A widely approved vaccine for meningitis may provide up to 40% protection against gonorrhea in young adults and adolescents, according to new research. This moderate efficacy paired with a targeted risk-based approach could reduce cases as well as lead to health care savings over 10 years, an additional modeling study showed.

The results – in three linked papers – were published in The Lancet Infectious Diseases.

Gonorrhea, caused by the bacterium Neisseria gonorrhoeae, is the second most commonly reported sexually transmitted infection in the United States, according to the Centers for Disease Control and Prevention. Globally, the World Health Organization estimates that there were 82.4 million new cases in people aged 15-49 in 2020. At the same time, it is becoming more difficult to treat the infection because of the increasing prevalence of drug-resistant strains of N. gonorrhoeae.

“New approaches, such as vaccination, are needed as long-term strategies to prevent gonorrhea and address the emerging threat of antimicrobial resistance,” Winston Abara, MD, PhD, Division of STD Prevention, Centers for Disease Control and Prevention, and colleagues wrote.

While there is currently no vaccine for gonorrhea, observational studies have found an association between a meningococcal serogroup B vaccine and reduced gonorrhea cases. One study in New Zealand found that people vaccinated with the MeNZB vaccine, which was produced to control an outbreak of meningococcal disease in the country, were 31% less likely to contract gonorrhea.

This cross-reactivity comes about because Neisseria meningitidis, the bacterium that can cause meningitis, is closely related to N. gonorrhoeae, Joseph Alex Duncan, MD, PhD, associate professor of medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, said in an interview. He was not involved with the research. The thought is that “a large proportion of the proteins that are in the vaccine also recognize proteins from Neisseria gonorrhea, because the bacteria are so similar at the genetic level,” he said.

To see if this association was still found for the four-component serogroup B meningococcal vaccine (MenB-4C), which is now widely available, Dr. Abara and colleagues looked through health records to identify laboratory-confirmed gonorrhea and chlamydia infections in adolescents and young adults in New York City and Philadelphia. All individuals included in the analysis were age 16-23 and all infections occurred between Jan. 1, 2016, and Dec. 31, 2018. These infections were then linked to vaccination records to determine individuals’ MenB-4C vaccination status. Complete vaccination was defined as two MenB-4C doses, delivered 30-180 days apart.

The research team identified over 167,700 infections, including 18,099 gonococcal infections, 124,876 chlamydial infections, and 24,731 coinfections, among 109,737 individuals. A total of 7,692 individuals had received at least one shot of the vaccine, and 3,660 people were fully vaccinated. Full MenB-4C vaccination was estimated to be 40% protective (APR 0.60; P < .0001) against gonorrhea, and partial vaccination was 26% protective (APR 0.74; P = .0012).

“The findings of our study add to the body of evidence that demonstrates that the MenB-4C may offer cross-protection against Neisseria gonorrhoeae, and it supports feasibility of an effective gonococcal vaccine with implications for gonorrhea prevention and control,” Dr. Abara told this news organization.

A second study conducted in South Australia looked at the effectiveness of the MenB-4C vaccine against meningitis and gonorrhea as part of a vaccination program. Using infection data from the Government of South Australia and vaccination records from the Australian Immunization Register, researchers identified individuals born between Feb. 1, 1998, and Feb. 1, 2005, with a documented gonorrhea or chlamydia infection between Feb. 1, 2019, and Jan. 31, 2021. Individuals with chlamydia served as the controls to account for similar sexual behavioral risks.

The analysis included 512 individuals with 575 cases of gonorrhea and 3,140 individuals with 3,847 episodes of chlamydia. In this group, the estimated vaccine effectiveness against gonorrhea was 32.7% (95% confidence interval, 8.3-50.6) in individuals who were fully vaccinated and 32.6% (95% CI, 10.6-49.1) in those who had received at least one dose of the MenB-4C.

While these findings are “confirmatory” because they showed results similar to those in previous observational studies, they are still exciting, Dr. Duncan said. “Up until now, we really haven’t had any real progress in knowing what type of immune responses could actually be protective from the disease,” he said. “These observational studies have really reinvigorated the Neisseria gonorrhea vaccine research community.”

A vaccine with moderate efficacy – like the protection demonstrated in both studies – could lead to a significant reduction in cases, he noted. A 2015 Australian modeling study estimated that a nonwaning vaccine with 20% efficacy could reduce cases by 40% over 20 years. Focusing on vaccinating higher-risk groups could also have an “outsize impact,” said Jeanne Marrazzo, MD, director, Division of Infectious Diseases, UAB Medicine, Birmingham, Alabama, in an interview. In the third study published in The Lancet, researchers estimated the possible reduction of cases and the potential health care cost savings in England in a vaccination effort focusing on men who have sex with men (MSM) at high risk for gonorrhea infection. They predicted that a vaccine with 31% efficacy could prevent 110,200 cases in MSM and save about £8 million ($10.4 million) over 10 years.

Both Dr. Duncan and Dr. Marrazzo agreed that clinical trials are needed to tease out whether the decrease in gonorrhea cases is due to the MenB-4C vaccine or the association is incidental. There are two ongoing clinical trials, one in Australia and one in the United States. Dr. Marrazzo leads the U.S. multicenter study, which also has two locations in Bangkok. The trial will also look at whether vaccination protection varies by the location of gonococcal infection: urethra, rectum, cervix, or pharynx. The two new observational studies did not distinguish the different sites of infection.

Dr. Marrazzo’s trial has enrolled almost 500 individuals so far, with the goal of enrolling over 2,000 participants in total. She hopes to see results by late 2023. “It’s a pretty ambitious effort, but I’m hoping it will give us not only a definitive answer in terms of reduction in infection by anatomic site,” she said, but “also give us a lot of information about how the immune response works to protect you from getting gonorrhea if you do get the vaccine.”

Dr. Duncan has received research grants from the National Institutes of Health. Dr. Marrazzo leads a clinical trial of the MenB-4C vaccine sponsored by the National Institute of Allergy and Infectious Diseases.

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

A widely approved vaccine for meningitis may provide up to 40% protection against gonorrhea in young adults and adolescents, according to new research. This moderate efficacy paired with a targeted risk-based approach could reduce cases as well as lead to health care savings over 10 years, an additional modeling study showed.

The results – in three linked papers – were published in The Lancet Infectious Diseases.

Gonorrhea, caused by the bacterium Neisseria gonorrhoeae, is the second most commonly reported sexually transmitted infection in the United States, according to the Centers for Disease Control and Prevention. Globally, the World Health Organization estimates that there were 82.4 million new cases in people aged 15-49 in 2020. At the same time, it is becoming more difficult to treat the infection because of the increasing prevalence of drug-resistant strains of N. gonorrhoeae.

“New approaches, such as vaccination, are needed as long-term strategies to prevent gonorrhea and address the emerging threat of antimicrobial resistance,” Winston Abara, MD, PhD, Division of STD Prevention, Centers for Disease Control and Prevention, and colleagues wrote.

While there is currently no vaccine for gonorrhea, observational studies have found an association between a meningococcal serogroup B vaccine and reduced gonorrhea cases. One study in New Zealand found that people vaccinated with the MeNZB vaccine, which was produced to control an outbreak of meningococcal disease in the country, were 31% less likely to contract gonorrhea.

