All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

[email protected]

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

[email protected]

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

[email protected]

COVID-19 infection altered the gut microbiota of adult patients and caused depletion of several types of bacteria with known immunomodulatory properties, based on data from a cohort study of 100 patients with confirmed COVID-19 infections from two hospitals.

“As the GI tract is the largest immunological organ in the body and its resident microbiota are known to modulate host immune responses, we hypothesized that the gut microbiota is associated with host inflammatory immune responses in COVID19,” wrote Yun Kit Yeoh, PhD, of the Chinese University of Hong Kong, and colleagues.

In a study published in Gut, the researchers investigated patient microbiota by collecting blood, stool, and patient records between February and May 2020 from 100 confirmed SARS-CoV-2–infected patients in Hong Kong during hospitalization, as well as follow-up stool samples from 27 patients up to 30 days after they cleared the COVID-19 virus; these observations were compared with 78 non–COVID-19 controls.

Overall, 274 stool samples were sequenced. Samples collected from patients during hospitalization for COVID-19 were compared with non–COVID-19 controls. The presence of phylum Bacteroidetes was significantly higher in COVID-19 patients compared with controls (23.9% vs. 12.8%; P < .001), as were Actinobacteria (26.1% vs. 19.0%; P < .001).

After controlling for antibiotics, the investigators found that “differences between cohorts were primarily linked to enrichment of taxa such as Parabacteroides, Sutterella wadsworthensis, and Bacteroides caccae and depletion of Adlercreutzia equolifaciens, Dorea formicigenerans, and Clostridium leptum in COVID-19 relative to non-COVID-19” (P < .05). In addition, Faecalibacterium prausnitzii and Bifidobacterium bifidum were negatively correlated with COVID-19 severity after investigators controlled for patient age and antibiotic use (P < .05).

The researchers also examined bacteria in COVID-19 patients and controls in the context of cytokines and other inflammatory markers. “We hypothesized that these compositional changes play a role in exacerbating disease by contributing to dysregulation of the immune response,” they said.

In fact, species depleted in COVID-19 patients including included B. adolescentis, E. rectale, and F. prausnitzii were negatively correlated with inflammatory markers including CXCL10, IL-10, TNF-alpha, and CCL2.

In addition, 42 stool samples from 27 patients showed significantly distinct gut microbiota from controls up to 30 days (median, 6 days) after virus clearance, regardless of antibiotics use (P < .05), the researchers said.
 

Long-term data needed

The study findings were limited by several factors, including the potential confounding of microbial signatures associated with COVID-19 because of heterogeneous patient management in the clinical setting and the potential that gut microbiota reflects a patient’s health with no impact on disease severity, as well as lack of data on the role of antibiotics for severe and critical patients, the researchers noted. In addition, “gut microbiota composition is highly heterogeneous across human populations and changes in compositions reported here may not necessarily be reflected in patients with COVID-19 from other biogeographies,” they wrote.

The “longer follow-up of patients with COVID-19 (e.g., 3 months to 1 year after clearing the virus) is needed to address questions related to the duration of gut microbiota dysbiosis post recovery, link between microbiota dysbiosis and long-term persistent symptoms, and whether the dysbiosis or enrichment/depletion of specific gut microorganisms predisposes recovered individuals to future health problems,” they wrote.

However, the results suggest a likely role for gut microorganisms in host inflammatory responses to COVID-19 infection, and “underscore an urgent need to understand the specific roles of gut microorganisms in human immune function and systemic inflammation,” they concluded.
 

More than infectious

“A growing body of evidence suggests that severity of illness from COVID-19 is largely determined by the patient’s aberrant immune response to the virus,” Jatin Roper, MD, of Duke University, Durham, N.C., said in an interview. “Therefore, a critical question is: What patient factors determine this immune response? The gut microbiota closely interact with the host immune system and are altered in many immunological diseases,” he said. “Furthermore, the SARS-CoV-2 virus infects enterocytes in the intestine and causes symptomatic gastrointestinal disease in a subset of patients. Therefore, understanding a possible association between gut microbiota and COVID-19 may reveal microbial species involved in disease pathogenesis,” he emphasized.   

In the current study, “I was surprised to find that COVID-19 infection is associated with depletion of immunomodulatory gut bacteria,” said Dr. Roper. “An open question is whether these changes are caused by the SARS-CoV-2 virus and then result in altered immune response. Alternatively, the changes in gut microbiota may be a result of the immune response or other changes associated with the disease,” he said.

“COVID-19 is an immunological disease, not just an infectious disease,” explained Dr. Roper. “The gut microbiota may play an important role in the pathogenesis of the disease. Thus, specific gut microbes could one day be analyzed to risk stratify patients, or even modified to treat the disease,” he noted.
 

Beyond COVID-19

“Given the impact of the gut microbiota on health and disease, as well as the impact of diseases on the microbiota, I am not at all surprised to find that there were significant changes in the microbiota of COVID-19 patients and that these changes are associated with inflammatory cytokines, chemokines, and blood markers of tissue damage,” said Anthony Sung, MD, also of Duke University.

According to Dr. Sung, researchers have already been investigating possible connections between gut microbiota and other conditions such as Alzheimer’s disease, and it’s been hypothesized that these connections are mediated by interactions between the gut microbiota and the immune system.

“While this is an important paper in our understanding of COVID-19, and highlights the microbiome as a potential therapeutic target, we need to conduct clinical trials of microbiota-based interventions before we can fully realize the clinical implications of these findings,” he said.

The study was supported by the Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region, and donations from Hui Hoy & Chow Sin Lan Charity Fund Limited, Pine and Crane Company Limited, Mr. Hui Ming, and The D.H. Chen Foundation. The researchers had no financial conflicts to disclose. Dr. Roper and Dr. Sung had no financial conflicts to disclose.

For the latest clinical guidance, education, research and physician resources about coronavirus, visit the AGA COVID-19 Resource Center at www.gastro.org/COVID.

COVID-19 infection altered the gut microbiota of adult patients and caused depletion of several types of bacteria with known immunomodulatory properties, based on data from a cohort study of 100 patients with confirmed COVID-19 infections from two hospitals.

“As the GI tract is the largest immunological organ in the body and its resident microbiota are known to modulate host immune responses, we hypothesized that the gut microbiota is associated with host inflammatory immune responses in COVID19,” wrote Yun Kit Yeoh, PhD, of the Chinese University of Hong Kong, and colleagues.

In a study published in Gut, the researchers investigated patient microbiota by collecting blood, stool, and patient records between February and May 2020 from 100 confirmed SARS-CoV-2–infected patients in Hong Kong during hospitalization, as well as follow-up stool samples from 27 patients up to 30 days after they cleared the COVID-19 virus; these observations were compared with 78 non–COVID-19 controls.

Overall, 274 stool samples were sequenced. Samples collected from patients during hospitalization for COVID-19 were compared with non–COVID-19 controls. The presence of phylum Bacteroidetes was significantly higher in COVID-19 patients compared with controls (23.9% vs. 12.8%; P < .001), as were Actinobacteria (26.1% vs. 19.0%; P < .001).

After controlling for antibiotics, the investigators found that “differences between cohorts were primarily linked to enrichment of taxa such as Parabacteroides, Sutterella wadsworthensis, and Bacteroides caccae and depletion of Adlercreutzia equolifaciens, Dorea formicigenerans, and Clostridium leptum in COVID-19 relative to non-COVID-19” (P < .05). In addition, Faecalibacterium prausnitzii and Bifidobacterium bifidum were negatively correlated with COVID-19 severity after investigators controlled for patient age and antibiotic use (P < .05).

The researchers also examined bacteria in COVID-19 patients and controls in the context of cytokines and other inflammatory markers. “We hypothesized that these compositional changes play a role in exacerbating disease by contributing to dysregulation of the immune response,” they said.

In fact, species depleted in COVID-19 patients including included B. adolescentis, E. rectale, and F. prausnitzii were negatively correlated with inflammatory markers including CXCL10, IL-10, TNF-alpha, and CCL2.

In addition, 42 stool samples from 27 patients showed significantly distinct gut microbiota from controls up to 30 days (median, 6 days) after virus clearance, regardless of antibiotics use (P < .05), the researchers said.
 

Long-term data needed

The study findings were limited by several factors, including the potential confounding of microbial signatures associated with COVID-19 because of heterogeneous patient management in the clinical setting and the potential that gut microbiota reflects a patient’s health with no impact on disease severity, as well as lack of data on the role of antibiotics for severe and critical patients, the researchers noted. In addition, “gut microbiota composition is highly heterogeneous across human populations and changes in compositions reported here may not necessarily be reflected in patients with COVID-19 from other biogeographies,” they wrote.

The “longer follow-up of patients with COVID-19 (e.g., 3 months to 1 year after clearing the virus) is needed to address questions related to the duration of gut microbiota dysbiosis post recovery, link between microbiota dysbiosis and long-term persistent symptoms, and whether the dysbiosis or enrichment/depletion of specific gut microorganisms predisposes recovered individuals to future health problems,” they wrote.

However, the results suggest a likely role for gut microorganisms in host inflammatory responses to COVID-19 infection, and “underscore an urgent need to understand the specific roles of gut microorganisms in human immune function and systemic inflammation,” they concluded.
 

More than infectious

“A growing body of evidence suggests that severity of illness from COVID-19 is largely determined by the patient’s aberrant immune response to the virus,” Jatin Roper, MD, of Duke University, Durham, N.C., said in an interview. “Therefore, a critical question is: What patient factors determine this immune response? The gut microbiota closely interact with the host immune system and are altered in many immunological diseases,” he said. “Furthermore, the SARS-CoV-2 virus infects enterocytes in the intestine and causes symptomatic gastrointestinal disease in a subset of patients. Therefore, understanding a possible association between gut microbiota and COVID-19 may reveal microbial species involved in disease pathogenesis,” he emphasized.   

In the current study, “I was surprised to find that COVID-19 infection is associated with depletion of immunomodulatory gut bacteria,” said Dr. Roper. “An open question is whether these changes are caused by the SARS-CoV-2 virus and then result in altered immune response. Alternatively, the changes in gut microbiota may be a result of the immune response or other changes associated with the disease,” he said.

“COVID-19 is an immunological disease, not just an infectious disease,” explained Dr. Roper. “The gut microbiota may play an important role in the pathogenesis of the disease. Thus, specific gut microbes could one day be analyzed to risk stratify patients, or even modified to treat the disease,” he noted.
 

Beyond COVID-19

“Given the impact of the gut microbiota on health and disease, as well as the impact of diseases on the microbiota, I am not at all surprised to find that there were significant changes in the microbiota of COVID-19 patients and that these changes are associated with inflammatory cytokines, chemokines, and blood markers of tissue damage,” said Anthony Sung, MD, also of Duke University.

According to Dr. Sung, researchers have already been investigating possible connections between gut microbiota and other conditions such as Alzheimer’s disease, and it’s been hypothesized that these connections are mediated by interactions between the gut microbiota and the immune system.

“While this is an important paper in our understanding of COVID-19, and highlights the microbiome as a potential therapeutic target, we need to conduct clinical trials of microbiota-based interventions before we can fully realize the clinical implications of these findings,” he said.

The study was supported by the Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region, and donations from Hui Hoy & Chow Sin Lan Charity Fund Limited, Pine and Crane Company Limited, Mr. Hui Ming, and The D.H. Chen Foundation. The researchers had no financial conflicts to disclose. Dr. Roper and Dr. Sung had no financial conflicts to disclose.

For the latest clinical guidance, education, research and physician resources about coronavirus, visit the AGA COVID-19 Resource Center at www.gastro.org/COVID.

COVID-19 infection altered the gut microbiota of adult patients and caused depletion of several types of bacteria with known immunomodulatory properties, based on data from a cohort study of 100 patients with confirmed COVID-19 infections from two hospitals.

“As the GI tract is the largest immunological organ in the body and its resident microbiota are known to modulate host immune responses, we hypothesized that the gut microbiota is associated with host inflammatory immune responses in COVID19,” wrote Yun Kit Yeoh, PhD, of the Chinese University of Hong Kong, and colleagues.

In a study published in Gut, the researchers investigated patient microbiota by collecting blood, stool, and patient records between February and May 2020 from 100 confirmed SARS-CoV-2–infected patients in Hong Kong during hospitalization, as well as follow-up stool samples from 27 patients up to 30 days after they cleared the COVID-19 virus; these observations were compared with 78 non–COVID-19 controls.

Overall, 274 stool samples were sequenced. Samples collected from patients during hospitalization for COVID-19 were compared with non–COVID-19 controls. The presence of phylum Bacteroidetes was significantly higher in COVID-19 patients compared with controls (23.9% vs. 12.8%; P < .001), as were Actinobacteria (26.1% vs. 19.0%; P < .001).

After controlling for antibiotics, the investigators found that “differences between cohorts were primarily linked to enrichment of taxa such as Parabacteroides, Sutterella wadsworthensis, and Bacteroides caccae and depletion of Adlercreutzia equolifaciens, Dorea formicigenerans, and Clostridium leptum in COVID-19 relative to non-COVID-19” (P < .05). In addition, Faecalibacterium prausnitzii and Bifidobacterium bifidum were negatively correlated with COVID-19 severity after investigators controlled for patient age and antibiotic use (P < .05).

The researchers also examined bacteria in COVID-19 patients and controls in the context of cytokines and other inflammatory markers. “We hypothesized that these compositional changes play a role in exacerbating disease by contributing to dysregulation of the immune response,” they said.

In fact, species depleted in COVID-19 patients including included B. adolescentis, E. rectale, and F. prausnitzii were negatively correlated with inflammatory markers including CXCL10, IL-10, TNF-alpha, and CCL2.

In addition, 42 stool samples from 27 patients showed significantly distinct gut microbiota from controls up to 30 days (median, 6 days) after virus clearance, regardless of antibiotics use (P < .05), the researchers said.
 

