effect on diversity and inclusion has only recently been recognized and addressed in the realm of health care as applied to clinicians. This is key to structural racism as providers inadvertently use unconscious bias every day to make their medical decisions quick and efficient. As Dayna Bowen Matthews points out in her book, “Just Medicine,” “where health and health care are concerned, even when implicit biases are based on seemingly benign distinctions, or supported by apparently rational or widely held observations, these biases can cause grave individual, group, and societal harm that is commensurate to and even exceeds the harm caused by outright racism.” To deny the prejudices that providers have when making decisions for patients will perpetuate the racism and hinder our ability to overcome health inequity. Americans of racial and ethnic minorities have a higher incidence of chronic diseases and premature death when compared to white Americans.⁴ These disparities exist even when controlling for individual variations such as availability of health insurance, education, and socioeconomic status.⁵ Social determinants of health because of racial differences is often talked about as a cause of health care inequity, but given the evidence that providers play a much more active role in this, we need to become more comfortable with the discomfort of using the word “racism” if we intend to bring awareness and create change. 

In order to tackle structural racism in health care, organizations must take a multifaceted approach. Evidence-based strategies include: creation of an inclusive workforce, diversification of the workforce to better represent patient populations, and education/training on the effect of implicit bias on equitable health care.⁶ These aspirations can provide a framework for interventions at all levels of health care organizations.

The JEDI (justice, equity, diversity, and inclusion) committee of the section of hospital medicine at Wake Forest Baptist Health System came into existence in November 2019. The objective for JEDI was to use evidence-based methods to help create an environment that would lead to the creation of a diverse and inclusive hospital medicine group. Prior to establishing our committee, we interviewed providers from traditional minority groups who were part of our practice to bring clarity to the discrimination faced by our providers from colleagues, staff, and patients. The discrimination varied from microaggressions caused by implicit biases to macroaggression from overt discrimination. We initiated our work on this burning platform by following the evidence-based methods mentioned earlier.
 

Creation of an inclusive workforce. Our working committee included members of varied backgrounds and experiences who were passionate about enhancing equity while focusing on inclusion and wellness. The committee brainstormed ideas for interventions that could make a positive impact for our teammates. Individual providers voted to choose the interventions that would positively impact their inclusion and health. Using a validated survey,⁷ we were able to measure the degree of inclusion of our work group based on multiple demographics including age, gender, race/ethnicity, training (physician vs. APP), etc. Our intention is to complete the proposed interventions before remeasuring inclusion to understand the effect of our work.

Diversifying the workforce. Although our section of hospital medicine at Wake Forest Baptist Health System consists of providers self-identifying as people of color, we do not adequately mirror the racial composition of the population we serve. To achieve the desired result, we have made changes to our recruiting program. The section of hospital medicine visibly demonstrates our commitment to diversity and displays our values on our website. We intend for this to attract diverse individuals who would intend to be part of our group.

Education and training on impact of implicit bias on equitable health care. Implicit bias training will have to consist of actions that would help our clinicians recognize their own prejudices and find means to mitigate them. We have committed to bystander education that would give practice and words to our providers to speak up in situations where they see discrimination in the workplace that is directed against patients, staff, and colleagues. A series of open and honest conversations about racial and gender discrimination in health care that involves inviting accomplished speakers from around the country has been planned. Continued attention to opportunities to further awareness on this subject is vital.
 

On Jan. 6, 2021, a day that should have filled citizens with pride and hope with the election of the first Black minister and the first Jewish man to the U.S. Senate in a historically conservative state, as well as the confirmation of the election of a president who pledged to address racial disparities, we instead saw another stark reminder of where we came from and just how far we have to go. White supremacists incited by their perceived threat to a legacy of centuries of suppression transformed into a mob of insurrectionists, blatantly bearing Confederate and Nazi flags, and seemingly easily invaded and desecrated the U.S. Capitol. On March 16, 2021, a white male who was “having a bad day” ended the lives of eight individuals, including six Asian Americans.

These instances have brought forth the reality that many of our interventions have been directed towards subtle prejudices and microaggressions alone. We have skirted around calling out overt discrimination of minority groups and failed to openly acknowledge our own contribution to the problem. This newly found awareness has created an opportunity for more impactful work. The equitable delivery of health care is dependent on creating a patient-provider relationship based on trust; addressing overt discrimination respectfully; and overcoming unconscious bias.