This cross-reactivity comes about because Neisseria meningitidis, the bacterium that can cause meningitis, is closely related to N. gonorrhoeae, Joseph Alex Duncan, MD, PhD, associate professor of medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, said in an interview. He was not involved with the research. The thought is that “a large proportion of the proteins that are in the vaccine also recognize proteins from Neisseria gonorrhea, because the bacteria are so similar at the genetic level,” he said.

To see if this association was still found for the four-component serogroup B meningococcal vaccine (MenB-4C), which is now widely available, Dr. Abara and colleagues looked through health records to identify laboratory-confirmed gonorrhea and chlamydia infections in adolescents and young adults in New York City and Philadelphia. All individuals included in the analysis were age 16-23 and all infections occurred between Jan. 1, 2016, and Dec. 31, 2018. These infections were then linked to vaccination records to determine individuals’ MenB-4C vaccination status. Complete vaccination was defined as two MenB-4C doses, delivered 30-180 days apart.

The research team identified over 167,700 infections, including 18,099 gonococcal infections, 124,876 chlamydial infections, and 24,731 coinfections, among 109,737 individuals. A total of 7,692 individuals had received at least one shot of the vaccine, and 3,660 people were fully vaccinated. Full MenB-4C vaccination was estimated to be 40% protective (APR 0.60; P < .0001) against gonorrhea, and partial vaccination was 26% protective (APR 0.74; P = .0012).

“The findings of our study add to the body of evidence that demonstrates that the MenB-4C may offer cross-protection against Neisseria gonorrhoeae, and it supports feasibility of an effective gonococcal vaccine with implications for gonorrhea prevention and control,” Dr. Abara told this news organization.

A second study conducted in South Australia looked at the effectiveness of the MenB-4C vaccine against meningitis and gonorrhea as part of a vaccination program. Using infection data from the Government of South Australia and vaccination records from the Australian Immunization Register, researchers identified individuals born between Feb. 1, 1998, and Feb. 1, 2005, with a documented gonorrhea or chlamydia infection between Feb. 1, 2019, and Jan. 31, 2021. Individuals with chlamydia served as the controls to account for similar sexual behavioral risks.

The analysis included 512 individuals with 575 cases of gonorrhea and 3,140 individuals with 3,847 episodes of chlamydia. In this group, the estimated vaccine effectiveness against gonorrhea was 32.7% (95% confidence interval, 8.3-50.6) in individuals who were fully vaccinated and 32.6% (95% CI, 10.6-49.1) in those who had received at least one dose of the MenB-4C.

While these findings are “confirmatory” because they showed results similar to those in previous observational studies, they are still exciting, Dr. Duncan said. “Up until now, we really haven’t had any real progress in knowing what type of immune responses could actually be protective from the disease,” he said. “These observational studies have really reinvigorated the Neisseria gonorrhea vaccine research community.”

A vaccine with moderate efficacy – like the protection demonstrated in both studies – could lead to a significant reduction in cases, he noted. A 2015 Australian modeling study estimated that a nonwaning vaccine with 20% efficacy could reduce cases by 40% over 20 years. Focusing on vaccinating higher-risk groups could also have an “outsize impact,” said Jeanne Marrazzo, MD, director, Division of Infectious Diseases, UAB Medicine, Birmingham, Alabama, in an interview. In the third study published in The Lancet, researchers estimated the possible reduction of cases and the potential health care cost savings in England in a vaccination effort focusing on men who have sex with men (MSM) at high risk for gonorrhea infection. They predicted that a vaccine with 31% efficacy could prevent 110,200 cases in MSM and save about £8 million ($10.4 million) over 10 years.

Both Dr. Duncan and Dr. Marrazzo agreed that clinical trials are needed to tease out whether the decrease in gonorrhea cases is due to the MenB-4C vaccine or the association is incidental. There are two ongoing clinical trials, one in Australia and one in the United States. Dr. Marrazzo leads the U.S. multicenter study, which also has two locations in Bangkok. The trial will also look at whether vaccination protection varies by the location of gonococcal infection: urethra, rectum, cervix, or pharynx. The two new observational studies did not distinguish the different sites of infection.

Dr. Marrazzo’s trial has enrolled almost 500 individuals so far, with the goal of enrolling over 2,000 participants in total. She hopes to see results by late 2023. “It’s a pretty ambitious effort, but I’m hoping it will give us not only a definitive answer in terms of reduction in infection by anatomic site,” she said, but “also give us a lot of information about how the immune response works to protect you from getting gonorrhea if you do get the vaccine.”

Dr. Duncan has received research grants from the National Institutes of Health. Dr. Marrazzo leads a clinical trial of the MenB-4C vaccine sponsored by the National Institute of Allergy and Infectious Diseases.

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

A widely approved vaccine for meningitis may provide up to 40% protection against gonorrhea in young adults and adolescents, according to new research. This moderate efficacy paired with a targeted risk-based approach could reduce cases as well as lead to health care savings over 10 years, an additional modeling study showed.

The results – in three linked papers – were published in The Lancet Infectious Diseases.

Gonorrhea, caused by the bacterium Neisseria gonorrhoeae, is the second most commonly reported sexually transmitted infection in the United States, according to the Centers for Disease Control and Prevention. Globally, the World Health Organization estimates that there were 82.4 million new cases in people aged 15-49 in 2020. At the same time, it is becoming more difficult to treat the infection because of the increasing prevalence of drug-resistant strains of N. gonorrhoeae.

“New approaches, such as vaccination, are needed as long-term strategies to prevent gonorrhea and address the emerging threat of antimicrobial resistance,” Winston Abara, MD, PhD, Division of STD Prevention, Centers for Disease Control and Prevention, and colleagues wrote.

While there is currently no vaccine for gonorrhea, observational studies have found an association between a meningococcal serogroup B vaccine and reduced gonorrhea cases. One study in New Zealand found that people vaccinated with the MeNZB vaccine, which was produced to control an outbreak of meningococcal disease in the country, were 31% less likely to contract gonorrhea.

This cross-reactivity comes about because Neisseria meningitidis, the bacterium that can cause meningitis, is closely related to N. gonorrhoeae, Joseph Alex Duncan, MD, PhD, associate professor of medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, said in an interview. He was not involved with the research. The thought is that “a large proportion of the proteins that are in the vaccine also recognize proteins from Neisseria gonorrhea, because the bacteria are so similar at the genetic level,” he said.

To see if this association was still found for the four-component serogroup B meningococcal vaccine (MenB-4C), which is now widely available, Dr. Abara and colleagues looked through health records to identify laboratory-confirmed gonorrhea and chlamydia infections in adolescents and young adults in New York City and Philadelphia. All individuals included in the analysis were age 16-23 and all infections occurred between Jan. 1, 2016, and Dec. 31, 2018. These infections were then linked to vaccination records to determine individuals’ MenB-4C vaccination status. Complete vaccination was defined as two MenB-4C doses, delivered 30-180 days apart.

The research team identified over 167,700 infections, including 18,099 gonococcal infections, 124,876 chlamydial infections, and 24,731 coinfections, among 109,737 individuals. A total of 7,692 individuals had received at least one shot of the vaccine, and 3,660 people were fully vaccinated. Full MenB-4C vaccination was estimated to be 40% protective (APR 0.60; P < .0001) against gonorrhea, and partial vaccination was 26% protective (APR 0.74; P = .0012).

“The findings of our study add to the body of evidence that demonstrates that the MenB-4C may offer cross-protection against Neisseria gonorrhoeae, and it supports feasibility of an effective gonococcal vaccine with implications for gonorrhea prevention and control,” Dr. Abara told this news organization.