Long-term data needed

The study findings were limited by several factors, including the potential confounding of microbial signatures associated with COVID-19 because of heterogeneous patient management in the clinical setting and the potential that gut microbiota reflects a patient’s health with no impact on disease severity, as well as lack of data on the role of antibiotics for severe and critical patients, the researchers noted. In addition, “gut microbiota composition is highly heterogeneous across human populations and changes in compositions reported here may not necessarily be reflected in patients with COVID-19 from other biogeographies,” they wrote.

The “longer follow-up of patients with COVID-19 (e.g., 3 months to 1 year after clearing the virus) is needed to address questions related to the duration of gut microbiota dysbiosis post recovery, link between microbiota dysbiosis and long-term persistent symptoms, and whether the dysbiosis or enrichment/depletion of specific gut microorganisms predisposes recovered individuals to future health problems,” they wrote.

However, the results suggest a likely role for gut microorganisms in host inflammatory responses to COVID-19 infection, and “underscore an urgent need to understand the specific roles of gut microorganisms in human immune function and systemic inflammation,” they concluded.
 

More than infectious

“A growing body of evidence suggests that severity of illness from COVID-19 is largely determined by the patient’s aberrant immune response to the virus,” Jatin Roper, MD, of Duke University, Durham, N.C., said in an interview. “Therefore, a critical question is: What patient factors determine this immune response? The gut microbiota closely interact with the host immune system and are altered in many immunological diseases,” he said. “Furthermore, the SARS-CoV-2 virus infects enterocytes in the intestine and causes symptomatic gastrointestinal disease in a subset of patients. Therefore, understanding a possible association between gut microbiota and COVID-19 may reveal microbial species involved in disease pathogenesis,” he emphasized.   

In the current study, “I was surprised to find that COVID-19 infection is associated with depletion of immunomodulatory gut bacteria,” said Dr. Roper. “An open question is whether these changes are caused by the SARS-CoV-2 virus and then result in altered immune response. Alternatively, the changes in gut microbiota may be a result of the immune response or other changes associated with the disease,” he said.

“COVID-19 is an immunological disease, not just an infectious disease,” explained Dr. Roper. “The gut microbiota may play an important role in the pathogenesis of the disease. Thus, specific gut microbes could one day be analyzed to risk stratify patients, or even modified to treat the disease,” he noted.
 

Beyond COVID-19

“Given the impact of the gut microbiota on health and disease, as well as the impact of diseases on the microbiota, I am not at all surprised to find that there were significant changes in the microbiota of COVID-19 patients and that these changes are associated with inflammatory cytokines, chemokines, and blood markers of tissue damage,” said Anthony Sung, MD, also of Duke University.

According to Dr. Sung, researchers have already been investigating possible connections between gut microbiota and other conditions such as Alzheimer’s disease, and it’s been hypothesized that these connections are mediated by interactions between the gut microbiota and the immune system.

“While this is an important paper in our understanding of COVID-19, and highlights the microbiome as a potential therapeutic target, we need to conduct clinical trials of microbiota-based interventions before we can fully realize the clinical implications of these findings,” he said.

The study was supported by the Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region, and donations from Hui Hoy & Chow Sin Lan Charity Fund Limited, Pine and Crane Company Limited, Mr. Hui Ming, and The D.H. Chen Foundation. The researchers had no financial conflicts to disclose. Dr. Roper and Dr. Sung had no financial conflicts to disclose.

For the latest clinical guidance, education, research and physician resources about coronavirus, visit the AGA COVID-19 Resource Center at www.gastro.org/COVID.

Patients with an implantable cardioverter defibrillator (ICD) should be warned that some newer models of smartphones equipped with magnets, such as the iPhone 12, can disable their device, inhibiting its lifesaving functions, according to investigators who tested and confirmed this effect.

SL/Getty Images

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted which persisted for the duration of the test,” reported the investigating team led by Joshua C. Greenberg, MD, who is an electrophysiology fellow at Henry Ford Hospital, Detroit. The results were published in Heart Rhythm.

The American Heart Association has already cautioned that magnetic fields can inhibit the pulse generators for ICDs and pacemakers. On the AHA website, there is a list of devices and their potential for functional interference, but cell phones and other common devices are identified as posing a low risk.

The most recent iPhone and perhaps other advanced smartphones appear to be different. According to the authors of a study that tested the iPhone 12, this model has a circular array of magnets around a central charging coil. This array interacts with Apple’s proprietary MagSafe technology, which accelerates charging. The magnets also serve to orient the phone on the charger and enable other MagSafe accessories.

The authors of the new study were concerned that this array of magnets might be sufficiently strong to interfere with ICDs or other devices at risk. In a previously published study, the strength of a magnetic field sufficient to interfere with implantable cardiac devices was estimated to be at least 10 gauss.

Tests were performed on a patient wearing a Medtronic ICD.

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted,” according to the authors of the study. The functional loss of the ICS persisted for the duration of proximity. It was reproduced multiple times and with multiple phone positions.

Previous studies have provided evidence that earlier models do not share this risk. In a study testing the iPhone 6 and an Apple Watch in 148 patients with various types of implantable electronic devices, including pacemakers, cardioverter defibrillators, resynchronization defibrillators, and resynchronization pacemakers, only one instance of interference was observed in 1,352 tests.

With wand telemetry, iPhone-induced interferences could be detected with the iPhone 6 in 14% of the patients, but these did not appear to be clinically meaningful, and this type of interference could not be detected with the Apple Watch, according to the report. The single observed interaction, which was between an iPhone 6 and a dual-chamber pacemaker, suggested device-device interactions are uncommon.

More recently, a woman with a single-chamber Medtronic ICD who went to sleep wearing an Apple Watch was awoken by warning beeps from her cardiac device, according to a case report published online. The Apple watch became the prime suspect in causing the ICD warning when proximity of the watch reproduced the warning during clinical examination. However, the magnetic interference was ultimately found to be emanating from the wristband, not the watch.

This case prompted additional studies with Fitbit and other Apple Watch wristbands. Both wristbands contain magnets used to track heart rate. Both were found capable of deactivating ICDs at distances of approximately 2 cm. On the basis of these results, the authors concluded that patients should be counseled about the risk posed by wristbands used in fitness tracking, concluding that they should be kept at least 6 inches away from ICDs and not worn while sleeping.

On their website, Apple maintains a page that specifically warns about the potential for interactions between iPhone 12s and medical devices . Although there is an acknowledgment that the iPhone12 contains more magnets than prior iPhone models, it is stated that iPhone 12 models are “not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” Nevertheless, the Apple instructions advise keeping the iPhone and MagSafe accessories more than 6 inches away from medical devices.

Dr. Greenberg and coinvestigators concluded that the iPhone 12 does pose a greater risk to the dysfunction of ICDs and other medical devices because of the more powerful magnets. As a result, the study brings forward “an important public health issue concerning the newer generation iPhone 12.”

Well aware of this issue and this study, Bruce L. Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices, Cleveland Clinic, agreed. He said the focus should not be restricted to the iPhone 12 series but other wearable devices as alluded to in the study.

“Pacemakers and implantable defibrillators are designed to respond to magnets for important reasons, but magnets have many common uses,” he said. These can change the function of the implantable cardiac devise, but “it is temporary and only when placed in close proximity.”

The solution is simple. “Patients should be careful to avoid locating these objects near these devices,” Dr. Wilkoff said.

However, the first step is awareness. According to the study authors, devices with magnets powerful enough to impair function of implantable devices, such as the iPhone 12 “can potentially inhibit lifesaving therapy.”

Patients should be counseled and provided with practical steps, according to the authors. This includes keeping these devices out of pockets near implantable devices. They called for more noise from makers of smartphones and other devices with strong enough magnets to alter pacemaker and ICD function, and they advised physicians to draw awareness to this issue.

Dr. Greenberg reported no potential conflicts of interest.

Patients with an implantable cardioverter defibrillator (ICD) should be warned that some newer models of smartphones equipped with magnets, such as the iPhone 12, can disable their device, inhibiting its lifesaving functions, according to investigators who tested and confirmed this effect.

SL/Getty Images

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted which persisted for the duration of the test,” reported the investigating team led by Joshua C. Greenberg, MD, who is an electrophysiology fellow at Henry Ford Hospital, Detroit. The results were published in Heart Rhythm.

The American Heart Association has already cautioned that magnetic fields can inhibit the pulse generators for ICDs and pacemakers. On the AHA website, there is a list of devices and their potential for functional interference, but cell phones and other common devices are identified as posing a low risk.

The most recent iPhone and perhaps other advanced smartphones appear to be different. According to the authors of a study that tested the iPhone 12, this model has a circular array of magnets around a central charging coil. This array interacts with Apple’s proprietary MagSafe technology, which accelerates charging. The magnets also serve to orient the phone on the charger and enable other MagSafe accessories.

The authors of the new study were concerned that this array of magnets might be sufficiently strong to interfere with ICDs or other devices at risk. In a previously published study, the strength of a magnetic field sufficient to interfere with implantable cardiac devices was estimated to be at least 10 gauss.

Tests were performed on a patient wearing a Medtronic ICD.

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted,” according to the authors of the study. The functional loss of the ICS persisted for the duration of proximity. It was reproduced multiple times and with multiple phone positions.

Previous studies have provided evidence that earlier models do not share this risk. In a study testing the iPhone 6 and an Apple Watch in 148 patients with various types of implantable electronic devices, including pacemakers, cardioverter defibrillators, resynchronization defibrillators, and resynchronization pacemakers, only one instance of interference was observed in 1,352 tests.

With wand telemetry, iPhone-induced interferences could be detected with the iPhone 6 in 14% of the patients, but these did not appear to be clinically meaningful, and this type of interference could not be detected with the Apple Watch, according to the report. The single observed interaction, which was between an iPhone 6 and a dual-chamber pacemaker, suggested device-device interactions are uncommon.

More recently, a woman with a single-chamber Medtronic ICD who went to sleep wearing an Apple Watch was awoken by warning beeps from her cardiac device, according to a case report published online. The Apple watch became the prime suspect in causing the ICD warning when proximity of the watch reproduced the warning during clinical examination. However, the magnetic interference was ultimately found to be emanating from the wristband, not the watch.

This case prompted additional studies with Fitbit and other Apple Watch wristbands. Both wristbands contain magnets used to track heart rate. Both were found capable of deactivating ICDs at distances of approximately 2 cm. On the basis of these results, the authors concluded that patients should be counseled about the risk posed by wristbands used in fitness tracking, concluding that they should be kept at least 6 inches away from ICDs and not worn while sleeping.

On their website, Apple maintains a page that specifically warns about the potential for interactions between iPhone 12s and medical devices . Although there is an acknowledgment that the iPhone12 contains more magnets than prior iPhone models, it is stated that iPhone 12 models are “not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” Nevertheless, the Apple instructions advise keeping the iPhone and MagSafe accessories more than 6 inches away from medical devices.

Dr. Greenberg and coinvestigators concluded that the iPhone 12 does pose a greater risk to the dysfunction of ICDs and other medical devices because of the more powerful magnets. As a result, the study brings forward “an important public health issue concerning the newer generation iPhone 12.”

Well aware of this issue and this study, Bruce L. Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices, Cleveland Clinic, agreed. He said the focus should not be restricted to the iPhone 12 series but other wearable devices as alluded to in the study.

“Pacemakers and implantable defibrillators are designed to respond to magnets for important reasons, but magnets have many common uses,” he said. These can change the function of the implantable cardiac devise, but “it is temporary and only when placed in close proximity.”

The solution is simple. “Patients should be careful to avoid locating these objects near these devices,” Dr. Wilkoff said.

However, the first step is awareness. According to the study authors, devices with magnets powerful enough to impair function of implantable devices, such as the iPhone 12 “can potentially inhibit lifesaving therapy.”

Patients should be counseled and provided with practical steps, according to the authors. This includes keeping these devices out of pockets near implantable devices. They called for more noise from makers of smartphones and other devices with strong enough magnets to alter pacemaker and ICD function, and they advised physicians to draw awareness to this issue.

Dr. Greenberg reported no potential conflicts of interest.

Patients with an implantable cardioverter defibrillator (ICD) should be warned that some newer models of smartphones equipped with magnets, such as the iPhone 12, can disable their device, inhibiting its lifesaving functions, according to investigators who tested and confirmed this effect.

SL/Getty Images

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted which persisted for the duration of the test,” reported the investigating team led by Joshua C. Greenberg, MD, who is an electrophysiology fellow at Henry Ford Hospital, Detroit. The results were published in Heart Rhythm.

The American Heart Association has already cautioned that magnetic fields can inhibit the pulse generators for ICDs and pacemakers. On the AHA website, there is a list of devices and their potential for functional interference, but cell phones and other common devices are identified as posing a low risk.

The most recent iPhone and perhaps other advanced smartphones appear to be different. According to the authors of a study that tested the iPhone 12, this model has a circular array of magnets around a central charging coil. This array interacts with Apple’s proprietary MagSafe technology, which accelerates charging. The magnets also serve to orient the phone on the charger and enable other MagSafe accessories.

The authors of the new study were concerned that this array of magnets might be sufficiently strong to interfere with ICDs or other devices at risk. In a previously published study, the strength of a magnetic field sufficient to interfere with implantable cardiac devices was estimated to be at least 10 gauss.

Tests were performed on a patient wearing a Medtronic ICD.

“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted,” according to the authors of the study. The functional loss of the ICS persisted for the duration of proximity. It was reproduced multiple times and with multiple phone positions.

Previous studies have provided evidence that earlier models do not share this risk. In a study testing the iPhone 6 and an Apple Watch in 148 patients with various types of implantable electronic devices, including pacemakers, cardioverter defibrillators, resynchronization defibrillators, and resynchronization pacemakers, only one instance of interference was observed in 1,352 tests.