While we have made the commitment to confront structural racism in our workplace and taken important steps to work towards this goal with the initiatives set forth by our JEDI committee, we certainly have a long way to go. George Floyd spent the last 8 minutes and 46 seconds of his life struggling to breathe and asking for his mother. Let’s not waste another second and instead be the change that we seek in health care.
 

Dr. Nagaraj is medical director, Hospital Medicine, at Lexington (N.C.) Medical Center, assistant professor at Wake Forest School of Medicine, and cochair, JEDI committee for diversity and inclusion, hospital medicine, at Wake Forest Baptist Health, Winston-Salem, NC. Ms. Haller is cochair, JEDI committee for diversity and inclusion, hospital medicine, Wake Forest Baptist Health. Dr. Huang is the executive medical director and service line director of general medicine and hospital medicine within the Wake Forest Baptist Health System and associate professor at Wake Forest School of Medicine. The authors would like to acknowledge Dr. Julie Freischlag, Dr. Kevin High, and Dr. David McIntosh at Wake Forest Baptist Health System for the support of the JEDI committee and the section on hospital medicine.

References

1. Holland B. The “father of modern gynecology” performed shocking experiments on enslaved women. History. 2017 Aug 29. www.history.com/news/the-father-of-modern-gynecology-performed-shocking-experiments-on-slaves.

2. Buseh AG et al. Community leaders’ perspectives on engaging African Americans in biobanks and other human genetics initiatives. J Community Genet. 2013 Oct;4(4):483-94. doi: 10.1007/s12687-013-0155-z.

3. National Center for Health Statistics. Health, United States, 2015: With special feature on racial and ethnic health disparities. 2016 May. www.cdc.gov/nchs/data/hus/hus15.pdf.

4. Bailey ZD et al. Structural racism and health inequities in the USA: evidence and interventions. Lancet. 2017 Apr 8;389(10077):1453-63. doi: 10.1016/S0140-6736(17)30569-X.

5. Arvizo C and Garrison E. Diversity and inclusion: the role of unconscious bias on patient care, health outcomes and the workforce in obstetrics and gynaecology. Curr Opin Obstet Gynecol. 2019 Oct;31(5):356-62. doi: 10.1097/GCO.0000000000000566.

6. Chung BG et al. Work group inclusion: test of a scale and model. Group & Organization Management. 2020;45(1):75-102. doi: 10.1177/1059601119839858.

The Atlanta spa massacre, the commencement of the George Floyd trial, and COVID-19 highlight societal inequalities and health disparities among minority groups. We can only hope that we have arrived at the tipping point to address historical institutional racism and structural violence in this country.

Admittedly, we, as health care professionals, have been at best apathetic and at worst complicit with this tragedy. Dr. James Sims, the father of gynecology, perfected his surgical techniques of vaginal fistula on slaves. Starting in 1845, he performed over thirty surgeries without anesthesia on Anarcha Westcott.¹ Moreover, the past century was dotted with similar transgressions such as the Tuskegee Untreated Syphilis Experiment from 1932 to 1972, the use of the cells of Henrietta Lack in 1951, and the disproportionate lack of funding of sickle cell research.² We must move from complicit/apathetic to being part of the discourse and solution. 

The juxtaposition of George Floyd’s cry of “I can’t breathe” and the disproportionate way in which COVID-19 has affected Black communities and people of color highlights how deeply entrenched the problem of systemic racism is in this country. The innumerable reported hate crimes against Asian Americans stemming from xenophobia linked to the COVID-19 pandemic and the stereotyping of Hispanic Americans as criminals during the last U.S. administration demonstrate that all minority racial/ethnic groups are affected. As clinicians who care for the health of our communities and strive to reduce suffering, we have a responsibility to identify discrimination that exists in the health care system – ranging from subtle implicit bias to overt discrimination.³