A second study conducted in South Australia looked at the effectiveness of the MenB-4C vaccine against meningitis and gonorrhea as part of a vaccination program. Using infection data from the Government of South Australia and vaccination records from the Australian Immunization Register, researchers identified individuals born between Feb. 1, 1998, and Feb. 1, 2005, with a documented gonorrhea or chlamydia infection between Feb. 1, 2019, and Jan. 31, 2021. Individuals with chlamydia served as the controls to account for similar sexual behavioral risks.

The analysis included 512 individuals with 575 cases of gonorrhea and 3,140 individuals with 3,847 episodes of chlamydia. In this group, the estimated vaccine effectiveness against gonorrhea was 32.7% (95% confidence interval, 8.3-50.6) in individuals who were fully vaccinated and 32.6% (95% CI, 10.6-49.1) in those who had received at least one dose of the MenB-4C.

While these findings are “confirmatory” because they showed results similar to those in previous observational studies, they are still exciting, Dr. Duncan said. “Up until now, we really haven’t had any real progress in knowing what type of immune responses could actually be protective from the disease,” he said. “These observational studies have really reinvigorated the Neisseria gonorrhea vaccine research community.”

A vaccine with moderate efficacy – like the protection demonstrated in both studies – could lead to a significant reduction in cases, he noted. A 2015 Australian modeling study estimated that a nonwaning vaccine with 20% efficacy could reduce cases by 40% over 20 years. Focusing on vaccinating higher-risk groups could also have an “outsize impact,” said Jeanne Marrazzo, MD, director, Division of Infectious Diseases, UAB Medicine, Birmingham, Alabama, in an interview. In the third study published in The Lancet, researchers estimated the possible reduction of cases and the potential health care cost savings in England in a vaccination effort focusing on men who have sex with men (MSM) at high risk for gonorrhea infection. They predicted that a vaccine with 31% efficacy could prevent 110,200 cases in MSM and save about £8 million ($10.4 million) over 10 years.

Both Dr. Duncan and Dr. Marrazzo agreed that clinical trials are needed to tease out whether the decrease in gonorrhea cases is due to the MenB-4C vaccine or the association is incidental. There are two ongoing clinical trials, one in Australia and one in the United States. Dr. Marrazzo leads the U.S. multicenter study, which also has two locations in Bangkok. The trial will also look at whether vaccination protection varies by the location of gonococcal infection: urethra, rectum, cervix, or pharynx. The two new observational studies did not distinguish the different sites of infection.

Dr. Marrazzo’s trial has enrolled almost 500 individuals so far, with the goal of enrolling over 2,000 participants in total. She hopes to see results by late 2023. “It’s a pretty ambitious effort, but I’m hoping it will give us not only a definitive answer in terms of reduction in infection by anatomic site,” she said, but “also give us a lot of information about how the immune response works to protect you from getting gonorrhea if you do get the vaccine.”

Dr. Duncan has received research grants from the National Institutes of Health. Dr. Marrazzo leads a clinical trial of the MenB-4C vaccine sponsored by the National Institute of Allergy and Infectious Diseases.

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

The vast majority of children and young people with rheumatic and musculoskeletal diseases (RMDs) and COVID-19 are not hospitalized, according to the most significant global investigation of short-term COVID-19 outcomes in this patient group to date.

In the study, only 1 in 15 (7%) children and young people (younger than 19 years) with RMDs and COVID-19 were hospitalized, and even then, they experienced only mild symptoms; 4 of 5 of those hospitalized did not require supplemental oxygen or ventilatory support.

The study also found that those with severe systemic RMDs and obesity were more likely to be hospitalized than children with juvenile idiopathic arthritis (JIA).

Treatment with biologics, such as tumor necrosis factor inhibitors, did not appear to be associated with more severe COVID-19; however, the study found that children and young people with obesity (body mass index ≥ 30) were more likely to be hospitalized, although only 6% of patients in this study had a BMI in this category. Three patients died – two from areas of lower resources who were diagnosed with systemic lupus erythematosus (SLE) at approximately the same time they were diagnosed with COVID-19, and one with a preexisting autoinflammatory syndrome who was being treated with low-dose glucocorticoids and methotrexate.

Published in Annals of the Rheumatic Diseases, the study was led by Kimme L. Hyrich, MD, PhD, and Lianne Kearsley-Fleet, PhD, both from the University of Manchester (England). Dr. Hyrich is also a consultant rheumatologist at Manchester University Hospitals NHS Foundation Trust.

In an interview, Dr. Hyrich explained that overall these data are reassuring and show that the majority of children and young people with RMDs are not at high risk of severe COVID-19.

“Many parents and families with children who have RMDs have lived with great fear over the pandemic about whether or not their children are at an increased risk of severe COVID-19,” said Dr. Hyrich. “Many are immunosuppressed or take other immunomodulatory medications. This has also had a great impact on schooling and children’s well-being.”

In the study, children with SLE, mixed connective tissue disease (MCTD), or vasculitis were more likely to have severe COVID-19. “[This] is not surprising given the typically greater systemic involvement and need for more aggressive immunosuppressive therapy than the majority of individuals with JIA,” the researchers wrote.

Dr. Hyrich added: “There may be times when children are on particularly high doses of immunosuppression or their disease is particularly active, when they may need more protection, and rheumatology teams can advise parents and young people about this.”

Studies such as those by Zimmerman and Curtis and Viner and colleagues have found that generally, children with no underlying disease are less susceptible to symptomatic COVID-19 and that reports of death are rare. Findings show that the younger the child, the less likely they will be symptomatic.

Adult data suggest a higher risk of COVID-related death among patients with arthritis, lupus, or psoriasis. A recent systematic review of the literature suggested that increased risk of COVID-related death only applies to subgroups of people with RMDs.

However, whether children and young people with RMDs are likely to have more severe COVID-19 and whether there is additional risk attributable to either their underlying disease or its therapy remain unknown. The goal of the study by Dr. Hyrich and colleagues was to address these questions.

The global analysis aimed to describe characteristics of those children and young people (younger than 19 years) with preexisting RMDs who also had COVID-19; to describe outcomes following COVID-19; and to identify characteristics associated with more severe COVID-19 outcomes.

Data were drawn from the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database.

Demographic information included primary RMD diagnosis; RMD disease activity (remission, low, moderate, high, or unknown); RMD treatments, including glucocorticoid use and which disease-modifying antirheumatic drug (DMARD) the patient was taking at the time of COVID-19; and comorbidities (none, ocular inflammation, interstitial lung disease, asthma, diabetes, obesity, hypertension, cerebrovascular accident, renal disease, inflammatory bowel disease, and heart disease).

With respect to COVID-19, information collected included diagnosis date, whether the case was presumptive or confirmed, clinical symptoms, hospitalization and/or death because of COVID-19, and whether the patient stopped receiving rheumatic therapies.

Rheumatology diagnoses were categorized into four groups: JIA; SLE, MCTD, vasculitis, or other RMD; autoinflammatory syndromes; and “other,” including chronic recurrent multifocal osteomyelitis, sarcoidosis, or ocular inflammation.

Of the 607 children and young people with reported SARS-CoV-2 infection from 25 different countries (464 from the EULAR COVID-19 Registry), 499 (82%) cases were polymerase chain reaction confirmed, and 399 (66%) patients were female (median age, 14 years). Most (62%) had JIA: 37%, polyarticular JIA; 30%, oligoarticular JIA; 12%, enthesitis-related JIA; 9%, systemic JIA; 4%, psoriatic JIA; and 9%, JIA of unknown subcategory. Furthermore, 13% of patients had autoinflammatory syndromes, 8% with SLE or MCTD, 3% with vasculitis, and 2% with inflammatory myopathy.