With wand telemetry, iPhone-induced interferences could be detected with the iPhone 6 in 14% of the patients, but these did not appear to be clinically meaningful, and this type of interference could not be detected with the Apple Watch, according to the report. The single observed interaction, which was between an iPhone 6 and a dual-chamber pacemaker, suggested device-device interactions are uncommon.

More recently, a woman with a single-chamber Medtronic ICD who went to sleep wearing an Apple Watch was awoken by warning beeps from her cardiac device, according to a case report published online. The Apple watch became the prime suspect in causing the ICD warning when proximity of the watch reproduced the warning during clinical examination. However, the magnetic interference was ultimately found to be emanating from the wristband, not the watch.

This case prompted additional studies with Fitbit and other Apple Watch wristbands. Both wristbands contain magnets used to track heart rate. Both were found capable of deactivating ICDs at distances of approximately 2 cm. On the basis of these results, the authors concluded that patients should be counseled about the risk posed by wristbands used in fitness tracking, concluding that they should be kept at least 6 inches away from ICDs and not worn while sleeping.

On their website, Apple maintains a page that specifically warns about the potential for interactions between iPhone 12s and medical devices . Although there is an acknowledgment that the iPhone12 contains more magnets than prior iPhone models, it is stated that iPhone 12 models are “not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” Nevertheless, the Apple instructions advise keeping the iPhone and MagSafe accessories more than 6 inches away from medical devices.

Dr. Greenberg and coinvestigators concluded that the iPhone 12 does pose a greater risk to the dysfunction of ICDs and other medical devices because of the more powerful magnets. As a result, the study brings forward “an important public health issue concerning the newer generation iPhone 12.”

Well aware of this issue and this study, Bruce L. Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices, Cleveland Clinic, agreed. He said the focus should not be restricted to the iPhone 12 series but other wearable devices as alluded to in the study.

“Pacemakers and implantable defibrillators are designed to respond to magnets for important reasons, but magnets have many common uses,” he said. These can change the function of the implantable cardiac devise, but “it is temporary and only when placed in close proximity.”

The solution is simple. “Patients should be careful to avoid locating these objects near these devices,” Dr. Wilkoff said.

However, the first step is awareness. According to the study authors, devices with magnets powerful enough to impair function of implantable devices, such as the iPhone 12 “can potentially inhibit lifesaving therapy.”

Patients should be counseled and provided with practical steps, according to the authors. This includes keeping these devices out of pockets near implantable devices. They called for more noise from makers of smartphones and other devices with strong enough magnets to alter pacemaker and ICD function, and they advised physicians to draw awareness to this issue.

Dr. Greenberg reported no potential conflicts of interest.

Long-term follow-up data show a continued benefit for patients with advanced hepatocellular carcinoma (HCC) treated with nivolumab and ipilimumab after disease progression on sorafenib, according to investigators from the Checkmate 040 trial.

At a minimum follow-up of 44 months, the 3-year overall survival rate ranged from 30% to 42% in patients who received three different nivolumab-ipilimumab regimens, reported Anthony B. El-Khoueiry, MD, of the University of Southern California in Los Angeles.

“Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases,” Dr. El-Khoueiry said at the 2021 Gastrointestinal Cancers Symposium (Abstract 269).

The Checkmate 040 trial was designed to compare second- or later-line therapy with the two checkpoint inhibitors at two different dose schedules, followed by maintenance therapy, plus a third continuous therapy arm.

The trial included 148 patients with advanced HCC who experienced disease progression on sorafenib or could not tolerate the drug. They were randomly assigned on a 1:1:1 basis to receive:

• Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance at 240 mg every 2 weeks (nivo 1 + ipi 3).
• Nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance (nivo 3 + ipi 1).
• Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity (nivo 3 + ipi 1 Q6).

Based on earlier results of this trial, the nivo 1 + ipi 3 dose with nivolumab maintenance was approved in the United States for patients with advanced HCC previously treated with sorafenib.
 

Four years on

“Response outcomes at 44 months of follow-up were consistent with the primary analysis,” Dr. El-Khoueiry said.

The overall response rate at the most recent follow-up was 32% for nivo 1 + ipi 3, and 31% in each of the other arms.

The disease control rate – a combination of complete and partial responses and stable disease – was 54% in the nivo 1 + ipi 3 arm, 43% in the nivo 3 + ipi 1 arm, and 49% in the nivo 3 + ipi 1 Q6 arm.

The 36-month overall survival rates were 42%, 26%, and 30%, respectively. Kaplan-Meier curves for overall survival for both the primary analysis and the long-term follow-up displayed a survival advantage for nivo 1 + ipi 3 compared with the other two arms.
 

Safety

Treatment-related adverse events occurred more frequently in the nivo 1 + ipi 3 arm, which investigators attribute to the higher dose of ipilimumab. The most common grade 3 or 4 events in this arm were elevated liver enzymes and hyponatremia.

Immune-related adverse events also occurred more frequently in the nivo 1 + ipi 3 arm.

“Most immune-mediated adverse events were reversible and resolved when treated using an established algorithm, with steroids being the most common immune-modulating medication used. There were no additional discontinuations due to immune-mediated adverse events during the longer follow-up,” Dr. El-Khoueiry said.
 

Best combination?

“It’s certainly good data, and we’re happy about the response rate of about 30%, and that was confirmed at [the Gastrointestinal Cancers Symposium] with further follow-up of these patients,” said Lipika Goyal, MD, of Mass General Cancer Center in Boston.

Whether the nivo/ipi combination will turn out to be the optimum choice for patients with advanced HCC is still unknown; however, many different combinations of checkpoint inhibitors with or without tyrosine kinase inhibitors are currently being explored, and have not been compared in head-to-head trials, Dr. Goyal said in an interview. Dr. Goyal was not involved in the Checkmate 040 study.

Checkmate 040 was supported by Bristol Myers Squibb. Dr. El-Khoueiry disclosed honoraria from and consulting/advising for the company and others. Dr. Goyal reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Long-term follow-up data show a continued benefit for patients with advanced hepatocellular carcinoma (HCC) treated with nivolumab and ipilimumab after disease progression on sorafenib, according to investigators from the Checkmate 040 trial.

At a minimum follow-up of 44 months, the 3-year overall survival rate ranged from 30% to 42% in patients who received three different nivolumab-ipilimumab regimens, reported Anthony B. El-Khoueiry, MD, of the University of Southern California in Los Angeles.

“Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases,” Dr. El-Khoueiry said at the 2021 Gastrointestinal Cancers Symposium (Abstract 269).

The Checkmate 040 trial was designed to compare second- or later-line therapy with the two checkpoint inhibitors at two different dose schedules, followed by maintenance therapy, plus a third continuous therapy arm.

The trial included 148 patients with advanced HCC who experienced disease progression on sorafenib or could not tolerate the drug. They were randomly assigned on a 1:1:1 basis to receive:

• Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance at 240 mg every 2 weeks (nivo 1 + ipi 3).
• Nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance (nivo 3 + ipi 1).
• Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity (nivo 3 + ipi 1 Q6).

Based on earlier results of this trial, the nivo 1 + ipi 3 dose with nivolumab maintenance was approved in the United States for patients with advanced HCC previously treated with sorafenib.
 

Four years on

“Response outcomes at 44 months of follow-up were consistent with the primary analysis,” Dr. El-Khoueiry said.

The overall response rate at the most recent follow-up was 32% for nivo 1 + ipi 3, and 31% in each of the other arms.

The disease control rate – a combination of complete and partial responses and stable disease – was 54% in the nivo 1 + ipi 3 arm, 43% in the nivo 3 + ipi 1 arm, and 49% in the nivo 3 + ipi 1 Q6 arm.

The 36-month overall survival rates were 42%, 26%, and 30%, respectively. Kaplan-Meier curves for overall survival for both the primary analysis and the long-term follow-up displayed a survival advantage for nivo 1 + ipi 3 compared with the other two arms.
 

Safety

Treatment-related adverse events occurred more frequently in the nivo 1 + ipi 3 arm, which investigators attribute to the higher dose of ipilimumab. The most common grade 3 or 4 events in this arm were elevated liver enzymes and hyponatremia.

Immune-related adverse events also occurred more frequently in the nivo 1 + ipi 3 arm.

“Most immune-mediated adverse events were reversible and resolved when treated using an established algorithm, with steroids being the most common immune-modulating medication used. There were no additional discontinuations due to immune-mediated adverse events during the longer follow-up,” Dr. El-Khoueiry said.
 

Best combination?

“It’s certainly good data, and we’re happy about the response rate of about 30%, and that was confirmed at [the Gastrointestinal Cancers Symposium] with further follow-up of these patients,” said Lipika Goyal, MD, of Mass General Cancer Center in Boston.

Whether the nivo/ipi combination will turn out to be the optimum choice for patients with advanced HCC is still unknown; however, many different combinations of checkpoint inhibitors with or without tyrosine kinase inhibitors are currently being explored, and have not been compared in head-to-head trials, Dr. Goyal said in an interview. Dr. Goyal was not involved in the Checkmate 040 study.

Checkmate 040 was supported by Bristol Myers Squibb. Dr. El-Khoueiry disclosed honoraria from and consulting/advising for the company and others. Dr. Goyal reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Long-term follow-up data show a continued benefit for patients with advanced hepatocellular carcinoma (HCC) treated with nivolumab and ipilimumab after disease progression on sorafenib, according to investigators from the Checkmate 040 trial.

At a minimum follow-up of 44 months, the 3-year overall survival rate ranged from 30% to 42% in patients who received three different nivolumab-ipilimumab regimens, reported Anthony B. El-Khoueiry, MD, of the University of Southern California in Los Angeles.

“Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases,” Dr. El-Khoueiry said at the 2021 Gastrointestinal Cancers Symposium (Abstract 269).

The Checkmate 040 trial was designed to compare second- or later-line therapy with the two checkpoint inhibitors at two different dose schedules, followed by maintenance therapy, plus a third continuous therapy arm.

The trial included 148 patients with advanced HCC who experienced disease progression on sorafenib or could not tolerate the drug. They were randomly assigned on a 1:1:1 basis to receive:

• Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance at 240 mg every 2 weeks (nivo 1 + ipi 3).
• Nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance (nivo 3 + ipi 1).
• Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity (nivo 3 + ipi 1 Q6).

Based on earlier results of this trial, the nivo 1 + ipi 3 dose with nivolumab maintenance was approved in the United States for patients with advanced HCC previously treated with sorafenib.
 

Four years on

“Response outcomes at 44 months of follow-up were consistent with the primary analysis,” Dr. El-Khoueiry said.

The overall response rate at the most recent follow-up was 32% for nivo 1 + ipi 3, and 31% in each of the other arms.

The disease control rate – a combination of complete and partial responses and stable disease – was 54% in the nivo 1 + ipi 3 arm, 43% in the nivo 3 + ipi 1 arm, and 49% in the nivo 3 + ipi 1 Q6 arm.

The 36-month overall survival rates were 42%, 26%, and 30%, respectively. Kaplan-Meier curves for overall survival for both the primary analysis and the long-term follow-up displayed a survival advantage for nivo 1 + ipi 3 compared with the other two arms.
 

Safety

Treatment-related adverse events occurred more frequently in the nivo 1 + ipi 3 arm, which investigators attribute to the higher dose of ipilimumab. The most common grade 3 or 4 events in this arm were elevated liver enzymes and hyponatremia.

Immune-related adverse events also occurred more frequently in the nivo 1 + ipi 3 arm.

“Most immune-mediated adverse events were reversible and resolved when treated using an established algorithm, with steroids being the most common immune-modulating medication used. There were no additional discontinuations due to immune-mediated adverse events during the longer follow-up,” Dr. El-Khoueiry said.
 

Best combination?

“It’s certainly good data, and we’re happy about the response rate of about 30%, and that was confirmed at [the Gastrointestinal Cancers Symposium] with further follow-up of these patients,” said Lipika Goyal, MD, of Mass General Cancer Center in Boston.

Whether the nivo/ipi combination will turn out to be the optimum choice for patients with advanced HCC is still unknown; however, many different combinations of checkpoint inhibitors with or without tyrosine kinase inhibitors are currently being explored, and have not been compared in head-to-head trials, Dr. Goyal said in an interview. Dr. Goyal was not involved in the Checkmate 040 study.

Checkmate 040 was supported by Bristol Myers Squibb. Dr. El-Khoueiry disclosed honoraria from and consulting/advising for the company and others. Dr. Goyal reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

School antibullying programs may have small effect sizes but a valuable population impact, according to research published in JAMA Pediatrics.

A meta-analysis of 69 randomized trials with more than 111,600 participants found that school antibullying programs had a statistically significant effect on reducing bullying and improving mental health.

The investigators estimated population effect numbers for the interventions, such as the number of students needed to participate in an antibullying program to prevent one case of bullying.

Assuming a bullying prevalence of 15%, “an average antibullying intervention needs to include 207 people to prevent 1 case of bullying perpetration or 140 people to prevent 1 case of bullying exposure,” reported David Fraguas, MD, PhD, of the Institute of Psychiatry and Mental Health at Hospital Clínico San Carlos in Madrid, and colleagues. To improve mental health, the average antibullying program needs to include 107 people, the results indicate.

Few trials assessed the same antibullying program, so the researchers examined antibullying programs as a whole. Still, “not all antibullying programs are efficacious,” and “effectiveness may vary in different settings,” they noted.
 

Public health implications

Schools frequently implement programs to address bullying, which research suggests is a prevalent, modifiable risk factor for mental health disorders and therefore a “major public health concern,” the authors said. Studies have suggested that antibullying programs may be effective, though the evidence has been unclear.