Unconscious bias and its effect on diversity and inclusion has only recently been recognized and addressed in the realm of health care as applied to clinicians. This is key to structural racism as providers inadvertently use unconscious bias every day to make their medical decisions quick and efficient. As Dayna Bowen Matthews points out in her book, “Just Medicine,” “where health and health care are concerned, even when implicit biases are based on seemingly benign distinctions, or supported by apparently rational or widely held observations, these biases can cause grave individual, group, and societal harm that is commensurate to and even exceeds the harm caused by outright racism.” To deny the prejudices that providers have when making decisions for patients will perpetuate the racism and hinder our ability to overcome health inequity. Americans of racial and ethnic minorities have a higher incidence of chronic diseases and premature death when compared to white Americans.⁴ These disparities exist even when controlling for individual variations such as availability of health insurance, education, and socioeconomic status.⁵ Social determinants of health because of racial differences is often talked about as a cause of health care inequity, but given the evidence that providers play a much more active role in this, we need to become more comfortable with the discomfort of using the word “racism” if we intend to bring awareness and create change. 

In order to tackle structural racism in health care, organizations must take a multifaceted approach. Evidence-based strategies include: creation of an inclusive workforce, diversification of the workforce to better represent patient populations, and education/training on the effect of implicit bias on equitable health care.⁶ These aspirations can provide a framework for interventions at all levels of health care organizations.

The JEDI (justice, equity, diversity, and inclusion) committee of the section of hospital medicine at Wake Forest Baptist Health System came into existence in November 2019. The objective for JEDI was to use evidence-based methods to help create an environment that would lead to the creation of a diverse and inclusive hospital medicine group. Prior to establishing our committee, we interviewed providers from traditional minority groups who were part of our practice to bring clarity to the discrimination faced by our providers from colleagues, staff, and patients. The discrimination varied from microaggressions caused by implicit biases to macroaggression from overt discrimination. We initiated our work on this burning platform by following the evidence-based methods mentioned earlier.
 

Creation of an inclusive workforce. Our working committee included members of varied backgrounds and experiences who were passionate about enhancing equity while focusing on inclusion and wellness. The committee brainstormed ideas for interventions that could make a positive impact for our teammates. Individual providers voted to choose the interventions that would positively impact their inclusion and health. Using a validated survey,⁷ we were able to measure the degree of inclusion of our work group based on multiple demographics including age, gender, race/ethnicity, training (physician vs. APP), etc. Our intention is to complete the proposed interventions before remeasuring inclusion to understand the effect of our work.

Diversifying the workforce. Although our section of hospital medicine at Wake Forest Baptist Health System consists of providers self-identifying as people of color, we do not adequately mirror the racial composition of the population we serve. To achieve the desired result, we have made changes to our recruiting program. The section of hospital medicine visibly demonstrates our commitment to diversity and displays our values on our website. We intend for this to attract diverse individuals who would intend to be part of our group.

Education and training on impact of implicit bias on equitable health care. Implicit bias training will have to consist of actions that would help our clinicians recognize their own prejudices and find means to mitigate them. We have committed to bystander education that would give practice and words to our providers to speak up in situations where they see discrimination in the workplace that is directed against patients, staff, and colleagues. A series of open and honest conversations about racial and gender discrimination in health care that involves inviting accomplished speakers from around the country has been planned. Continued attention to opportunities to further awareness on this subject is vital.
 

On Jan. 6, 2021, a day that should have filled citizens with pride and hope with the election of the first Black minister and the first Jewish man to the U.S. Senate in a historically conservative state, as well as the confirmation of the election of a president who pledged to address racial disparities, we instead saw another stark reminder of where we came from and just how far we have to go. White supremacists incited by their perceived threat to a legacy of centuries of suppression transformed into a mob of insurrectionists, blatantly bearing Confederate and Nazi flags, and seemingly easily invaded and desecrated the U.S. Capitol. On March 16, 2021, a white male who was “having a bad day” ended the lives of eight individuals, including six Asian Americans.

These instances have brought forth the reality that many of our interventions have been directed towards subtle prejudices and microaggressions alone. We have skirted around calling out overt discrimination of minority groups and failed to openly acknowledge our own contribution to the problem. This newly found awareness has created an opportunity for more impactful work. The equitable delivery of health care is dependent on creating a patient-provider relationship based on trust; addressing overt discrimination respectfully; and overcoming unconscious bias.