No associations were seen between DMARD treatment (conventional-synthetic, biologic/targeted-synthetic, or combination therapy), compared with no DMARD treatment, glucocorticoid use, and hospitalization.

Owing to substantial differences in reporting of race and ethnicity between data sources, the researchers were unable to analyze whether Black, Asian, and minority ethnic groups with pediatric RMDs are at higher risk of COVID-19–related death, compared with those of White ethnicity, as has been reported for the general population.

The study also did not account for variants of SARS-CoV-2 other than to note that data were collected prior to the spread of the Omicron variant. Also, the registries did not capture vaccination status (though very few children had received vaccines at the time of data collection) or information on long COVID or multisystem inflammatory syndrome in children.

Dr. Hyrich and Dr. Kearsley-Fleet have disclosed no relevant financial relationships.

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

The vast majority of children and young people with rheumatic and musculoskeletal diseases (RMDs) and COVID-19 are not hospitalized, according to the most significant global investigation of short-term COVID-19 outcomes in this patient group to date.

In the study, only 1 in 15 (7%) children and young people (younger than 19 years) with RMDs and COVID-19 were hospitalized, and even then, they experienced only mild symptoms; 4 of 5 of those hospitalized did not require supplemental oxygen or ventilatory support.

The study also found that those with severe systemic RMDs and obesity were more likely to be hospitalized than children with juvenile idiopathic arthritis (JIA).

Treatment with biologics, such as tumor necrosis factor inhibitors, did not appear to be associated with more severe COVID-19; however, the study found that children and young people with obesity (body mass index ≥ 30) were more likely to be hospitalized, although only 6% of patients in this study had a BMI in this category. Three patients died – two from areas of lower resources who were diagnosed with systemic lupus erythematosus (SLE) at approximately the same time they were diagnosed with COVID-19, and one with a preexisting autoinflammatory syndrome who was being treated with low-dose glucocorticoids and methotrexate.

Published in Annals of the Rheumatic Diseases, the study was led by Kimme L. Hyrich, MD, PhD, and Lianne Kearsley-Fleet, PhD, both from the University of Manchester (England). Dr. Hyrich is also a consultant rheumatologist at Manchester University Hospitals NHS Foundation Trust.

In an interview, Dr. Hyrich explained that overall these data are reassuring and show that the majority of children and young people with RMDs are not at high risk of severe COVID-19.

“Many parents and families with children who have RMDs have lived with great fear over the pandemic about whether or not their children are at an increased risk of severe COVID-19,” said Dr. Hyrich. “Many are immunosuppressed or take other immunomodulatory medications. This has also had a great impact on schooling and children’s well-being.”

In the study, children with SLE, mixed connective tissue disease (MCTD), or vasculitis were more likely to have severe COVID-19. “[This] is not surprising given the typically greater systemic involvement and need for more aggressive immunosuppressive therapy than the majority of individuals with JIA,” the researchers wrote.

Dr. Hyrich added: “There may be times when children are on particularly high doses of immunosuppression or their disease is particularly active, when they may need more protection, and rheumatology teams can advise parents and young people about this.”

Studies such as those by Zimmerman and Curtis and Viner and colleagues have found that generally, children with no underlying disease are less susceptible to symptomatic COVID-19 and that reports of death are rare. Findings show that the younger the child, the less likely they will be symptomatic.

Adult data suggest a higher risk of COVID-related death among patients with arthritis, lupus, or psoriasis. A recent systematic review of the literature suggested that increased risk of COVID-related death only applies to subgroups of people with RMDs.

However, whether children and young people with RMDs are likely to have more severe COVID-19 and whether there is additional risk attributable to either their underlying disease or its therapy remain unknown. The goal of the study by Dr. Hyrich and colleagues was to address these questions.

The global analysis aimed to describe characteristics of those children and young people (younger than 19 years) with preexisting RMDs who also had COVID-19; to describe outcomes following COVID-19; and to identify characteristics associated with more severe COVID-19 outcomes.

Data were drawn from the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database.

Demographic information included primary RMD diagnosis; RMD disease activity (remission, low, moderate, high, or unknown); RMD treatments, including glucocorticoid use and which disease-modifying antirheumatic drug (DMARD) the patient was taking at the time of COVID-19; and comorbidities (none, ocular inflammation, interstitial lung disease, asthma, diabetes, obesity, hypertension, cerebrovascular accident, renal disease, inflammatory bowel disease, and heart disease).

With respect to COVID-19, information collected included diagnosis date, whether the case was presumptive or confirmed, clinical symptoms, hospitalization and/or death because of COVID-19, and whether the patient stopped receiving rheumatic therapies.

Rheumatology diagnoses were categorized into four groups: JIA; SLE, MCTD, vasculitis, or other RMD; autoinflammatory syndromes; and “other,” including chronic recurrent multifocal osteomyelitis, sarcoidosis, or ocular inflammation.

Of the 607 children and young people with reported SARS-CoV-2 infection from 25 different countries (464 from the EULAR COVID-19 Registry), 499 (82%) cases were polymerase chain reaction confirmed, and 399 (66%) patients were female (median age, 14 years). Most (62%) had JIA: 37%, polyarticular JIA; 30%, oligoarticular JIA; 12%, enthesitis-related JIA; 9%, systemic JIA; 4%, psoriatic JIA; and 9%, JIA of unknown subcategory. Furthermore, 13% of patients had autoinflammatory syndromes, 8% with SLE or MCTD, 3% with vasculitis, and 2% with inflammatory myopathy.

No associations were seen between DMARD treatment (conventional-synthetic, biologic/targeted-synthetic, or combination therapy), compared with no DMARD treatment, glucocorticoid use, and hospitalization.

Owing to substantial differences in reporting of race and ethnicity between data sources, the researchers were unable to analyze whether Black, Asian, and minority ethnic groups with pediatric RMDs are at higher risk of COVID-19–related death, compared with those of White ethnicity, as has been reported for the general population.

The study also did not account for variants of SARS-CoV-2 other than to note that data were collected prior to the spread of the Omicron variant. Also, the registries did not capture vaccination status (though very few children had received vaccines at the time of data collection) or information on long COVID or multisystem inflammatory syndrome in children.

Dr. Hyrich and Dr. Kearsley-Fleet have disclosed no relevant financial relationships.

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

The vast majority of children and young people with rheumatic and musculoskeletal diseases (RMDs) and COVID-19 are not hospitalized, according to the most significant global investigation of short-term COVID-19 outcomes in this patient group to date.

In the study, only 1 in 15 (7%) children and young people (younger than 19 years) with RMDs and COVID-19 were hospitalized, and even then, they experienced only mild symptoms; 4 of 5 of those hospitalized did not require supplemental oxygen or ventilatory support.

The study also found that those with severe systemic RMDs and obesity were more likely to be hospitalized than children with juvenile idiopathic arthritis (JIA).

Treatment with biologics, such as tumor necrosis factor inhibitors, did not appear to be associated with more severe COVID-19; however, the study found that children and young people with obesity (body mass index ≥ 30) were more likely to be hospitalized, although only 6% of patients in this study had a BMI in this category. Three patients died – two from areas of lower resources who were diagnosed with systemic lupus erythematosus (SLE) at approximately the same time they were diagnosed with COVID-19, and one with a preexisting autoinflammatory syndrome who was being treated with low-dose glucocorticoids and methotrexate.