“I see teens with mental health issues frequently in my practice, and often during their assessment, these patients and parents disclose a history of bullying at school or online,” said Kelly A. Curran, MD, associate professor of pediatrics at the University of Oklahoma, Oklahoma City. “The impact of bullying on these teens is obvious – from the mental health issues to school absenteeism and dropouts to long-term health consequences. Often, parents ask for guidance on how to ‘make it stop’ or for help working with the teen’s school. It’s hard in these cases as a clinician to know what to recommend – while it’s clear that the bullying is contributing to the teen’s health issues, giving evidenced-based guidance on bullying has been difficult.”

Relative to control groups

To assess the population impact of antibullying interventions, Dr. Fraguas and collaborators conducted random-effects meta-analyses. They identified 69 trials that included 56,511 participants in intervention groups and 55,148 in control groups. Five of the trials tested interventions targeting cyberbullying.

Participants ranged in age from 4 to 17 years, and the weighted average age was 11 years. The durations of the interventions ranged from 1 week to more than 2 years, with an average duration of 29.4 weeks.

“Antibullying interventions showed statistically significant effectiveness compared with control groups on all assessed bullying-related outcomes after the intervention,” the researchers reported. “The effect sizes were mostly statistically significant and small ... with high statistical heterogeneity and risk of publication bias. Antibullying interventions also showed statistically significant effectiveness in improving mental health problems (e.g., anxiety and depression) at study endpoint, with small effect size.”

Consistent with prior research, results varied by region. For example, interventions in Europe, where 31 of the trials were conducted, significantly decreased bullying exposure and attitudes that encourage bullying, whereas interventions in North America, where 19 of the trials were conducted, did not. In addition, European trials found greater effect sizes for the outcome measure of increasing attitudes that discourage bullying, compared with North American trials. The regional differences could reflect different programs or study designs, or differences in “social, educational, or cultural context,” the authors said.
 

‘Substantial’ impact

Together, the findings suggest that “universal antibullying interventions have a substantial population impact,” Dr. Fraguas and coauthors wrote. “To put these results into context, the [population impact number] is 35,450 for taking aspirin to avoid 1 death during the 6 months after a first nonhemorrhagic stroke, and the [population impact number] is 324 for human papillomavirus vaccination in girls to prevent cervical cancer.”

Furthermore, the interventions appear to be safe, they said. None of the trials in the meta-analysis reported an increase in bullying perpetration or bullying exposure at the end of the study or during follow-up, and mental health improved in all trials that assessed that outcome.
 

Pediatricians may be seen as resource

“From our survey work among parents all across Chicago, we know that almost one-half of all parents with children in school are concerned that their children get bullied,” said Matthew M. Davis, MD chair of the department of pediatrics at Ann & Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics, medicine, medical social sciences, and preventive medicine at Northwestern University in Chicago. “Among those parents, about one-half sought help from a teacher and about one-third asked a school administrator or school social worker for help. That means that schools are, by far, the go-to source for help when parents are worried about bullying.”

The survey of 1,642 parents in Chicago also found that 20% of parents with concerns sought help from mental health care providers, and 16% sought help from their pediatricians.

“Pediatricians can provide psychosocial support for their patients who are being bullied,” Dr. Davis said. “They can also talk with patients and their parents/guardians about how to team up with school personnel to address the bullying in the school environment.”

The meta-analysis was supported by grants from Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation), cofinanced by the European Regional Development Fund from the European Commission. It also was supported by Madrid Regional Government, European Union programs, Fundación Familia Alonso, Fundación Alicia Koplowitz, and Fundación Mutua Madrileña.

Dr. Fraguas disclosed consulting for or receiving fees from Angelini, Eisai, IE4Lab, Janssen, Lundbeck, and Otsuka and grant support from Fundación Alicia Koplowitz and Instituto de Salud Carlos III. Coauthors disclosed financial ties to pharmaceutical companies, as well as government and foundation grants. Dr. Curran is a member of the Pediatric News editorial advisory board. Dr. Davis had no relevant disclosures.

[email protected]

School antibullying programs may have small effect sizes but a valuable population impact, according to research published in JAMA Pediatrics.

A meta-analysis of 69 randomized trials with more than 111,600 participants found that school antibullying programs had a statistically significant effect on reducing bullying and improving mental health.

The investigators estimated population effect numbers for the interventions, such as the number of students needed to participate in an antibullying program to prevent one case of bullying.

Assuming a bullying prevalence of 15%, “an average antibullying intervention needs to include 207 people to prevent 1 case of bullying perpetration or 140 people to prevent 1 case of bullying exposure,” reported David Fraguas, MD, PhD, of the Institute of Psychiatry and Mental Health at Hospital Clínico San Carlos in Madrid, and colleagues. To improve mental health, the average antibullying program needs to include 107 people, the results indicate.

Few trials assessed the same antibullying program, so the researchers examined antibullying programs as a whole. Still, “not all antibullying programs are efficacious,” and “effectiveness may vary in different settings,” they noted.
 

Public health implications

Schools frequently implement programs to address bullying, which research suggests is a prevalent, modifiable risk factor for mental health disorders and therefore a “major public health concern,” the authors said. Studies have suggested that antibullying programs may be effective, though the evidence has been unclear.

“I see teens with mental health issues frequently in my practice, and often during their assessment, these patients and parents disclose a history of bullying at school or online,” said Kelly A. Curran, MD, associate professor of pediatrics at the University of Oklahoma, Oklahoma City. “The impact of bullying on these teens is obvious – from the mental health issues to school absenteeism and dropouts to long-term health consequences. Often, parents ask for guidance on how to ‘make it stop’ or for help working with the teen’s school. It’s hard in these cases as a clinician to know what to recommend – while it’s clear that the bullying is contributing to the teen’s health issues, giving evidenced-based guidance on bullying has been difficult.”

Relative to control groups

To assess the population impact of antibullying interventions, Dr. Fraguas and collaborators conducted random-effects meta-analyses. They identified 69 trials that included 56,511 participants in intervention groups and 55,148 in control groups. Five of the trials tested interventions targeting cyberbullying.

Participants ranged in age from 4 to 17 years, and the weighted average age was 11 years. The durations of the interventions ranged from 1 week to more than 2 years, with an average duration of 29.4 weeks.

“Antibullying interventions showed statistically significant effectiveness compared with control groups on all assessed bullying-related outcomes after the intervention,” the researchers reported. “The effect sizes were mostly statistically significant and small ... with high statistical heterogeneity and risk of publication bias. Antibullying interventions also showed statistically significant effectiveness in improving mental health problems (e.g., anxiety and depression) at study endpoint, with small effect size.”

Consistent with prior research, results varied by region. For example, interventions in Europe, where 31 of the trials were conducted, significantly decreased bullying exposure and attitudes that encourage bullying, whereas interventions in North America, where 19 of the trials were conducted, did not. In addition, European trials found greater effect sizes for the outcome measure of increasing attitudes that discourage bullying, compared with North American trials. The regional differences could reflect different programs or study designs, or differences in “social, educational, or cultural context,” the authors said.
 

‘Substantial’ impact

Together, the findings suggest that “universal antibullying interventions have a substantial population impact,” Dr. Fraguas and coauthors wrote. “To put these results into context, the [population impact number] is 35,450 for taking aspirin to avoid 1 death during the 6 months after a first nonhemorrhagic stroke, and the [population impact number] is 324 for human papillomavirus vaccination in girls to prevent cervical cancer.”

Furthermore, the interventions appear to be safe, they said. None of the trials in the meta-analysis reported an increase in bullying perpetration or bullying exposure at the end of the study or during follow-up, and mental health improved in all trials that assessed that outcome.
 

Pediatricians may be seen as resource

“From our survey work among parents all across Chicago, we know that almost one-half of all parents with children in school are concerned that their children get bullied,” said Matthew M. Davis, MD chair of the department of pediatrics at Ann & Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics, medicine, medical social sciences, and preventive medicine at Northwestern University in Chicago. “Among those parents, about one-half sought help from a teacher and about one-third asked a school administrator or school social worker for help. That means that schools are, by far, the go-to source for help when parents are worried about bullying.”

The survey of 1,642 parents in Chicago also found that 20% of parents with concerns sought help from mental health care providers, and 16% sought help from their pediatricians.

“Pediatricians can provide psychosocial support for their patients who are being bullied,” Dr. Davis said. “They can also talk with patients and their parents/guardians about how to team up with school personnel to address the bullying in the school environment.”

The meta-analysis was supported by grants from Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation), cofinanced by the European Regional Development Fund from the European Commission. It also was supported by Madrid Regional Government, European Union programs, Fundación Familia Alonso, Fundación Alicia Koplowitz, and Fundación Mutua Madrileña.

Dr. Fraguas disclosed consulting for or receiving fees from Angelini, Eisai, IE4Lab, Janssen, Lundbeck, and Otsuka and grant support from Fundación Alicia Koplowitz and Instituto de Salud Carlos III. Coauthors disclosed financial ties to pharmaceutical companies, as well as government and foundation grants. Dr. Curran is a member of the Pediatric News editorial advisory board. Dr. Davis had no relevant disclosures.

[email protected]

School antibullying programs may have small effect sizes but a valuable population impact, according to research published in JAMA Pediatrics.

A meta-analysis of 69 randomized trials with more than 111,600 participants found that school antibullying programs had a statistically significant effect on reducing bullying and improving mental health.

The investigators estimated population effect numbers for the interventions, such as the number of students needed to participate in an antibullying program to prevent one case of bullying.

Assuming a bullying prevalence of 15%, “an average antibullying intervention needs to include 207 people to prevent 1 case of bullying perpetration or 140 people to prevent 1 case of bullying exposure,” reported David Fraguas, MD, PhD, of the Institute of Psychiatry and Mental Health at Hospital Clínico San Carlos in Madrid, and colleagues. To improve mental health, the average antibullying program needs to include 107 people, the results indicate.

Few trials assessed the same antibullying program, so the researchers examined antibullying programs as a whole. Still, “not all antibullying programs are efficacious,” and “effectiveness may vary in different settings,” they noted.
 

Public health implications

Schools frequently implement programs to address bullying, which research suggests is a prevalent, modifiable risk factor for mental health disorders and therefore a “major public health concern,” the authors said. Studies have suggested that antibullying programs may be effective, though the evidence has been unclear.

“I see teens with mental health issues frequently in my practice, and often during their assessment, these patients and parents disclose a history of bullying at school or online,” said Kelly A. Curran, MD, associate professor of pediatrics at the University of Oklahoma, Oklahoma City. “The impact of bullying on these teens is obvious – from the mental health issues to school absenteeism and dropouts to long-term health consequences. Often, parents ask for guidance on how to ‘make it stop’ or for help working with the teen’s school. It’s hard in these cases as a clinician to know what to recommend – while it’s clear that the bullying is contributing to the teen’s health issues, giving evidenced-based guidance on bullying has been difficult.”

Relative to control groups

To assess the population impact of antibullying interventions, Dr. Fraguas and collaborators conducted random-effects meta-analyses. They identified 69 trials that included 56,511 participants in intervention groups and 55,148 in control groups. Five of the trials tested interventions targeting cyberbullying.

Participants ranged in age from 4 to 17 years, and the weighted average age was 11 years. The durations of the interventions ranged from 1 week to more than 2 years, with an average duration of 29.4 weeks.

“Antibullying interventions showed statistically significant effectiveness compared with control groups on all assessed bullying-related outcomes after the intervention,” the researchers reported. “The effect sizes were mostly statistically significant and small ... with high statistical heterogeneity and risk of publication bias. Antibullying interventions also showed statistically significant effectiveness in improving mental health problems (e.g., anxiety and depression) at study endpoint, with small effect size.”

Consistent with prior research, results varied by region. For example, interventions in Europe, where 31 of the trials were conducted, significantly decreased bullying exposure and attitudes that encourage bullying, whereas interventions in North America, where 19 of the trials were conducted, did not. In addition, European trials found greater effect sizes for the outcome measure of increasing attitudes that discourage bullying, compared with North American trials. The regional differences could reflect different programs or study designs, or differences in “social, educational, or cultural context,” the authors said.
 

‘Substantial’ impact

Together, the findings suggest that “universal antibullying interventions have a substantial population impact,” Dr. Fraguas and coauthors wrote. “To put these results into context, the [population impact number] is 35,450 for taking aspirin to avoid 1 death during the 6 months after a first nonhemorrhagic stroke, and the [population impact number] is 324 for human papillomavirus vaccination in girls to prevent cervical cancer.”

Furthermore, the interventions appear to be safe, they said. None of the trials in the meta-analysis reported an increase in bullying perpetration or bullying exposure at the end of the study or during follow-up, and mental health improved in all trials that assessed that outcome.
 

Pediatricians may be seen as resource

“From our survey work among parents all across Chicago, we know that almost one-half of all parents with children in school are concerned that their children get bullied,” said Matthew M. Davis, MD chair of the department of pediatrics at Ann & Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics, medicine, medical social sciences, and preventive medicine at Northwestern University in Chicago. “Among those parents, about one-half sought help from a teacher and about one-third asked a school administrator or school social worker for help. That means that schools are, by far, the go-to source for help when parents are worried about bullying.”

The survey of 1,642 parents in Chicago also found that 20% of parents with concerns sought help from mental health care providers, and 16% sought help from their pediatricians.

“Pediatricians can provide psychosocial support for their patients who are being bullied,” Dr. Davis said. “They can also talk with patients and their parents/guardians about how to team up with school personnel to address the bullying in the school environment.”

The meta-analysis was supported by grants from Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation), cofinanced by the European Regional Development Fund from the European Commission. It also was supported by Madrid Regional Government, European Union programs, Fundación Familia Alonso, Fundación Alicia Koplowitz, and Fundación Mutua Madrileña.

Dr. Fraguas disclosed consulting for or receiving fees from Angelini, Eisai, IE4Lab, Janssen, Lundbeck, and Otsuka and grant support from Fundación Alicia Koplowitz and Instituto de Salud Carlos III. Coauthors disclosed financial ties to pharmaceutical companies, as well as government and foundation grants. Dr. Curran is a member of the Pediatric News editorial advisory board. Dr. Davis had no relevant disclosures.