While we have made the commitment to confront structural racism in our workplace and taken important steps to work towards this goal with the initiatives set forth by our JEDI committee, we certainly have a long way to go. George Floyd spent the last 8 minutes and 46 seconds of his life struggling to breathe and asking for his mother. Let’s not waste another second and instead be the change that we seek in health care.
 

Dr. Nagaraj is medical director, Hospital Medicine, at Lexington (N.C.) Medical Center, assistant professor at Wake Forest School of Medicine, and cochair, JEDI committee for diversity and inclusion, hospital medicine, at Wake Forest Baptist Health, Winston-Salem, NC. Ms. Haller is cochair, JEDI committee for diversity and inclusion, hospital medicine, Wake Forest Baptist Health. Dr. Huang is the executive medical director and service line director of general medicine and hospital medicine within the Wake Forest Baptist Health System and associate professor at Wake Forest School of Medicine. The authors would like to acknowledge Dr. Julie Freischlag, Dr. Kevin High, and Dr. David McIntosh at Wake Forest Baptist Health System for the support of the JEDI committee and the section on hospital medicine.

References

1. Holland B. The “father of modern gynecology” performed shocking experiments on enslaved women. History. 2017 Aug 29. www.history.com/news/the-father-of-modern-gynecology-performed-shocking-experiments-on-slaves.

2. Buseh AG et al. Community leaders’ perspectives on engaging African Americans in biobanks and other human genetics initiatives. J Community Genet. 2013 Oct;4(4):483-94. doi: 10.1007/s12687-013-0155-z.

3. National Center for Health Statistics. Health, United States, 2015: With special feature on racial and ethnic health disparities. 2016 May. www.cdc.gov/nchs/data/hus/hus15.pdf.

4. Bailey ZD et al. Structural racism and health inequities in the USA: evidence and interventions. Lancet. 2017 Apr 8;389(10077):1453-63. doi: 10.1016/S0140-6736(17)30569-X.

5. Arvizo C and Garrison E. Diversity and inclusion: the role of unconscious bias on patient care, health outcomes and the workforce in obstetrics and gynaecology. Curr Opin Obstet Gynecol. 2019 Oct;31(5):356-62. doi: 10.1097/GCO.0000000000000566.

6. Chung BG et al. Work group inclusion: test of a scale and model. Group & Organization Management. 2020;45(1):75-102. doi: 10.1177/1059601119839858.

An investigational vaginal gel significantly reduced urogenital chlamydia and gonorrhea in women at high risk for infection, compared with placebo, opening up new possibilities for an on-demand prevention option. Investigators of a randomized trial reported these findings in the American Journal of Obstetrics and Gynecology.

Rates of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are on the rise in the United States, despite wide availability of male and female condoms to prevent sexually transmitted infections. This suggests that women need a more discrete method that they can better control. Other vaginal microbicides developed over the last few decades haven’t performed well in protecting against STIs or HIV in clinical trials.

The slightly alkaline nature of human semen has the potential to neutralize vaginal pH after intercourse, creating a more vulnerable environment for STIs. EVO100 is an investigational antimicrobial, bioadhesive vaginal gel that contains L-lactic acid, citric acid, and potassium bitartrate. In preclinical studies, it was highly effective at buffering the alkaline properties of human semen and maintaining vaginal pH levels. Patients generally tolerated it well, aside from some reports of vaginal itching and burning.

An investigational vaginal gel significantly reduced urogenital chlamydia and gonorrhea in women at high risk for infection, compared with placebo, opening up new possibilities for an on-demand prevention option. Investigators of a randomized trial reported these findings in the American Journal of Obstetrics and Gynecology.

Rates of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are on the rise in the United States, despite wide availability of male and female condoms to prevent sexually transmitted infections. This suggests that women need a more discrete method that they can better control. Other vaginal microbicides developed over the last few decades haven’t performed well in protecting against STIs or HIV in clinical trials.

The slightly alkaline nature of human semen has the potential to neutralize vaginal pH after intercourse, creating a more vulnerable environment for STIs. EVO100 is an investigational antimicrobial, bioadhesive vaginal gel that contains L-lactic acid, citric acid, and potassium bitartrate. In preclinical studies, it was highly effective at buffering the alkaline properties of human semen and maintaining vaginal pH levels. Patients generally tolerated it well, aside from some reports of vaginal itching and burning.