Published in Annals of the Rheumatic Diseases, the study was led by Kimme L. Hyrich, MD, PhD, and Lianne Kearsley-Fleet, PhD, both from the University of Manchester (England). Dr. Hyrich is also a consultant rheumatologist at Manchester University Hospitals NHS Foundation Trust.

In an interview, Dr. Hyrich explained that overall these data are reassuring and show that the majority of children and young people with RMDs are not at high risk of severe COVID-19.

“Many parents and families with children who have RMDs have lived with great fear over the pandemic about whether or not their children are at an increased risk of severe COVID-19,” said Dr. Hyrich. “Many are immunosuppressed or take other immunomodulatory medications. This has also had a great impact on schooling and children’s well-being.”

In the study, children with SLE, mixed connective tissue disease (MCTD), or vasculitis were more likely to have severe COVID-19. “[This] is not surprising given the typically greater systemic involvement and need for more aggressive immunosuppressive therapy than the majority of individuals with JIA,” the researchers wrote.

Dr. Hyrich added: “There may be times when children are on particularly high doses of immunosuppression or their disease is particularly active, when they may need more protection, and rheumatology teams can advise parents and young people about this.”

Studies such as those by Zimmerman and Curtis and Viner and colleagues have found that generally, children with no underlying disease are less susceptible to symptomatic COVID-19 and that reports of death are rare. Findings show that the younger the child, the less likely they will be symptomatic.

Adult data suggest a higher risk of COVID-related death among patients with arthritis, lupus, or psoriasis. A recent systematic review of the literature suggested that increased risk of COVID-related death only applies to subgroups of people with RMDs.

However, whether children and young people with RMDs are likely to have more severe COVID-19 and whether there is additional risk attributable to either their underlying disease or its therapy remain unknown. The goal of the study by Dr. Hyrich and colleagues was to address these questions.

The global analysis aimed to describe characteristics of those children and young people (younger than 19 years) with preexisting RMDs who also had COVID-19; to describe outcomes following COVID-19; and to identify characteristics associated with more severe COVID-19 outcomes.

Data were drawn from the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database.

Demographic information included primary RMD diagnosis; RMD disease activity (remission, low, moderate, high, or unknown); RMD treatments, including glucocorticoid use and which disease-modifying antirheumatic drug (DMARD) the patient was taking at the time of COVID-19; and comorbidities (none, ocular inflammation, interstitial lung disease, asthma, diabetes, obesity, hypertension, cerebrovascular accident, renal disease, inflammatory bowel disease, and heart disease).

With respect to COVID-19, information collected included diagnosis date, whether the case was presumptive or confirmed, clinical symptoms, hospitalization and/or death because of COVID-19, and whether the patient stopped receiving rheumatic therapies.

Rheumatology diagnoses were categorized into four groups: JIA; SLE, MCTD, vasculitis, or other RMD; autoinflammatory syndromes; and “other,” including chronic recurrent multifocal osteomyelitis, sarcoidosis, or ocular inflammation.

Of the 607 children and young people with reported SARS-CoV-2 infection from 25 different countries (464 from the EULAR COVID-19 Registry), 499 (82%) cases were polymerase chain reaction confirmed, and 399 (66%) patients were female (median age, 14 years). Most (62%) had JIA: 37%, polyarticular JIA; 30%, oligoarticular JIA; 12%, enthesitis-related JIA; 9%, systemic JIA; 4%, psoriatic JIA; and 9%, JIA of unknown subcategory. Furthermore, 13% of patients had autoinflammatory syndromes, 8% with SLE or MCTD, 3% with vasculitis, and 2% with inflammatory myopathy.

No associations were seen between DMARD treatment (conventional-synthetic, biologic/targeted-synthetic, or combination therapy), compared with no DMARD treatment, glucocorticoid use, and hospitalization.

Owing to substantial differences in reporting of race and ethnicity between data sources, the researchers were unable to analyze whether Black, Asian, and minority ethnic groups with pediatric RMDs are at higher risk of COVID-19–related death, compared with those of White ethnicity, as has been reported for the general population.

The study also did not account for variants of SARS-CoV-2 other than to note that data were collected prior to the spread of the Omicron variant. Also, the registries did not capture vaccination status (though very few children had received vaccines at the time of data collection) or information on long COVID or multisystem inflammatory syndrome in children.

Dr. Hyrich and Dr. Kearsley-Fleet have disclosed no relevant financial relationships.

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

The use of bridging locoregional therapy (LRT) before liver transplantation in patients with hepatocellular carcinoma (HCC) has significantly increased in the United States within the past 15 years, a recent analysis suggests. Data show that liver transplant candidates with HCC who have elevated tumor burden and patients with more compensated liver disease have received a greater number of treatments while awaiting transplant.

According to the researchers, led by Allison Kwong, MD, of Stanford (Calif.) University, liver transplant remains a curative option for individuals with unresectable HCC who meet prespecified size criteria. In the United States, a mandated waiting period of 6 months prior “to gaining exception points has been implemented” in an effort “to allow for consideration of tumor biology and reduce the disparities in wait-list dropout between HCC and non-HCC patients,” the researchers wrote.

Several forms of LRT are now available for HCC, including chemoembolization, external beam radiation, radioembolization, and radiofrequency or microwave ablation. In the liver transplant setting, these LRT options enable management of intrahepatic disease in patients who are waiting for liver transplant, Dr. Kwong and colleagues explained.

The researchers, who published their study findings in the May issue of Clinical Gastroenterology and Hepatology, sought to examine the national temporal trends and wait-list outcomes of LRT in 31,609 patients eligible for liver transplant with greater than or equal to one approved HCC exception application in the United States.

Patient data were obtained from the Organ Procurement and Transplantation Network database and comprised primary adult LT candidates who were listed from the years 2003 to 2018. The investigators assessed explant histology and performed multivariable competing risk analysis to examine the relationship between the type of first LRT and time to wait-list dropout.

The wait-list dropout variable was defined by list removal because of death or excessive illness. The researchers noted that list removal likely represents disease progression “beyond transplantable criteria and beyond which patients were unlikely to benefit from or be eligible for further LRT.”

In the study population, the median age was 59 years, and approximately 77% of patients were male. More than half (53.1%) of the cohort had hepatitis C as the predominant liver disease etiology. Patients had a median follow-up period of 214 days on the waiting list.

Most patients (79%) received deceased or living-donor transplants, and 18.6% of patients were removed from the waiting list. Between the 2003 and 2006 period, the median wait-list time was 123 days, but this median wait-list duration increased to 257 days for patients listed between 2015 and 2018.

A total of 34,610 LRTs were performed among 24,145 liver transplant candidates during the study period. From 2003 to 2018, the proportion of patients with greater than or equal to 1 LRT recorded in the database rose from 42.3% to 92.4%, respectively. Most patients (67.8%) who received liver-directed therapy had a single LRT, while 23.8% of patients had two LRTs, 6.2% had three LRTs, and 2.2% had greater than or equal to four LRTs.

The most frequent type of LRT performed was chemoembolization, followed by thermal ablation. Radioembolization increased from less than 5% in 2013 to 19% in 2018. Moreover, in 2018, chemoembolization accounted for 50% of LRTs, while thermal ablation accounted for 22% of LRTs.