[email protected]

ILLUSTRATIVE CASE

An 8-year-old girl with congenital heart disease (status: post repair) arrives at your clinic for a routine appointment. Since the age of 12 months, she has experienced significant anxiety during medical visits, especially with blood draws and injections. She enjoys playing video games on her new tablet computer. Her parents want to know what you can do to reduce her anxiety and pain during today’s scheduled blood draw. Should you recommend that she continue playing video games during the venipuncture?

Adequately managing pain while performing venipuncture in children can improve the quality of the experience, reduce children’s fear of going to the doctor, and increase efficiency in medical practice.² Since pharmacologic pain-control methods may have adverse effects, distraction techniques—engaging the child in another activity during a procedure—are commonly used instead to help reduce a child’s pain. These techniques can be active or passive.

Studies have demonstrated that both active and passive distraction techniques reduce children’s pain during medical procedures, including venipuncture. Passive techniques, such as nurse coaching³ and watching cartoons,⁴ have been found to reduce distress and pain. Active distraction techniques, such as playing video games while undergoing a painful procedure (eg, dressing a wound), have been shown to be more effective than passive techniques.^5,6

A Cochrane review and meta-analysis of distraction and hypnosis for needle-related pain and distress in children demonstrated reduced pain, but the quality of evidence was low and the review recommended improved methodological rigor and trial reporting.⁷ Another systematic review and analysis showed strong support for distraction for reducing pain; however, the quality of evidence was low and the researchers cited problems with characteristics of the distraction interventions, child age, and risk of bias in the studies.⁸

There has been a lack of RCTs comparing the effectiveness and superiority of active vs passive distraction techniques. The first high-quality RCT to directly compare 3 of the most common distraction techniques to a control group was recently conducted in a large training and research hospital in Turkey.¹

STUDY SUMMARY

Pain and anxiety levels were lowest in actively distracted children

The RCT included 180 children ages 6 to 10 years randomly assigned to 1 of 3 intervention groups or a control group.¹ Phlebotomy was performed while children watched a cartoon, played a video game, were distracted by parental interaction, or had no distraction (control group).

Investigators independently measured pain and anxiety in the patient and perceived pain and anxiety according to both a family member and a health care worker (medical observer). Researchers used the previously validated Children’s Fear Scale and the Wong-Baker Pain Scale.^9,10 The Children’s Fear Scale was used to assess anxiety in children on a scale of 0 (picture of a calm face) to 4 (picture of the most fearful face). The Wong-Baker Pain Scale was used to assess pain on a scale of 0 (no hurt: happy face) to 10 (hurts worst: saddest face).

Continue to: Results

Results. The pain and anxiety scores were significantly lower in all of the intervention groups compared with the control group (P < .05). The video game (active distraction) group had the lowest levels of both pain and anxiety. The self-reported Children’s Fear Scale scores of children in the video game group were 0.27, compared with 0.76 in the cartoon group, 1.24 in the parental distraction group, and 2.22 in the control group. The anxiety scores recorded by the family member and the medical observer showed similar significant differences.

Allow children to play a video game during procedures such as venipuncture; doing so reduces pain and anxiety.

The Wong-Baker Pain Scale scores showed similar differences in self-reported pain for the video game group (1.42) compared with the cartoon group (3.02), the parental distraction group (2.89), and the control group (5.11). Pain scores reported by the family member and the medical observer (respectively) also reflected benefit from any type of distraction, with active game-playing as the most effective type of distraction (video game: 1.69 and 1.96; cartoon: 3.07 and 3.20; parental distraction: 3.56 and 4.22; and control: 5.29 and 6.13).

In addition, the intraclass correlation coefficient was 0.67 to 0.924 (P < .01), suggesting that the reports from the child, parent, and medical observer about the child’s pain and anxiety were highly correlated.

WHAT'S NEW

All distraction techniques provide benefit, but there’s a clear winner

In this RCT of children undergoing phlebotomy, both active and passive distraction techniques were superior to no distraction in terms of perceived pain and anxiety by the child, a health care provider, or a parent. The active-distraction group played a video game, while the passive-distraction groups watched a cartoon or interacted with a parent. Active distraction was superior to passive distraction.

CAVEATS

Procedure time was short; intervention not blinded

One potential weakness of this study is that it was not a double-blinded trial. Blinding was not possible for much of the study as the patient, parent, and medical observer were fully aware of the intervention or lack thereof. However, the parent and medical observer were blinded to each other’s assessments of the child’s pain and anxiety.

Continue to: Furthermore, the study...

Furthermore, the study was conducted at a single institution in Turkey. There could be cultural differences in reporting of pain and anxiety compared to Western cultures.

Finally, the average duration of the procedure in this study was 3 minutes, with a range of 1 to 5 minutes. It is unclear if the findings can be extrapolated to more time-consuming procedures.

CHALLENGES TO IMPLEMENTATION

Technology is not available to all

The use of tablet computers may seem increasingly ubiquitous, but not all families have access to these devices. Another challenge is that phlebotomy/clinic personnel must learn to work around the device.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

An 8-year-old girl with congenital heart disease (status: post repair) arrives at your clinic for a routine appointment. Since the age of 12 months, she has experienced significant anxiety during medical visits, especially with blood draws and injections. She enjoys playing video games on her new tablet computer. Her parents want to know what you can do to reduce her anxiety and pain during today’s scheduled blood draw. Should you recommend that she continue playing video games during the venipuncture?

Adequately managing pain while performing venipuncture in children can improve the quality of the experience, reduce children’s fear of going to the doctor, and increase efficiency in medical practice.² Since pharmacologic pain-control methods may have adverse effects, distraction techniques—engaging the child in another activity during a procedure—are commonly used instead to help reduce a child’s pain. These techniques can be active or passive.

Studies have demonstrated that both active and passive distraction techniques reduce children’s pain during medical procedures, including venipuncture. Passive techniques, such as nurse coaching³ and watching cartoons,⁴ have been found to reduce distress and pain. Active distraction techniques, such as playing video games while undergoing a painful procedure (eg, dressing a wound), have been shown to be more effective than passive techniques.^5,6

A Cochrane review and meta-analysis of distraction and hypnosis for needle-related pain and distress in children demonstrated reduced pain, but the quality of evidence was low and the review recommended improved methodological rigor and trial reporting.⁷ Another systematic review and analysis showed strong support for distraction for reducing pain; however, the quality of evidence was low and the researchers cited problems with characteristics of the distraction interventions, child age, and risk of bias in the studies.⁸

There has been a lack of RCTs comparing the effectiveness and superiority of active vs passive distraction techniques. The first high-quality RCT to directly compare 3 of the most common distraction techniques to a control group was recently conducted in a large training and research hospital in Turkey.¹

STUDY SUMMARY

Pain and anxiety levels were lowest in actively distracted children

The RCT included 180 children ages 6 to 10 years randomly assigned to 1 of 3 intervention groups or a control group.¹ Phlebotomy was performed while children watched a cartoon, played a video game, were distracted by parental interaction, or had no distraction (control group).

Investigators independently measured pain and anxiety in the patient and perceived pain and anxiety according to both a family member and a health care worker (medical observer). Researchers used the previously validated Children’s Fear Scale and the Wong-Baker Pain Scale.^9,10 The Children’s Fear Scale was used to assess anxiety in children on a scale of 0 (picture of a calm face) to 4 (picture of the most fearful face). The Wong-Baker Pain Scale was used to assess pain on a scale of 0 (no hurt: happy face) to 10 (hurts worst: saddest face).

Continue to: Results

Results. The pain and anxiety scores were significantly lower in all of the intervention groups compared with the control group (P < .05). The video game (active distraction) group had the lowest levels of both pain and anxiety. The self-reported Children’s Fear Scale scores of children in the video game group were 0.27, compared with 0.76 in the cartoon group, 1.24 in the parental distraction group, and 2.22 in the control group. The anxiety scores recorded by the family member and the medical observer showed similar significant differences.

Allow children to play a video game during procedures such as venipuncture; doing so reduces pain and anxiety.

The Wong-Baker Pain Scale scores showed similar differences in self-reported pain for the video game group (1.42) compared with the cartoon group (3.02), the parental distraction group (2.89), and the control group (5.11). Pain scores reported by the family member and the medical observer (respectively) also reflected benefit from any type of distraction, with active game-playing as the most effective type of distraction (video game: 1.69 and 1.96; cartoon: 3.07 and 3.20; parental distraction: 3.56 and 4.22; and control: 5.29 and 6.13).

In addition, the intraclass correlation coefficient was 0.67 to 0.924 (P < .01), suggesting that the reports from the child, parent, and medical observer about the child’s pain and anxiety were highly correlated.

WHAT'S NEW

All distraction techniques provide benefit, but there’s a clear winner

In this RCT of children undergoing phlebotomy, both active and passive distraction techniques were superior to no distraction in terms of perceived pain and anxiety by the child, a health care provider, or a parent. The active-distraction group played a video game, while the passive-distraction groups watched a cartoon or interacted with a parent. Active distraction was superior to passive distraction.

CAVEATS

Procedure time was short; intervention not blinded

One potential weakness of this study is that it was not a double-blinded trial. Blinding was not possible for much of the study as the patient, parent, and medical observer were fully aware of the intervention or lack thereof. However, the parent and medical observer were blinded to each other’s assessments of the child’s pain and anxiety.

Continue to: Furthermore, the study...

Furthermore, the study was conducted at a single institution in Turkey. There could be cultural differences in reporting of pain and anxiety compared to Western cultures.

Finally, the average duration of the procedure in this study was 3 minutes, with a range of 1 to 5 minutes. It is unclear if the findings can be extrapolated to more time-consuming procedures.

CHALLENGES TO IMPLEMENTATION

Technology is not available to all

The use of tablet computers may seem increasingly ubiquitous, but not all families have access to these devices. Another challenge is that phlebotomy/clinic personnel must learn to work around the device.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

An 8-year-old girl with congenital heart disease (status: post repair) arrives at your clinic for a routine appointment. Since the age of 12 months, she has experienced significant anxiety during medical visits, especially with blood draws and injections. She enjoys playing video games on her new tablet computer. Her parents want to know what you can do to reduce her anxiety and pain during today’s scheduled blood draw. Should you recommend that she continue playing video games during the venipuncture?

Adequately managing pain while performing venipuncture in children can improve the quality of the experience, reduce children’s fear of going to the doctor, and increase efficiency in medical practice.² Since pharmacologic pain-control methods may have adverse effects, distraction techniques—engaging the child in another activity during a procedure—are commonly used instead to help reduce a child’s pain. These techniques can be active or passive.

Studies have demonstrated that both active and passive distraction techniques reduce children’s pain during medical procedures, including venipuncture. Passive techniques, such as nurse coaching³ and watching cartoons,⁴ have been found to reduce distress and pain. Active distraction techniques, such as playing video games while undergoing a painful procedure (eg, dressing a wound), have been shown to be more effective than passive techniques.^5,6

A Cochrane review and meta-analysis of distraction and hypnosis for needle-related pain and distress in children demonstrated reduced pain, but the quality of evidence was low and the review recommended improved methodological rigor and trial reporting.⁷ Another systematic review and analysis showed strong support for distraction for reducing pain; however, the quality of evidence was low and the researchers cited problems with characteristics of the distraction interventions, child age, and risk of bias in the studies.⁸

There has been a lack of RCTs comparing the effectiveness and superiority of active vs passive distraction techniques. The first high-quality RCT to directly compare 3 of the most common distraction techniques to a control group was recently conducted in a large training and research hospital in Turkey.¹

STUDY SUMMARY

Pain and anxiety levels were lowest in actively distracted children

The RCT included 180 children ages 6 to 10 years randomly assigned to 1 of 3 intervention groups or a control group.¹ Phlebotomy was performed while children watched a cartoon, played a video game, were distracted by parental interaction, or had no distraction (control group).

Investigators independently measured pain and anxiety in the patient and perceived pain and anxiety according to both a family member and a health care worker (medical observer). Researchers used the previously validated Children’s Fear Scale and the Wong-Baker Pain Scale.^9,10 The Children’s Fear Scale was used to assess anxiety in children on a scale of 0 (picture of a calm face) to 4 (picture of the most fearful face). The Wong-Baker Pain Scale was used to assess pain on a scale of 0 (no hurt: happy face) to 10 (hurts worst: saddest face).

Continue to: Results

Results. The pain and anxiety scores were significantly lower in all of the intervention groups compared with the control group (P < .05). The video game (active distraction) group had the lowest levels of both pain and anxiety. The self-reported Children’s Fear Scale scores of children in the video game group were 0.27, compared with 0.76 in the cartoon group, 1.24 in the parental distraction group, and 2.22 in the control group. The anxiety scores recorded by the family member and the medical observer showed similar significant differences.

Allow children to play a video game during procedures such as venipuncture; doing so reduces pain and anxiety.

The Wong-Baker Pain Scale scores showed similar differences in self-reported pain for the video game group (1.42) compared with the cartoon group (3.02), the parental distraction group (2.89), and the control group (5.11). Pain scores reported by the family member and the medical observer (respectively) also reflected benefit from any type of distraction, with active game-playing as the most effective type of distraction (video game: 1.69 and 1.96; cartoon: 3.07 and 3.20; parental distraction: 3.56 and 4.22; and control: 5.29 and 6.13).

In addition, the intraclass correlation coefficient was 0.67 to 0.924 (P < .01), suggesting that the reports from the child, parent, and medical observer about the child’s pain and anxiety were highly correlated.

WHAT'S NEW

All distraction techniques provide benefit, but there’s a clear winner

In this RCT of children undergoing phlebotomy, both active and passive distraction techniques were superior to no distraction in terms of perceived pain and anxiety by the child, a health care provider, or a parent. The active-distraction group played a video game, while the passive-distraction groups watched a cartoon or interacted with a parent. Active distraction was superior to passive distraction.