An investigational vaginal gel significantly reduced urogenital chlamydia and gonorrhea in women at high risk for infection, compared with placebo, opening up new possibilities for an on-demand prevention option. Investigators of a randomized trial reported these findings in the American Journal of Obstetrics and Gynecology.

Rates of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are on the rise in the United States, despite wide availability of male and female condoms to prevent sexually transmitted infections. This suggests that women need a more discrete method that they can better control. Other vaginal microbicides developed over the last few decades haven’t performed well in protecting against STIs or HIV in clinical trials.

The slightly alkaline nature of human semen has the potential to neutralize vaginal pH after intercourse, creating a more vulnerable environment for STIs. EVO100 is an investigational antimicrobial, bioadhesive vaginal gel that contains L-lactic acid, citric acid, and potassium bitartrate. In preclinical studies, it was highly effective at buffering the alkaline properties of human semen and maintaining vaginal pH levels. Patients generally tolerated it well, aside from some reports of vaginal itching and burning.

Approximately 40,000 children in the United States have lost a parent to COVID-19, based on data from a combination of death counts and simulation models.

dtiberio/iStock/Getty Images

The scale of mortality from COVID-19 among adults in the United States merits efforts to monitor how many children have lost a parent as a result of the pandemic, wrote Rachel Kidman, PhD, of Stony Brook (N.Y.) University and colleagues.

In a study published in JAMA Pediatrics, the researchers used kinship networks of White and Black individuals in the United States to estimate parental bereavement. They combined deaths from COVID-19 as of February 2021 and combined them with excess deaths, and estimated future bereavement based on a herd immunity scenario.

Overall, the model suggested that each death from COVID-19 results in potential parental bereavement for 0.78 children aged 0-17 years, representing an increase of 17.5%-20.2% in parental bereavement. The model indicated that, as of February 2021, 37,337 children aged 0-17 years had lost a parent to COVID-19, including 11,366 children age 0-9 years and 31,661 children and teens aged 10-17 years. A total of 20,600 of these children were non-Hispanic White and 7,600 were Black. Black children accounted for 20% of the bereaved children, although they account for approximately 14% of children aged 0-17 years in the United States, the researchers noted.

Including the excess death estimate, which refers to the difference between observed and expected deaths for the remainder of the pandemic, raised the total bereaved children to 43,000. A future mortality scenario using a total of 1,500,000 deaths from COVID-19 based on a natural herd immunity strategy increased the total estimate of bereaved children to 116,922.

The study findings were limited by several factors including the lack of data on nonparental primary caregivers, and the use of demographic models rather than survey or administrative data, the researchers noted.

However, the huge number of children who have experienced the death of a parent because of COVID-19 emphasizes the need for reforms to address health, educational, and economic impacts of this mass bereavement on children and teens, they said.

“Parentally bereaved children will also need targeted support to help with grief, particularly during this period of heightened social isolation,” they emphasized.

Establishment of a national child bereavement cohort could identify children early in the bereavement process to help ensure that they are connected to local supportive care and monitored for health and behavior problems, the researchers said. In addition, such a cohort could be used as a basis for a longitudinal study of the impact of mass parental bereavement during a unique period of social isolation and economic uncertainty, they concluded.
 

Study spotlights gaps in mental health care

The study is an important reminder of how COVID-19 has disrupted children’s lives, said Herschel Lessin, MD, of Children’s Medical Group in Poughkeepsie, N.Y., in an interview. Losing a parent because of COVID-19 is one more tragedy on the list of social and emotional disasters the pandemic has wrought on children, he said.

“There has to be some sort of national response to help children through all of this, not just one item at a time,” Dr. Lessin said. However, the management of children’s mental health in the United States has been subpar for decades, he noted, with few clinicians trained to specialize in treating behavioral and mental health issues in children. Consequently, more general pediatricians will continue to be faced with the mental health issues of bereaved children who desperately need support, he said.

Money remains a key barrier, as it keeps qualified clinicians from entering the field of pediatric mental and behavioral health, and even where there are mental health providers, most do not take insurance and have long waiting lists, Dr. Lessin noted.