The incidence rates of LRT per 100 wait-list days was above average in patients who had an initial tumor burden beyond the Milan criteria (0.188), an alpha-fetoprotein level of 21-40 (0.171) or 41-500 ng/mL (0.179), Child-Pugh class A (0.160), patients in short (0.151) and medium (0.154) wait-time regions, as well as patients who were listed following implementation of cap-and-delay in October 2015 (0.192).

In the multivariable competing-risk analysis for wait-list dropout, adjusting for initial tumor burden and AFP, Child-Pugh class, wait region, and listing era, no locoregional therapy was associated with an increased risk of wait-list dropout versus chemoembolization as the first LRT in a multivariable competing-risk analysis (subhazard ratio, 1.37; 95% CI, 1.28-1.47). The inverse probability of treatment weighting–adjusted analysis found an association between radioembolization, when compared with chemoembolization, and a reduced risk of wait-list dropout (sHR, 0.85; 95% CI, 0.81-0.89). Thermal ablation was also associated with a reduced risk of wait-list dropout, compared with chemoembolization (sHR, 0.95; 95% CI, 0.91-0.99). “Radioembolization and thermal ablation may be superior to chemoembolization and prove to be more cost-effective options, depending on the clinical context,” the researchers wrote.

The researchers noted that they were unable to distinguish patients who were removed from the waiting list between those with disease progression versus liver failure.

The researchers reported no conflicts of interest with the pharmaceutical industry. The study received no industry funding.

The use of bridging locoregional therapy (LRT) before liver transplantation in patients with hepatocellular carcinoma (HCC) has significantly increased in the United States within the past 15 years, a recent analysis suggests. Data show that liver transplant candidates with HCC who have elevated tumor burden and patients with more compensated liver disease have received a greater number of treatments while awaiting transplant.

According to the researchers, led by Allison Kwong, MD, of Stanford (Calif.) University, liver transplant remains a curative option for individuals with unresectable HCC who meet prespecified size criteria. In the United States, a mandated waiting period of 6 months prior “to gaining exception points has been implemented” in an effort “to allow for consideration of tumor biology and reduce the disparities in wait-list dropout between HCC and non-HCC patients,” the researchers wrote.

Several forms of LRT are now available for HCC, including chemoembolization, external beam radiation, radioembolization, and radiofrequency or microwave ablation. In the liver transplant setting, these LRT options enable management of intrahepatic disease in patients who are waiting for liver transplant, Dr. Kwong and colleagues explained.

The researchers, who published their study findings in the May issue of Clinical Gastroenterology and Hepatology, sought to examine the national temporal trends and wait-list outcomes of LRT in 31,609 patients eligible for liver transplant with greater than or equal to one approved HCC exception application in the United States.

Patient data were obtained from the Organ Procurement and Transplantation Network database and comprised primary adult LT candidates who were listed from the years 2003 to 2018. The investigators assessed explant histology and performed multivariable competing risk analysis to examine the relationship between the type of first LRT and time to wait-list dropout.

The wait-list dropout variable was defined by list removal because of death or excessive illness. The researchers noted that list removal likely represents disease progression “beyond transplantable criteria and beyond which patients were unlikely to benefit from or be eligible for further LRT.”

In the study population, the median age was 59 years, and approximately 77% of patients were male. More than half (53.1%) of the cohort had hepatitis C as the predominant liver disease etiology. Patients had a median follow-up period of 214 days on the waiting list.

Most patients (79%) received deceased or living-donor transplants, and 18.6% of patients were removed from the waiting list. Between the 2003 and 2006 period, the median wait-list time was 123 days, but this median wait-list duration increased to 257 days for patients listed between 2015 and 2018.

A total of 34,610 LRTs were performed among 24,145 liver transplant candidates during the study period. From 2003 to 2018, the proportion of patients with greater than or equal to 1 LRT recorded in the database rose from 42.3% to 92.4%, respectively. Most patients (67.8%) who received liver-directed therapy had a single LRT, while 23.8% of patients had two LRTs, 6.2% had three LRTs, and 2.2% had greater than or equal to four LRTs.

The most frequent type of LRT performed was chemoembolization, followed by thermal ablation. Radioembolization increased from less than 5% in 2013 to 19% in 2018. Moreover, in 2018, chemoembolization accounted for 50% of LRTs, while thermal ablation accounted for 22% of LRTs.

The incidence rates of LRT per 100 wait-list days was above average in patients who had an initial tumor burden beyond the Milan criteria (0.188), an alpha-fetoprotein level of 21-40 (0.171) or 41-500 ng/mL (0.179), Child-Pugh class A (0.160), patients in short (0.151) and medium (0.154) wait-time regions, as well as patients who were listed following implementation of cap-and-delay in October 2015 (0.192).

In the multivariable competing-risk analysis for wait-list dropout, adjusting for initial tumor burden and AFP, Child-Pugh class, wait region, and listing era, no locoregional therapy was associated with an increased risk of wait-list dropout versus chemoembolization as the first LRT in a multivariable competing-risk analysis (subhazard ratio, 1.37; 95% CI, 1.28-1.47). The inverse probability of treatment weighting–adjusted analysis found an association between radioembolization, when compared with chemoembolization, and a reduced risk of wait-list dropout (sHR, 0.85; 95% CI, 0.81-0.89). Thermal ablation was also associated with a reduced risk of wait-list dropout, compared with chemoembolization (sHR, 0.95; 95% CI, 0.91-0.99). “Radioembolization and thermal ablation may be superior to chemoembolization and prove to be more cost-effective options, depending on the clinical context,” the researchers wrote.

The researchers noted that they were unable to distinguish patients who were removed from the waiting list between those with disease progression versus liver failure.

The researchers reported no conflicts of interest with the pharmaceutical industry. The study received no industry funding.

The use of bridging locoregional therapy (LRT) before liver transplantation in patients with hepatocellular carcinoma (HCC) has significantly increased in the United States within the past 15 years, a recent analysis suggests. Data show that liver transplant candidates with HCC who have elevated tumor burden and patients with more compensated liver disease have received a greater number of treatments while awaiting transplant.

According to the researchers, led by Allison Kwong, MD, of Stanford (Calif.) University, liver transplant remains a curative option for individuals with unresectable HCC who meet prespecified size criteria. In the United States, a mandated waiting period of 6 months prior “to gaining exception points has been implemented” in an effort “to allow for consideration of tumor biology and reduce the disparities in wait-list dropout between HCC and non-HCC patients,” the researchers wrote.

Several forms of LRT are now available for HCC, including chemoembolization, external beam radiation, radioembolization, and radiofrequency or microwave ablation. In the liver transplant setting, these LRT options enable management of intrahepatic disease in patients who are waiting for liver transplant, Dr. Kwong and colleagues explained.

The researchers, who published their study findings in the May issue of Clinical Gastroenterology and Hepatology, sought to examine the national temporal trends and wait-list outcomes of LRT in 31,609 patients eligible for liver transplant with greater than or equal to one approved HCC exception application in the United States.

Patient data were obtained from the Organ Procurement and Transplantation Network database and comprised primary adult LT candidates who were listed from the years 2003 to 2018. The investigators assessed explant histology and performed multivariable competing risk analysis to examine the relationship between the type of first LRT and time to wait-list dropout.

The wait-list dropout variable was defined by list removal because of death or excessive illness. The researchers noted that list removal likely represents disease progression “beyond transplantable criteria and beyond which patients were unlikely to benefit from or be eligible for further LRT.”