CAVEATS

Procedure time was short; intervention not blinded

One potential weakness of this study is that it was not a double-blinded trial. Blinding was not possible for much of the study as the patient, parent, and medical observer were fully aware of the intervention or lack thereof. However, the parent and medical observer were blinded to each other’s assessments of the child’s pain and anxiety.

Continue to: Furthermore, the study...

Furthermore, the study was conducted at a single institution in Turkey. There could be cultural differences in reporting of pain and anxiety compared to Western cultures.

Finally, the average duration of the procedure in this study was 3 minutes, with a range of 1 to 5 minutes. It is unclear if the findings can be extrapolated to more time-consuming procedures.

CHALLENGES TO IMPLEMENTATION

Technology is not available to all

The use of tablet computers may seem increasingly ubiquitous, but not all families have access to these devices. Another challenge is that phlebotomy/clinic personnel must learn to work around the device.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

EVIDENCE SUMMARY

Higher odds of depression in youth and adolescents with concussion

A 2019 prospective cohort study used data from the 2017 Nevada Youth Risk Behavior Surveillance Survey (YRBSS) to evaluate the relationship between concussion and depression in high school students.¹ Included students were physically active for at least 60 minutes on 5 or more days per week or played on at least 1 sports team (N = 3427; 9th-12th grade students from 98 schools). When compared to the total population of included students and controlled for covariates, those who self-reported a concussion within the past 12 months (N = 664) had a higher adjusted odds ratio (aOR) of depressive symptoms (aOR = 1.5; 95% confidence interval [CI], 1.1-1.9). Depressive symptoms were reported in 38.1% of patients with a history of concussion, compared to 29.2% of patients who did not report a concussion in the past 12 months.

A 2014 retrospective cohort study examined data from the 2007-2008 National Survey of Children’s Health and evaluated the association between previous concussion and current depression diagnosis in youth ages 12 to 17 years without a current concussion (N = 36,060).² Parents were contacted by random-digit dialing, prompted with a description of depression, and asked if their child currently had a clinical diagnosis of depression and whether a concussion had ever been diagnosed. A prior diagnosis of concussion was associated with greater risk for current depression compared to youth with no concussion history (aOR = 3.3; 95% CI, 2-5.5). Current depression was reported in 10.1% of patients with a history of concussion compared to 3.4% of patients with no history of concussion.

Findings vary among college athletes

A 2015 case-control study examined the prevalence of depressive symptoms in college athletes diagnosed with concussion compared to an athletic control group.³ The intervention group (N = 84; 77% male; average age, 18.4 years) received a concussion diagnosis from the team physician or certified athletic trainer. The athletic control group (N = 42; 55% male; average age, 18.9 years) reported no concussions in the past year.

The Beck Depression Inventory–Fast Screen (BDI-FS) was administered to the concussion group at baseline and postconcussion, and to the control group at 2 time points, with an average interval of 6.8 weeks. A score of ≥ 4 on the BDI-FS (scoring range, 0-21; higher score suggestive of more severe depression) indicated athletes at risk for depression. Concussed athletes exhibited a statistically significant increase in depression symptoms compared to control participants (20% vs 5%; x²₁ = 5.2; P = .02).

A 2018 cross-sectional study examined the association between concussion and adverse health outcomes in former college football players who played at least 1 year in college (1999-2001) but had no professional football experience.⁴ The cohort (N = 204; average age, 35) self-reported (15 years after their college career ended) the number of concussions sustained during high school and college sports performance. Reports were then stratified into 3 categories: no concussions, 1 or 2 concussions, and ≥ 3 concussions. The Patient Health Questionnaire (PHQ-9) was used to screen for depression, with scores categorized to no or mild depression (< 10) and moderate-to-­severe depression (≥ 10).

Controlling for body mass index, athletes reporting ≥ 3 concussions had a higher prevalence of depression compared to those reporting no concussions (prevalence ratio [PR] = 4.2; 95% CI, 1.0-16.3) or 1 to 2 concussions (PR = 2.8; 95% CI, 1.3-6.0). No statistically significant association between concussion and depression was observed with athletes reporting 1 to 2 concussions compared to 0 concussions.

The exact relationship— degree and context— between concussion and depression remains vague.

A 2015 prospective longitudinal cohort study examined postinjury depressive symptoms in 3 groups of Division 1 male and female college student athletes (N = 21; ages 18-22).⁵ Physician-diagnosed ­concussed (N = 7) and injured but nonconcussed (N = 7) athletes completed the Center for Epidemiological Studies Depression Scale (CES-D) at baseline and at 1 week, 1 month, and 3 months postinjury. Sport-matched healthy athletes (N = 7) completed it only at baseline. A CES-D score of ≥ 16 (range, 0-60) indicated a risk for clinical depression. Participants with a history of depression or other injury resulting in ≥ 1 day of time lost within the past 3 months were excluded.

Continue to: While both groups...

While both groups showed a significant increase from baseline CES-D scores, there were no significant differences in depressive symptoms between concussed (mean CES-D score ± standard deviation [SD]: baseline, 6.7 ± 3.9; 1 week, 11 ± 5.3; 1 month, 8.3 ± 5; 3 months, 6.4 ± 5.4) and injured but nonconcussed participants (mean CES-D score ± SD: baseline, 5.7 ± 2.8; 1 week, 9.1 ± 4; 1 month, 8.9 ± 4.6; 3 months, 6.9 ± 2.8) at any of the postinjury time points.

Findings among semipro and pro athletes appear to vary by sport

A 2016 prospective cohort study assessed the impact of concussive events on incidence of depression in active semiprofessional and professional football players who had previously sustained ≥ 1 concussions.⁶ Participants (N = 27) answered an anonymous online survey that included the revised version of the CES-D (CESD-R) to determine level of depression (a score of ≥ 16 defined clinical depression). Players with a CESD-R score ≥ 16 (N = 16) sustained a significantly greater average number of concussions compared to those who scored < 16 (N = 11; 3.8 vs. 1.6, P = .0004). Players who sustained ≥ 3 concussions scored significantly higher on the CESD-R than players with ≤ 2 concussions (average score, 24 vs 15.6; P = .03).

A 2017 case-control study examined the long-term health outcomes of retired Scottish male rugby players (N = 52; mean age, 54 years) with a history of mild concussion compared to males of similar age with no previous history of concussion (N = 29; mean age, 55).⁷ The Hospital Anxiety and Depression Scale (HADS) was used to assess depression on a 21-point scale (normal = 0-7; borderline, 8-10; abnormal, 11-21). There was no significant difference observed in mean HADS scores between the rugby players and controls, respectively (2.8 ± 2.1 vs 2.6 ± 2 .8; P = .941).

A 2013 case-control study of 30 retired NFL players with 29 controls matched for age, estimated IQ, and education examined the relationship between a remote history of concussion and current symptoms of depression.⁸ Concussion history was self-reported by the retired players. Controls with a history of concussion were excluded from the study. The Beck Depression Inventory-II (BDI-II) was used to measure depression symptoms, with a score of 1 to 9 designating minimal depression and ≥ 10 mild-to-moderate depression. Retired players scored significantly higher on the BDI-II compared to the controls (8.8 vs 2.8; P = .001).

Editor’s takeaway

Concussions include cognitive compromise. An astute clinician’s concern for depression as a sequela makes sense. This evidence contributes to that conjecture. However, the authors of this Clinical Inquiry correctly outline the limitations, inconsistencies, and biases of the evidence. The exact relationship—degree and context—between concussion and depression remains vague.

EVIDENCE SUMMARY

Higher odds of depression in youth and adolescents with concussion

A 2019 prospective cohort study used data from the 2017 Nevada Youth Risk Behavior Surveillance Survey (YRBSS) to evaluate the relationship between concussion and depression in high school students.¹ Included students were physically active for at least 60 minutes on 5 or more days per week or played on at least 1 sports team (N = 3427; 9th-12th grade students from 98 schools). When compared to the total population of included students and controlled for covariates, those who self-reported a concussion within the past 12 months (N = 664) had a higher adjusted odds ratio (aOR) of depressive symptoms (aOR = 1.5; 95% confidence interval [CI], 1.1-1.9). Depressive symptoms were reported in 38.1% of patients with a history of concussion, compared to 29.2% of patients who did not report a concussion in the past 12 months.

A 2014 retrospective cohort study examined data from the 2007-2008 National Survey of Children’s Health and evaluated the association between previous concussion and current depression diagnosis in youth ages 12 to 17 years without a current concussion (N = 36,060).² Parents were contacted by random-digit dialing, prompted with a description of depression, and asked if their child currently had a clinical diagnosis of depression and whether a concussion had ever been diagnosed. A prior diagnosis of concussion was associated with greater risk for current depression compared to youth with no concussion history (aOR = 3.3; 95% CI, 2-5.5). Current depression was reported in 10.1% of patients with a history of concussion compared to 3.4% of patients with no history of concussion.

Findings vary among college athletes

A 2015 case-control study examined the prevalence of depressive symptoms in college athletes diagnosed with concussion compared to an athletic control group.³ The intervention group (N = 84; 77% male; average age, 18.4 years) received a concussion diagnosis from the team physician or certified athletic trainer. The athletic control group (N = 42; 55% male; average age, 18.9 years) reported no concussions in the past year.

The Beck Depression Inventory–Fast Screen (BDI-FS) was administered to the concussion group at baseline and postconcussion, and to the control group at 2 time points, with an average interval of 6.8 weeks. A score of ≥ 4 on the BDI-FS (scoring range, 0-21; higher score suggestive of more severe depression) indicated athletes at risk for depression. Concussed athletes exhibited a statistically significant increase in depression symptoms compared to control participants (20% vs 5%; x²₁ = 5.2; P = .02).

A 2018 cross-sectional study examined the association between concussion and adverse health outcomes in former college football players who played at least 1 year in college (1999-2001) but had no professional football experience.⁴ The cohort (N = 204; average age, 35) self-reported (15 years after their college career ended) the number of concussions sustained during high school and college sports performance. Reports were then stratified into 3 categories: no concussions, 1 or 2 concussions, and ≥ 3 concussions. The Patient Health Questionnaire (PHQ-9) was used to screen for depression, with scores categorized to no or mild depression (< 10) and moderate-to-­severe depression (≥ 10).

Controlling for body mass index, athletes reporting ≥ 3 concussions had a higher prevalence of depression compared to those reporting no concussions (prevalence ratio [PR] = 4.2; 95% CI, 1.0-16.3) or 1 to 2 concussions (PR = 2.8; 95% CI, 1.3-6.0). No statistically significant association between concussion and depression was observed with athletes reporting 1 to 2 concussions compared to 0 concussions.

The exact relationship— degree and context— between concussion and depression remains vague.

A 2015 prospective longitudinal cohort study examined postinjury depressive symptoms in 3 groups of Division 1 male and female college student athletes (N = 21; ages 18-22).⁵ Physician-diagnosed ­concussed (N = 7) and injured but nonconcussed (N = 7) athletes completed the Center for Epidemiological Studies Depression Scale (CES-D) at baseline and at 1 week, 1 month, and 3 months postinjury. Sport-matched healthy athletes (N = 7) completed it only at baseline. A CES-D score of ≥ 16 (range, 0-60) indicated a risk for clinical depression. Participants with a history of depression or other injury resulting in ≥ 1 day of time lost within the past 3 months were excluded.

Continue to: While both groups...

While both groups showed a significant increase from baseline CES-D scores, there were no significant differences in depressive symptoms between concussed (mean CES-D score ± standard deviation [SD]: baseline, 6.7 ± 3.9; 1 week, 11 ± 5.3; 1 month, 8.3 ± 5; 3 months, 6.4 ± 5.4) and injured but nonconcussed participants (mean CES-D score ± SD: baseline, 5.7 ± 2.8; 1 week, 9.1 ± 4; 1 month, 8.9 ± 4.6; 3 months, 6.9 ± 2.8) at any of the postinjury time points.

Findings among semipro and pro athletes appear to vary by sport

A 2016 prospective cohort study assessed the impact of concussive events on incidence of depression in active semiprofessional and professional football players who had previously sustained ≥ 1 concussions.⁶ Participants (N = 27) answered an anonymous online survey that included the revised version of the CES-D (CESD-R) to determine level of depression (a score of ≥ 16 defined clinical depression). Players with a CESD-R score ≥ 16 (N = 16) sustained a significantly greater average number of concussions compared to those who scored < 16 (N = 11; 3.8 vs. 1.6, P = .0004). Players who sustained ≥ 3 concussions scored significantly higher on the CESD-R than players with ≤ 2 concussions (average score, 24 vs 15.6; P = .03).

A 2017 case-control study examined the long-term health outcomes of retired Scottish male rugby players (N = 52; mean age, 54 years) with a history of mild concussion compared to males of similar age with no previous history of concussion (N = 29; mean age, 55).⁷ The Hospital Anxiety and Depression Scale (HADS) was used to assess depression on a 21-point scale (normal = 0-7; borderline, 8-10; abnormal, 11-21). There was no significant difference observed in mean HADS scores between the rugby players and controls, respectively (2.8 ± 2.1 vs 2.6 ± 2 .8; P = .941).

A 2013 case-control study of 30 retired NFL players with 29 controls matched for age, estimated IQ, and education examined the relationship between a remote history of concussion and current symptoms of depression.⁸ Concussion history was self-reported by the retired players. Controls with a history of concussion were excluded from the study. The Beck Depression Inventory-II (BDI-II) was used to measure depression symptoms, with a score of 1 to 9 designating minimal depression and ≥ 10 mild-to-moderate depression. Retired players scored significantly higher on the BDI-II compared to the controls (8.8 vs 2.8; P = .001).