General pediatricians were seeing more patients with ADHD, anxiety, and depression before the advent of COVID-19, though most are not trained in managing these conditions, said Dr. Lessin. “Approximately 25%-30% of my visits now are mental health related, and the pandemic will make it geometrically worse,” he said.

The current study, with its dramatic estimates of the number of children who have lost a parent because of COVID-19, may bring attention to the fact that more training and money are needed to support mental health programs for children, he said.

Lead author Dr. Kidman had no financial conflicts to disclose. The study was supported by grants to corresponding author Ashton M. Verdery, PhD, from the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Lessin had no financial conflicts but serves on the Pediatric News editorial advisory board.

SOURCE: Kidman R et al. JAMA Pediatr. .

Approximately 40,000 children in the United States have lost a parent to COVID-19, based on data from a combination of death counts and simulation models.

dtiberio/iStock/Getty Images

The scale of mortality from COVID-19 among adults in the United States merits efforts to monitor how many children have lost a parent as a result of the pandemic, wrote Rachel Kidman, PhD, of Stony Brook (N.Y.) University and colleagues.

In a study published in JAMA Pediatrics, the researchers used kinship networks of White and Black individuals in the United States to estimate parental bereavement. They combined deaths from COVID-19 as of February 2021 and combined them with excess deaths, and estimated future bereavement based on a herd immunity scenario.

Overall, the model suggested that each death from COVID-19 results in potential parental bereavement for 0.78 children aged 0-17 years, representing an increase of 17.5%-20.2% in parental bereavement. The model indicated that, as of February 2021, 37,337 children aged 0-17 years had lost a parent to COVID-19, including 11,366 children age 0-9 years and 31,661 children and teens aged 10-17 years. A total of 20,600 of these children were non-Hispanic White and 7,600 were Black. Black children accounted for 20% of the bereaved children, although they account for approximately 14% of children aged 0-17 years in the United States, the researchers noted.

Including the excess death estimate, which refers to the difference between observed and expected deaths for the remainder of the pandemic, raised the total bereaved children to 43,000. A future mortality scenario using a total of 1,500,000 deaths from COVID-19 based on a natural herd immunity strategy increased the total estimate of bereaved children to 116,922.

The study findings were limited by several factors including the lack of data on nonparental primary caregivers, and the use of demographic models rather than survey or administrative data, the researchers noted.

However, the huge number of children who have experienced the death of a parent because of COVID-19 emphasizes the need for reforms to address health, educational, and economic impacts of this mass bereavement on children and teens, they said.

“Parentally bereaved children will also need targeted support to help with grief, particularly during this period of heightened social isolation,” they emphasized.

Establishment of a national child bereavement cohort could identify children early in the bereavement process to help ensure that they are connected to local supportive care and monitored for health and behavior problems, the researchers said. In addition, such a cohort could be used as a basis for a longitudinal study of the impact of mass parental bereavement during a unique period of social isolation and economic uncertainty, they concluded.
 

Study spotlights gaps in mental health care

The study is an important reminder of how COVID-19 has disrupted children’s lives, said Herschel Lessin, MD, of Children’s Medical Group in Poughkeepsie, N.Y., in an interview. Losing a parent because of COVID-19 is one more tragedy on the list of social and emotional disasters the pandemic has wrought on children, he said.

“There has to be some sort of national response to help children through all of this, not just one item at a time,” Dr. Lessin said. However, the management of children’s mental health in the United States has been subpar for decades, he noted, with few clinicians trained to specialize in treating behavioral and mental health issues in children. Consequently, more general pediatricians will continue to be faced with the mental health issues of bereaved children who desperately need support, he said.

Money remains a key barrier, as it keeps qualified clinicians from entering the field of pediatric mental and behavioral health, and even where there are mental health providers, most do not take insurance and have long waiting lists, Dr. Lessin noted.

General pediatricians were seeing more patients with ADHD, anxiety, and depression before the advent of COVID-19, though most are not trained in managing these conditions, said Dr. Lessin. “Approximately 25%-30% of my visits now are mental health related, and the pandemic will make it geometrically worse,” he said.