In the study population, the median age was 59 years, and approximately 77% of patients were male. More than half (53.1%) of the cohort had hepatitis C as the predominant liver disease etiology. Patients had a median follow-up period of 214 days on the waiting list.

Most patients (79%) received deceased or living-donor transplants, and 18.6% of patients were removed from the waiting list. Between the 2003 and 2006 period, the median wait-list time was 123 days, but this median wait-list duration increased to 257 days for patients listed between 2015 and 2018.

A total of 34,610 LRTs were performed among 24,145 liver transplant candidates during the study period. From 2003 to 2018, the proportion of patients with greater than or equal to 1 LRT recorded in the database rose from 42.3% to 92.4%, respectively. Most patients (67.8%) who received liver-directed therapy had a single LRT, while 23.8% of patients had two LRTs, 6.2% had three LRTs, and 2.2% had greater than or equal to four LRTs.

The most frequent type of LRT performed was chemoembolization, followed by thermal ablation. Radioembolization increased from less than 5% in 2013 to 19% in 2018. Moreover, in 2018, chemoembolization accounted for 50% of LRTs, while thermal ablation accounted for 22% of LRTs.

The incidence rates of LRT per 100 wait-list days was above average in patients who had an initial tumor burden beyond the Milan criteria (0.188), an alpha-fetoprotein level of 21-40 (0.171) or 41-500 ng/mL (0.179), Child-Pugh class A (0.160), patients in short (0.151) and medium (0.154) wait-time regions, as well as patients who were listed following implementation of cap-and-delay in October 2015 (0.192).

In the multivariable competing-risk analysis for wait-list dropout, adjusting for initial tumor burden and AFP, Child-Pugh class, wait region, and listing era, no locoregional therapy was associated with an increased risk of wait-list dropout versus chemoembolization as the first LRT in a multivariable competing-risk analysis (subhazard ratio, 1.37; 95% CI, 1.28-1.47). The inverse probability of treatment weighting–adjusted analysis found an association between radioembolization, when compared with chemoembolization, and a reduced risk of wait-list dropout (sHR, 0.85; 95% CI, 0.81-0.89). Thermal ablation was also associated with a reduced risk of wait-list dropout, compared with chemoembolization (sHR, 0.95; 95% CI, 0.91-0.99). “Radioembolization and thermal ablation may be superior to chemoembolization and prove to be more cost-effective options, depending on the clinical context,” the researchers wrote.

The researchers noted that they were unable to distinguish patients who were removed from the waiting list between those with disease progression versus liver failure.

The researchers reported no conflicts of interest with the pharmaceutical industry. The study received no industry funding.

Women in midlife exposed to combinations of perfluoroalkyl and polyfluoroalkyl substances (PFASs), dubbed “forever and everywhere chemicals”, are at increased risk of developing diabetes, similar to the magnitude of risk associated with overweight and even greater than the risk associated with smoking, new research shows.

“This is the first study to examine the joint effect of PFAS on incident diabetes,” first author Sung Kyun Park, ScD, MPH, told this news organization.

“We showed that multiple PFAS as mixtures have larger effects than individual PFAS,” said Dr. Park, of the department of epidemiology, School of Public Health, University of Michigan, Ann Arbor.

The results suggest that, “given that 1.5 million Americans are newly diagnosed with diabetes each year in the USA, approximately 370,000 new cases of diabetes annually in the U.S. are attributable to PFAS exposure,” Dr. Park and authors note in the study, published in Diabetologia.

However, Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., told the UK Science Media Centre: “[Some] doubt about cause still remains. Yes, this study does show that PFAS may increase diabetes risk in middle-aged women, but it certainly can’t rule out other explanations for its findings.”
 

Is there any way to reduce exposure?

PFASs, known to be ubiquitous in the environment and also often dubbed “endocrine-disrupting” chemicals, have structures similar to fatty acids. They have been detected in the blood of most people and linked to health concerns including pre-eclampsia, altered levels of liver enzymes, inflammation, and altered lipid and glucose metabolism.

Sources of PFAS exposure can run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

The authors note a recent Consumer Reports investigation of 118 food packaging products, for instance, which reported finding PFAS chemicals in the packaging of every fast-food chain and retailer examined, including Burger King, McDonald’s, and even more health-focused chains, such as Trader Joe’s.

While efforts to pressure industry to limit PFAS in products are ongoing, Dr. Park asserted that “PFAS exposure reduction at the individual-level is very limited, so a more important way is to change policies and to limit PFAS in the air, drinking water, and foods, etc.”

“It is impossible to completely avoid exposure to PFAS, but I think it is important to acknowledge such sources and change our mindset,” he said.

In terms of clinical practice, the authors add that “it is also important for clinicians to be aware of PFAS as unrecognized risk factors for diabetes and to be prepared to counsel patients in terms of sources of exposure and potential health effects.”
 

Prospective findings from the SWAN-MPS study

The findings come from a prospective study of 1,237 women, with a median age of 49.4 years, who were diabetes-free upon entering the Study of Women’s Health Across the Nation – Multi-Pollutant Study (SWAN-MPS) between 1999 and 2000 and followed until 2017.

Blood samples taken throughout the study were analyzed for serum concentrations of seven PFASs.

Over the study period, there were 102 cases of incident diabetes, representing a rate of 6 cases per 1,000 person-years. Type of diabetes was not determined, but given the age of study participants, most were assumed to have type 2 diabetes, Dr. Park and colleagues note.

namiroz/iStock/Getty Images

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

Women in midlife exposed to combinations of perfluoroalkyl and polyfluoroalkyl substances (PFASs), dubbed “forever and everywhere chemicals”, are at increased risk of developing diabetes, similar to the magnitude of risk associated with overweight and even greater than the risk associated with smoking, new research shows.

“This is the first study to examine the joint effect of PFAS on incident diabetes,” first author Sung Kyun Park, ScD, MPH, told this news organization.

“We showed that multiple PFAS as mixtures have larger effects than individual PFAS,” said Dr. Park, of the department of epidemiology, School of Public Health, University of Michigan, Ann Arbor.

The results suggest that, “given that 1.5 million Americans are newly diagnosed with diabetes each year in the USA, approximately 370,000 new cases of diabetes annually in the U.S. are attributable to PFAS exposure,” Dr. Park and authors note in the study, published in Diabetologia.

However, Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., told the UK Science Media Centre: “[Some] doubt about cause still remains. Yes, this study does show that PFAS may increase diabetes risk in middle-aged women, but it certainly can’t rule out other explanations for its findings.”
 

Is there any way to reduce exposure?

PFASs, known to be ubiquitous in the environment and also often dubbed “endocrine-disrupting” chemicals, have structures similar to fatty acids. They have been detected in the blood of most people and linked to health concerns including pre-eclampsia, altered levels of liver enzymes, inflammation, and altered lipid and glucose metabolism.

Sources of PFAS exposure can run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

The authors note a recent Consumer Reports investigation of 118 food packaging products, for instance, which reported finding PFAS chemicals in the packaging of every fast-food chain and retailer examined, including Burger King, McDonald’s, and even more health-focused chains, such as Trader Joe’s.

While efforts to pressure industry to limit PFAS in products are ongoing, Dr. Park asserted that “PFAS exposure reduction at the individual-level is very limited, so a more important way is to change policies and to limit PFAS in the air, drinking water, and foods, etc.”

“It is impossible to completely avoid exposure to PFAS, but I think it is important to acknowledge such sources and change our mindset,” he said.