Editor’s takeaway

Concussions include cognitive compromise. An astute clinician’s concern for depression as a sequela makes sense. This evidence contributes to that conjecture. However, the authors of this Clinical Inquiry correctly outline the limitations, inconsistencies, and biases of the evidence. The exact relationship—degree and context—between concussion and depression remains vague.

EVIDENCE SUMMARY

Higher odds of depression in youth and adolescents with concussion

A 2019 prospective cohort study used data from the 2017 Nevada Youth Risk Behavior Surveillance Survey (YRBSS) to evaluate the relationship between concussion and depression in high school students.¹ Included students were physically active for at least 60 minutes on 5 or more days per week or played on at least 1 sports team (N = 3427; 9th-12th grade students from 98 schools). When compared to the total population of included students and controlled for covariates, those who self-reported a concussion within the past 12 months (N = 664) had a higher adjusted odds ratio (aOR) of depressive symptoms (aOR = 1.5; 95% confidence interval [CI], 1.1-1.9). Depressive symptoms were reported in 38.1% of patients with a history of concussion, compared to 29.2% of patients who did not report a concussion in the past 12 months.

A 2014 retrospective cohort study examined data from the 2007-2008 National Survey of Children’s Health and evaluated the association between previous concussion and current depression diagnosis in youth ages 12 to 17 years without a current concussion (N = 36,060).² Parents were contacted by random-digit dialing, prompted with a description of depression, and asked if their child currently had a clinical diagnosis of depression and whether a concussion had ever been diagnosed. A prior diagnosis of concussion was associated with greater risk for current depression compared to youth with no concussion history (aOR = 3.3; 95% CI, 2-5.5). Current depression was reported in 10.1% of patients with a history of concussion compared to 3.4% of patients with no history of concussion.

Findings vary among college athletes

A 2015 case-control study examined the prevalence of depressive symptoms in college athletes diagnosed with concussion compared to an athletic control group.³ The intervention group (N = 84; 77% male; average age, 18.4 years) received a concussion diagnosis from the team physician or certified athletic trainer. The athletic control group (N = 42; 55% male; average age, 18.9 years) reported no concussions in the past year.

The Beck Depression Inventory–Fast Screen (BDI-FS) was administered to the concussion group at baseline and postconcussion, and to the control group at 2 time points, with an average interval of 6.8 weeks. A score of ≥ 4 on the BDI-FS (scoring range, 0-21; higher score suggestive of more severe depression) indicated athletes at risk for depression. Concussed athletes exhibited a statistically significant increase in depression symptoms compared to control participants (20% vs 5%; x²₁ = 5.2; P = .02).

A 2018 cross-sectional study examined the association between concussion and adverse health outcomes in former college football players who played at least 1 year in college (1999-2001) but had no professional football experience.⁴ The cohort (N = 204; average age, 35) self-reported (15 years after their college career ended) the number of concussions sustained during high school and college sports performance. Reports were then stratified into 3 categories: no concussions, 1 or 2 concussions, and ≥ 3 concussions. The Patient Health Questionnaire (PHQ-9) was used to screen for depression, with scores categorized to no or mild depression (< 10) and moderate-to-­severe depression (≥ 10).

Controlling for body mass index, athletes reporting ≥ 3 concussions had a higher prevalence of depression compared to those reporting no concussions (prevalence ratio [PR] = 4.2; 95% CI, 1.0-16.3) or 1 to 2 concussions (PR = 2.8; 95% CI, 1.3-6.0). No statistically significant association between concussion and depression was observed with athletes reporting 1 to 2 concussions compared to 0 concussions.

The exact relationship— degree and context— between concussion and depression remains vague.

A 2015 prospective longitudinal cohort study examined postinjury depressive symptoms in 3 groups of Division 1 male and female college student athletes (N = 21; ages 18-22).⁵ Physician-diagnosed ­concussed (N = 7) and injured but nonconcussed (N = 7) athletes completed the Center for Epidemiological Studies Depression Scale (CES-D) at baseline and at 1 week, 1 month, and 3 months postinjury. Sport-matched healthy athletes (N = 7) completed it only at baseline. A CES-D score of ≥ 16 (range, 0-60) indicated a risk for clinical depression. Participants with a history of depression or other injury resulting in ≥ 1 day of time lost within the past 3 months were excluded.

Continue to: While both groups...

While both groups showed a significant increase from baseline CES-D scores, there were no significant differences in depressive symptoms between concussed (mean CES-D score ± standard deviation [SD]: baseline, 6.7 ± 3.9; 1 week, 11 ± 5.3; 1 month, 8.3 ± 5; 3 months, 6.4 ± 5.4) and injured but nonconcussed participants (mean CES-D score ± SD: baseline, 5.7 ± 2.8; 1 week, 9.1 ± 4; 1 month, 8.9 ± 4.6; 3 months, 6.9 ± 2.8) at any of the postinjury time points.

Findings among semipro and pro athletes appear to vary by sport

A 2016 prospective cohort study assessed the impact of concussive events on incidence of depression in active semiprofessional and professional football players who had previously sustained ≥ 1 concussions.⁶ Participants (N = 27) answered an anonymous online survey that included the revised version of the CES-D (CESD-R) to determine level of depression (a score of ≥ 16 defined clinical depression). Players with a CESD-R score ≥ 16 (N = 16) sustained a significantly greater average number of concussions compared to those who scored < 16 (N = 11; 3.8 vs. 1.6, P = .0004). Players who sustained ≥ 3 concussions scored significantly higher on the CESD-R than players with ≤ 2 concussions (average score, 24 vs 15.6; P = .03).

A 2017 case-control study examined the long-term health outcomes of retired Scottish male rugby players (N = 52; mean age, 54 years) with a history of mild concussion compared to males of similar age with no previous history of concussion (N = 29; mean age, 55).⁷ The Hospital Anxiety and Depression Scale (HADS) was used to assess depression on a 21-point scale (normal = 0-7; borderline, 8-10; abnormal, 11-21). There was no significant difference observed in mean HADS scores between the rugby players and controls, respectively (2.8 ± 2.1 vs 2.6 ± 2 .8; P = .941).

A 2013 case-control study of 30 retired NFL players with 29 controls matched for age, estimated IQ, and education examined the relationship between a remote history of concussion and current symptoms of depression.⁸ Concussion history was self-reported by the retired players. Controls with a history of concussion were excluded from the study. The Beck Depression Inventory-II (BDI-II) was used to measure depression symptoms, with a score of 1 to 9 designating minimal depression and ≥ 10 mild-to-moderate depression. Retired players scored significantly higher on the BDI-II compared to the controls (8.8 vs 2.8; P = .001).

Editor’s takeaway

Concussions include cognitive compromise. An astute clinician’s concern for depression as a sequela makes sense. This evidence contributes to that conjecture. However, the authors of this Clinical Inquiry correctly outline the limitations, inconsistencies, and biases of the evidence. The exact relationship—degree and context—between concussion and depression remains vague.

A model that crunches data from routine blood tests can accurately identify cancer patients who will develop acute kidney injury (AKI) up to a month before it happens, according to a cohort study.

The algorithm spotted nearly 74% of the patients who went on to develop AKI within 30 days, providing a window for intervention and possibly prevention, according to investigators.

These results were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (abstract PR-11).

“Cancer patients are a high-risk population for AKI due to the nature of their treatment and illness,” said presenter Lauren A. Scanlon, PhD, a data scientist at The Christie NHS Foundation Trust in Huddersfield, England. “AKI causes a huge disruption in treatment and distress for the patient, so it would be amazing if we could, say, predict the AKI before it occurs and prevent it from even happening.”

U.K. health care providers are already using an algorithm to monitor patients’ creatinine levels, comparing new values against historic ones, Dr. Scanlon explained. When that algorithm detects AKI, it issues an alert that triggers implementation of an AKI care bundle, including measures such as fluid monitoring and medication review, within 24 hours.

Taking this concept further, Dr. Scanlon and colleagues developed a random forest model, a type of machine learning algorithm, that incorporates other markers from blood tests routinely obtained for all patients, with the aim of predicting AKI up to 30 days in advance.

“Using routinely collected blood test results will ensure that the model is applicable to all our patients and can be implemented in an automated manner,” Dr. Scanlon noted.

The investigators developed and trained the model using 597,403 blood test results from 48,865 patients undergoing cancer treatment between January 2017 and May 2020.

The model assigns patients to five categories of risk for AKI in the next 30 days: very low, low, medium, high, and very high.

“We wanted the model to output in this way so that it could be used by clinicians alongside their own insight and knowledge on a case-by-case basis,” Dr. Scanlon explained.

The investigators then prospectively validated the model and its risk categories in another 9,913 patients who underwent cancer treatment between June and August 2020.

Using a model threshold of medium risk or higher, the model correctly predicted AKI in 330 (73.8%) of the 447 patients in the validation cohort who ultimately developed AKI.

“This is pretty amazing and shows that this model really is working and can correctly detect these AKIs up to 30 days before they occur, giving a huge window to put in place preventive strategies,” Dr. Scanlon said.

Among the 154 patients in whom the model incorrectly predicted AKI, 9 patients had only a single follow-up blood test and 17 patients did not have any, leaving their actual outcomes unclear.

“Given that AKI detection uses blood tests, an AKI in these patients was never confirmed,” Dr. Scanlon noted. “So this could give a potential benefit of the model that we never intended: It could reduce undiagnosed AKI by flagging those who are at risk.”

“Our next steps are to test the model through a technology clinical trial to see if putting intervention strategies in place does prevent these AKIs from taking place,” Dr. Scanlon concluded. “We are also going to move to ongoing monitoring of the model performance.”

Dr. Scanlon disclosed no conflicts of interest. The study did not receive specific funding.

A model that crunches data from routine blood tests can accurately identify cancer patients who will develop acute kidney injury (AKI) up to a month before it happens, according to a cohort study.

The algorithm spotted nearly 74% of the patients who went on to develop AKI within 30 days, providing a window for intervention and possibly prevention, according to investigators.

These results were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (abstract PR-11).

“Cancer patients are a high-risk population for AKI due to the nature of their treatment and illness,” said presenter Lauren A. Scanlon, PhD, a data scientist at The Christie NHS Foundation Trust in Huddersfield, England. “AKI causes a huge disruption in treatment and distress for the patient, so it would be amazing if we could, say, predict the AKI before it occurs and prevent it from even happening.”

U.K. health care providers are already using an algorithm to monitor patients’ creatinine levels, comparing new values against historic ones, Dr. Scanlon explained. When that algorithm detects AKI, it issues an alert that triggers implementation of an AKI care bundle, including measures such as fluid monitoring and medication review, within 24 hours.

Taking this concept further, Dr. Scanlon and colleagues developed a random forest model, a type of machine learning algorithm, that incorporates other markers from blood tests routinely obtained for all patients, with the aim of predicting AKI up to 30 days in advance.

“Using routinely collected blood test results will ensure that the model is applicable to all our patients and can be implemented in an automated manner,” Dr. Scanlon noted.

The investigators developed and trained the model using 597,403 blood test results from 48,865 patients undergoing cancer treatment between January 2017 and May 2020.

The model assigns patients to five categories of risk for AKI in the next 30 days: very low, low, medium, high, and very high.

“We wanted the model to output in this way so that it could be used by clinicians alongside their own insight and knowledge on a case-by-case basis,” Dr. Scanlon explained.

The investigators then prospectively validated the model and its risk categories in another 9,913 patients who underwent cancer treatment between June and August 2020.

Using a model threshold of medium risk or higher, the model correctly predicted AKI in 330 (73.8%) of the 447 patients in the validation cohort who ultimately developed AKI.

“This is pretty amazing and shows that this model really is working and can correctly detect these AKIs up to 30 days before they occur, giving a huge window to put in place preventive strategies,” Dr. Scanlon said.

Among the 154 patients in whom the model incorrectly predicted AKI, 9 patients had only a single follow-up blood test and 17 patients did not have any, leaving their actual outcomes unclear.

“Given that AKI detection uses blood tests, an AKI in these patients was never confirmed,” Dr. Scanlon noted. “So this could give a potential benefit of the model that we never intended: It could reduce undiagnosed AKI by flagging those who are at risk.”

“Our next steps are to test the model through a technology clinical trial to see if putting intervention strategies in place does prevent these AKIs from taking place,” Dr. Scanlon concluded. “We are also going to move to ongoing monitoring of the model performance.”

Dr. Scanlon disclosed no conflicts of interest. The study did not receive specific funding.

A model that crunches data from routine blood tests can accurately identify cancer patients who will develop acute kidney injury (AKI) up to a month before it happens, according to a cohort study.

The algorithm spotted nearly 74% of the patients who went on to develop AKI within 30 days, providing a window for intervention and possibly prevention, according to investigators.

These results were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (abstract PR-11).

“Cancer patients are a high-risk population for AKI due to the nature of their treatment and illness,” said presenter Lauren A. Scanlon, PhD, a data scientist at The Christie NHS Foundation Trust in Huddersfield, England. “AKI causes a huge disruption in treatment and distress for the patient, so it would be amazing if we could, say, predict the AKI before it occurs and prevent it from even happening.”

U.K. health care providers are already using an algorithm to monitor patients’ creatinine levels, comparing new values against historic ones, Dr. Scanlon explained. When that algorithm detects AKI, it issues an alert that triggers implementation of an AKI care bundle, including measures such as fluid monitoring and medication review, within 24 hours.

Taking this concept further, Dr. Scanlon and colleagues developed a random forest model, a type of machine learning algorithm, that incorporates other markers from blood tests routinely obtained for all patients, with the aim of predicting AKI up to 30 days in advance.

“Using routinely collected blood test results will ensure that the model is applicable to all our patients and can be implemented in an automated manner,” Dr. Scanlon noted.

The investigators developed and trained the model using 597,403 blood test results from 48,865 patients undergoing cancer treatment between January 2017 and May 2020.

The model assigns patients to five categories of risk for AKI in the next 30 days: very low, low, medium, high, and very high.