The current study, with its dramatic estimates of the number of children who have lost a parent because of COVID-19, may bring attention to the fact that more training and money are needed to support mental health programs for children, he said.

Lead author Dr. Kidman had no financial conflicts to disclose. The study was supported by grants to corresponding author Ashton M. Verdery, PhD, from the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Lessin had no financial conflicts but serves on the Pediatric News editorial advisory board.

SOURCE: Kidman R et al. JAMA Pediatr. .

Approximately 40,000 children in the United States have lost a parent to COVID-19, based on data from a combination of death counts and simulation models.

dtiberio/iStock/Getty Images

The scale of mortality from COVID-19 among adults in the United States merits efforts to monitor how many children have lost a parent as a result of the pandemic, wrote Rachel Kidman, PhD, of Stony Brook (N.Y.) University and colleagues.

In a study published in JAMA Pediatrics, the researchers used kinship networks of White and Black individuals in the United States to estimate parental bereavement. They combined deaths from COVID-19 as of February 2021 and combined them with excess deaths, and estimated future bereavement based on a herd immunity scenario.

Overall, the model suggested that each death from COVID-19 results in potential parental bereavement for 0.78 children aged 0-17 years, representing an increase of 17.5%-20.2% in parental bereavement. The model indicated that, as of February 2021, 37,337 children aged 0-17 years had lost a parent to COVID-19, including 11,366 children age 0-9 years and 31,661 children and teens aged 10-17 years. A total of 20,600 of these children were non-Hispanic White and 7,600 were Black. Black children accounted for 20% of the bereaved children, although they account for approximately 14% of children aged 0-17 years in the United States, the researchers noted.

Including the excess death estimate, which refers to the difference between observed and expected deaths for the remainder of the pandemic, raised the total bereaved children to 43,000. A future mortality scenario using a total of 1,500,000 deaths from COVID-19 based on a natural herd immunity strategy increased the total estimate of bereaved children to 116,922.

The study findings were limited by several factors including the lack of data on nonparental primary caregivers, and the use of demographic models rather than survey or administrative data, the researchers noted.

However, the huge number of children who have experienced the death of a parent because of COVID-19 emphasizes the need for reforms to address health, educational, and economic impacts of this mass bereavement on children and teens, they said.

“Parentally bereaved children will also need targeted support to help with grief, particularly during this period of heightened social isolation,” they emphasized.

Establishment of a national child bereavement cohort could identify children early in the bereavement process to help ensure that they are connected to local supportive care and monitored for health and behavior problems, the researchers said. In addition, such a cohort could be used as a basis for a longitudinal study of the impact of mass parental bereavement during a unique period of social isolation and economic uncertainty, they concluded.
 

Study spotlights gaps in mental health care

The study is an important reminder of how COVID-19 has disrupted children’s lives, said Herschel Lessin, MD, of Children’s Medical Group in Poughkeepsie, N.Y., in an interview. Losing a parent because of COVID-19 is one more tragedy on the list of social and emotional disasters the pandemic has wrought on children, he said.

“There has to be some sort of national response to help children through all of this, not just one item at a time,” Dr. Lessin said. However, the management of children’s mental health in the United States has been subpar for decades, he noted, with few clinicians trained to specialize in treating behavioral and mental health issues in children. Consequently, more general pediatricians will continue to be faced with the mental health issues of bereaved children who desperately need support, he said.

Money remains a key barrier, as it keeps qualified clinicians from entering the field of pediatric mental and behavioral health, and even where there are mental health providers, most do not take insurance and have long waiting lists, Dr. Lessin noted.

General pediatricians were seeing more patients with ADHD, anxiety, and depression before the advent of COVID-19, though most are not trained in managing these conditions, said Dr. Lessin. “Approximately 25%-30% of my visits now are mental health related, and the pandemic will make it geometrically worse,” he said.

The current study, with its dramatic estimates of the number of children who have lost a parent because of COVID-19, may bring attention to the fact that more training and money are needed to support mental health programs for children, he said.

Lead author Dr. Kidman had no financial conflicts to disclose. The study was supported by grants to corresponding author Ashton M. Verdery, PhD, from the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Lessin had no financial conflicts but serves on the Pediatric News editorial advisory board.

SOURCE: Kidman R et al. JAMA Pediatr. .