“We wanted the model to output in this way so that it could be used by clinicians alongside their own insight and knowledge on a case-by-case basis,” Dr. Scanlon explained.

The investigators then prospectively validated the model and its risk categories in another 9,913 patients who underwent cancer treatment between June and August 2020.

Using a model threshold of medium risk or higher, the model correctly predicted AKI in 330 (73.8%) of the 447 patients in the validation cohort who ultimately developed AKI.

“This is pretty amazing and shows that this model really is working and can correctly detect these AKIs up to 30 days before they occur, giving a huge window to put in place preventive strategies,” Dr. Scanlon said.

Among the 154 patients in whom the model incorrectly predicted AKI, 9 patients had only a single follow-up blood test and 17 patients did not have any, leaving their actual outcomes unclear.

“Given that AKI detection uses blood tests, an AKI in these patients was never confirmed,” Dr. Scanlon noted. “So this could give a potential benefit of the model that we never intended: It could reduce undiagnosed AKI by flagging those who are at risk.”

“Our next steps are to test the model through a technology clinical trial to see if putting intervention strategies in place does prevent these AKIs from taking place,” Dr. Scanlon concluded. “We are also going to move to ongoing monitoring of the model performance.”

Dr. Scanlon disclosed no conflicts of interest. The study did not receive specific funding.

More people with fever and body aches are turning to NSAIDs to ease symptoms, but the drugs have come under new scrutiny as investigators work to determine whether they are a safe way to relieve the pain of COVID-19 vaccination or symptoms of the disease.

Early on in the pandemic, French health officials warned that NSAIDs, such as ibuprofen, could worsen coronavirus disease, and they recommended switching to acetaminophen instead.

The National Health Service in the United Kingdom followed with a similar recommendation for acetaminophen.

But the European Medicines Agency took a different approach, reporting “no scientific evidence” that NSAIDs could worsen COVID-19. The U.S. Food and Drug Administration also opted not to take a stance.

The debate prompted discussion on social media, with various reactions from around the world. It also inspired Craig Wilen, MD, PhD, from Yale University, New Haven, Conn., and associates to examine the effect of NSAIDs on COVID-19 infection and immune response. Their findings were published online Jan.20 in the Journal of Virology.

“It really bothered me that non–evidence-based decisions were driving the conversation,” Dr. Wilen said. “Millions of people are taking NSAIDs every day and clinical decisions about their care shouldn’t be made on a hypothesis.”

One theory is that NSAIDs alter susceptibility to infection by modifying ACE2. The drugs might also change the cell entry receptor for SARS-CoV-2, alter virus replication, or even modify the immune response.

British researchers, also questioning the safety of NSAIDs in patients with COVID-19, delved into National Health Service records to study two large groups of patients, some of whom were taking the pain relievers.

“We were watching the controversy and the lack of evidence and wanted to contribute,” lead investigator Angel Wong, PhD, from the London School of Hygiene and Tropical Medicine, said in an interview.

And with nearly 11 million NSAID prescriptions dispensed in primary care in England alone in the past 12 months, the inconsistency was concerning.

The team compared COVID-19–related deaths in two groups: one group of more than 700,000 people taking NSAIDs, including patients with rheumatoid arthritis and osteoarthritis; and another of almost 3.5 million people not on the medication.

NSAIDs work by inhibiting cyclooxygenase-1 and COX-2 enzymes in the body, which are crucial for the generation of prostaglandins. These lipid molecules play a role in inflammation and are blocked by NSAIDs.

The investigators found no evidence of a harmful effect of NSAIDs on COVID-19-related deaths; their results were published online Jan. 21 in the Annals of the Rheumatic Diseases.

The results, they pointed out, are in line with a Danish study that also showed no evidence of a higher risk for severe COVID-19 outcomes with NSAID use.

“It’s reassuring,” Dr. Wong said, “that patients can safely continue treatment.”
 

More new evidence

Dr. Wilen’s team found that SARS-CoV-2 infection stimulated COX-2 expression in human and mice cells. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication.

In their mouse model of SARS-CoV-2 infection, the investigators saw that NSAIDs impaired the production of proinflammatory cytokines and neutralizing antibodies. The findings suggest that NSAIDs influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies, rather than modifying susceptibility to infection or viral replication.

Understanding the effect of NSAIDs on cytokine production is critical, Dr. Wilen pointed out, because they might be protective early in COVID-19 but pathologic at later stages.

Timing is crucial in the case of other immunomodulatory drugs. For example, dexamethasone lowers mortality in COVID-19 patients on respiratory support but is potentially harmful for those with milder disease.

There still is a lot to learn, Dr. Wilen acknowledged. “We may be seeing something similar going on with NSAIDs, where the timing of treatment is important.”

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

More people with fever and body aches are turning to NSAIDs to ease symptoms, but the drugs have come under new scrutiny as investigators work to determine whether they are a safe way to relieve the pain of COVID-19 vaccination or symptoms of the disease.

Early on in the pandemic, French health officials warned that NSAIDs, such as ibuprofen, could worsen coronavirus disease, and they recommended switching to acetaminophen instead.

The National Health Service in the United Kingdom followed with a similar recommendation for acetaminophen.

But the European Medicines Agency took a different approach, reporting “no scientific evidence” that NSAIDs could worsen COVID-19. The U.S. Food and Drug Administration also opted not to take a stance.

The debate prompted discussion on social media, with various reactions from around the world. It also inspired Craig Wilen, MD, PhD, from Yale University, New Haven, Conn., and associates to examine the effect of NSAIDs on COVID-19 infection and immune response. Their findings were published online Jan.20 in the Journal of Virology.

“It really bothered me that non–evidence-based decisions were driving the conversation,” Dr. Wilen said. “Millions of people are taking NSAIDs every day and clinical decisions about their care shouldn’t be made on a hypothesis.”

One theory is that NSAIDs alter susceptibility to infection by modifying ACE2. The drugs might also change the cell entry receptor for SARS-CoV-2, alter virus replication, or even modify the immune response.

British researchers, also questioning the safety of NSAIDs in patients with COVID-19, delved into National Health Service records to study two large groups of patients, some of whom were taking the pain relievers.

“We were watching the controversy and the lack of evidence and wanted to contribute,” lead investigator Angel Wong, PhD, from the London School of Hygiene and Tropical Medicine, said in an interview.

And with nearly 11 million NSAID prescriptions dispensed in primary care in England alone in the past 12 months, the inconsistency was concerning.

The team compared COVID-19–related deaths in two groups: one group of more than 700,000 people taking NSAIDs, including patients with rheumatoid arthritis and osteoarthritis; and another of almost 3.5 million people not on the medication.

NSAIDs work by inhibiting cyclooxygenase-1 and COX-2 enzymes in the body, which are crucial for the generation of prostaglandins. These lipid molecules play a role in inflammation and are blocked by NSAIDs.

The investigators found no evidence of a harmful effect of NSAIDs on COVID-19-related deaths; their results were published online Jan. 21 in the Annals of the Rheumatic Diseases.

The results, they pointed out, are in line with a Danish study that also showed no evidence of a higher risk for severe COVID-19 outcomes with NSAID use.

“It’s reassuring,” Dr. Wong said, “that patients can safely continue treatment.”
 

More new evidence

Dr. Wilen’s team found that SARS-CoV-2 infection stimulated COX-2 expression in human and mice cells. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication.

In their mouse model of SARS-CoV-2 infection, the investigators saw that NSAIDs impaired the production of proinflammatory cytokines and neutralizing antibodies. The findings suggest that NSAIDs influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies, rather than modifying susceptibility to infection or viral replication.

Understanding the effect of NSAIDs on cytokine production is critical, Dr. Wilen pointed out, because they might be protective early in COVID-19 but pathologic at later stages.

Timing is crucial in the case of other immunomodulatory drugs. For example, dexamethasone lowers mortality in COVID-19 patients on respiratory support but is potentially harmful for those with milder disease.

There still is a lot to learn, Dr. Wilen acknowledged. “We may be seeing something similar going on with NSAIDs, where the timing of treatment is important.”

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

More people with fever and body aches are turning to NSAIDs to ease symptoms, but the drugs have come under new scrutiny as investigators work to determine whether they are a safe way to relieve the pain of COVID-19 vaccination or symptoms of the disease.

Early on in the pandemic, French health officials warned that NSAIDs, such as ibuprofen, could worsen coronavirus disease, and they recommended switching to acetaminophen instead.

The National Health Service in the United Kingdom followed with a similar recommendation for acetaminophen.

But the European Medicines Agency took a different approach, reporting “no scientific evidence” that NSAIDs could worsen COVID-19. The U.S. Food and Drug Administration also opted not to take a stance.

The debate prompted discussion on social media, with various reactions from around the world. It also inspired Craig Wilen, MD, PhD, from Yale University, New Haven, Conn., and associates to examine the effect of NSAIDs on COVID-19 infection and immune response. Their findings were published online Jan.20 in the Journal of Virology.

“It really bothered me that non–evidence-based decisions were driving the conversation,” Dr. Wilen said. “Millions of people are taking NSAIDs every day and clinical decisions about their care shouldn’t be made on a hypothesis.”

One theory is that NSAIDs alter susceptibility to infection by modifying ACE2. The drugs might also change the cell entry receptor for SARS-CoV-2, alter virus replication, or even modify the immune response.

British researchers, also questioning the safety of NSAIDs in patients with COVID-19, delved into National Health Service records to study two large groups of patients, some of whom were taking the pain relievers.

“We were watching the controversy and the lack of evidence and wanted to contribute,” lead investigator Angel Wong, PhD, from the London School of Hygiene and Tropical Medicine, said in an interview.

And with nearly 11 million NSAID prescriptions dispensed in primary care in England alone in the past 12 months, the inconsistency was concerning.

The team compared COVID-19–related deaths in two groups: one group of more than 700,000 people taking NSAIDs, including patients with rheumatoid arthritis and osteoarthritis; and another of almost 3.5 million people not on the medication.

NSAIDs work by inhibiting cyclooxygenase-1 and COX-2 enzymes in the body, which are crucial for the generation of prostaglandins. These lipid molecules play a role in inflammation and are blocked by NSAIDs.

The investigators found no evidence of a harmful effect of NSAIDs on COVID-19-related deaths; their results were published online Jan. 21 in the Annals of the Rheumatic Diseases.

The results, they pointed out, are in line with a Danish study that also showed no evidence of a higher risk for severe COVID-19 outcomes with NSAID use.

“It’s reassuring,” Dr. Wong said, “that patients can safely continue treatment.”
 

More new evidence

Dr. Wilen’s team found that SARS-CoV-2 infection stimulated COX-2 expression in human and mice cells. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication.

In their mouse model of SARS-CoV-2 infection, the investigators saw that NSAIDs impaired the production of proinflammatory cytokines and neutralizing antibodies. The findings suggest that NSAIDs influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies, rather than modifying susceptibility to infection or viral replication.

Understanding the effect of NSAIDs on cytokine production is critical, Dr. Wilen pointed out, because they might be protective early in COVID-19 but pathologic at later stages.

Timing is crucial in the case of other immunomodulatory drugs. For example, dexamethasone lowers mortality in COVID-19 patients on respiratory support but is potentially harmful for those with milder disease.

There still is a lot to learn, Dr. Wilen acknowledged. “We may be seeing something similar going on with NSAIDs, where the timing of treatment is important.”

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

I started reading “Becoming a Doctors’ Doctor: A Memoir” by Michael F. Myers, MD, with high expectations and enthusiasm. Dr. Myers is a Canadian psychiatrist who has devoted his career to caring for physicians in his half-time private practice; he turns all other comers away.

This career path began in 1962 during his first year in medical school when Dr. Myers returned to his apartment after Thanksgiving break to be greeted with tragic news: One of the young men he shared the apartment with had died of suicide. The tragedy marked him – along with the silence about what had transpired – and he would later look back to realize it was the beginning of his journey to becoming a psychiatrist, one who cares for other physicians.

The book is filled with patient vignettes, gentle musings that Dr. Myers recounts with warmth, adding what he has learned from them.

Dr. Miller is coauthor of “Committed: The Battle over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins, both in Baltimore. Dr. Miller has no conflicts of interest.

I started reading “Becoming a Doctors’ Doctor: A Memoir” by Michael F. Myers, MD, with high expectations and enthusiasm. Dr. Myers is a Canadian psychiatrist who has devoted his career to caring for physicians in his half-time private practice; he turns all other comers away.

This career path began in 1962 during his first year in medical school when Dr. Myers returned to his apartment after Thanksgiving break to be greeted with tragic news: One of the young men he shared the apartment with had died of suicide. The tragedy marked him – along with the silence about what had transpired – and he would later look back to realize it was the beginning of his journey to becoming a psychiatrist, one who cares for other physicians.

The book is filled with patient vignettes, gentle musings that Dr. Myers recounts with warmth, adding what he has learned from them.

Dr. Miller is coauthor of “Committed: The Battle over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins, both in Baltimore. Dr. Miller has no conflicts of interest.

I started reading “Becoming a Doctors’ Doctor: A Memoir” by Michael F. Myers, MD, with high expectations and enthusiasm. Dr. Myers is a Canadian psychiatrist who has devoted his career to caring for physicians in his half-time private practice; he turns all other comers away.

This career path began in 1962 during his first year in medical school when Dr. Myers returned to his apartment after Thanksgiving break to be greeted with tragic news: One of the young men he shared the apartment with had died of suicide. The tragedy marked him – along with the silence about what had transpired – and he would later look back to realize it was the beginning of his journey to becoming a psychiatrist, one who cares for other physicians.

The book is filled with patient vignettes, gentle musings that Dr. Myers recounts with warmth, adding what he has learned from them.

Dr. Miller is coauthor of “Committed: The Battle over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins, both in Baltimore. Dr. Miller has no conflicts of interest.