In terms of clinical practice, the authors add that “it is also important for clinicians to be aware of PFAS as unrecognized risk factors for diabetes and to be prepared to counsel patients in terms of sources of exposure and potential health effects.”
 

Prospective findings from the SWAN-MPS study

The findings come from a prospective study of 1,237 women, with a median age of 49.4 years, who were diabetes-free upon entering the Study of Women’s Health Across the Nation – Multi-Pollutant Study (SWAN-MPS) between 1999 and 2000 and followed until 2017.

Blood samples taken throughout the study were analyzed for serum concentrations of seven PFASs.

Over the study period, there were 102 cases of incident diabetes, representing a rate of 6 cases per 1,000 person-years. Type of diabetes was not determined, but given the age of study participants, most were assumed to have type 2 diabetes, Dr. Park and colleagues note.

namiroz/iStock/Getty Images

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

Women in midlife exposed to combinations of perfluoroalkyl and polyfluoroalkyl substances (PFASs), dubbed “forever and everywhere chemicals”, are at increased risk of developing diabetes, similar to the magnitude of risk associated with overweight and even greater than the risk associated with smoking, new research shows.

“This is the first study to examine the joint effect of PFAS on incident diabetes,” first author Sung Kyun Park, ScD, MPH, told this news organization.

“We showed that multiple PFAS as mixtures have larger effects than individual PFAS,” said Dr. Park, of the department of epidemiology, School of Public Health, University of Michigan, Ann Arbor.

The results suggest that, “given that 1.5 million Americans are newly diagnosed with diabetes each year in the USA, approximately 370,000 new cases of diabetes annually in the U.S. are attributable to PFAS exposure,” Dr. Park and authors note in the study, published in Diabetologia.

However, Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., told the UK Science Media Centre: “[Some] doubt about cause still remains. Yes, this study does show that PFAS may increase diabetes risk in middle-aged women, but it certainly can’t rule out other explanations for its findings.”
 

Is there any way to reduce exposure?

PFASs, known to be ubiquitous in the environment and also often dubbed “endocrine-disrupting” chemicals, have structures similar to fatty acids. They have been detected in the blood of most people and linked to health concerns including pre-eclampsia, altered levels of liver enzymes, inflammation, and altered lipid and glucose metabolism.

Sources of PFAS exposure can run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

The authors note a recent Consumer Reports investigation of 118 food packaging products, for instance, which reported finding PFAS chemicals in the packaging of every fast-food chain and retailer examined, including Burger King, McDonald’s, and even more health-focused chains, such as Trader Joe’s.

While efforts to pressure industry to limit PFAS in products are ongoing, Dr. Park asserted that “PFAS exposure reduction at the individual-level is very limited, so a more important way is to change policies and to limit PFAS in the air, drinking water, and foods, etc.”

“It is impossible to completely avoid exposure to PFAS, but I think it is important to acknowledge such sources and change our mindset,” he said.

In terms of clinical practice, the authors add that “it is also important for clinicians to be aware of PFAS as unrecognized risk factors for diabetes and to be prepared to counsel patients in terms of sources of exposure and potential health effects.”
 

Prospective findings from the SWAN-MPS study

The findings come from a prospective study of 1,237 women, with a median age of 49.4 years, who were diabetes-free upon entering the Study of Women’s Health Across the Nation – Multi-Pollutant Study (SWAN-MPS) between 1999 and 2000 and followed until 2017.

Blood samples taken throughout the study were analyzed for serum concentrations of seven PFASs.

Over the study period, there were 102 cases of incident diabetes, representing a rate of 6 cases per 1,000 person-years. Type of diabetes was not determined, but given the age of study participants, most were assumed to have type 2 diabetes, Dr. Park and colleagues note.

namiroz/iStock/Getty Images

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

THE CASE

A 52-year-old man presented to the emergency department after vomiting a large volume of blood and was admitted to the intensive care unit. His past medical history was remarkable for untreated chronic hepatitis C resulting from injection drug use and cirrhosis without prior history of esophageal varices.

Due to ongoing hematemesis, he was intubated for airway protection and underwent esophagogastroduodenoscopy with banding of large esophageal varices on hospital day (HD) 1. He was extubated on HD 2 after clinical stability was achieved; however, he became encephalopathic over the subsequent days despite treatment with lactulose. On HD 4, the patient required re-intubation for progressive respiratory failure. Chest imaging revealed a large, simple-appearing right pleural effusion and extensive bilateral patchy ground-glass opacities (FIGURE 1).

Thoracentesis was ordered and revealed transudative pleural fluid; this finding, along with negative infectious studies, was consistent with hepatic hydrothorax. In the setting of initial decompensation, empiric treatment with vancomycin and meropenem was started for suspected hospital-acquired pneumonia.

The patient had persistent fevers that had developed during his hospital stay and pulmonary opacities, despite 72 hours of treatment with broad-spectrum antibiotics. Thus, a diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL cell count and differential revealed 363 nucleated cells/µL, with profound eosinophilia (42% eosinophils, 44% macrophages, 14% neutrophils).

Bacterial and fungal cultures and a viral polymerase chain reaction panel were negative. HIV antibody-antigen and RNA testing were also negative. The patient had no evidence or history of underlying malignancy, autoimmune disease, or recent immunosuppressive therapy, including corticosteroids. Due to consistent imaging findings and lack of improvement with appropriate treatment for bacterial pneumonia, further work-up was pursued.

THE DIAGNOSIS

Given the consistent radiographic pattern, the differential diagnosis for this patient included pneumocystis pneumonia (PCP), a potentially life-threatening opportunistic infection. Work-up therefore included direct fluorescent antibody testing, which was positive for Pneumocystis jirovecii, a fungus that can cause PCP.

Of note, the patient’s white blood cell count was elevated on admission (11.44 × 10³/µL) but low for much of his hospital stay (nadir = 1.97 × 10³/µL), with associated lymphopenia (nadir = 0.22 × 10³/µl). No peripheral eosinophilia was noted.

Continue to: DISCUSSION

PCP typically occurs in immunocompromised individuals and may be related to HIV infection, malignancy, or exposure to immunosuppressive therapies.^1,2 While rare cases of PCP have been described in adults without predisposing factors, many of these cases occurred at the beginning of the AIDS epidemic, prior to reliable HIV testing.^3-5

Uncharted territory. We were confident in our diagnosis because immunofluorescence testing has very few false-positives and a high specificity.^6-8 But there were informational gaps. The eosinophilia recorded on BAL is poorly described in HIV-negative patients with PCP but well-described in HIV-positive patients, with the level of eosinophilia associated with disease severity.^9,10 Eosinophils are thought to contribute to pulmonary inflammation, which may explain the severity of our patient’s course.¹⁰

A first of its kind case?

To our knowledge, this is the first report of PCP in a patient with cirrhosis from chronic hepatitis C virus infection and no other predisposing conditions or preceding immunosuppressive therapy. We suspect that his lymphopenia, which was noted during his critical illness, predisposed him to PCP.

Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of pneumocystis pneumonia.

Lymphocytes (in particular CD4+ T cells) have been shown to play an important role, along with alveolar macrophages and neutrophils, in directing the host defense against P jirovecii infection.^1,3,11 Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of PCP; risk increases markedly with CD4+ T cells below 200 cells/µL.^11-13

Typical risk factors for lymphopenia had not been observed in this patient. However, cirrhosis has been associated with low CD4+ T-cell counts and disruption of cell-mediated immunity, even in HIV-­seronegative patients.^14,15 There are several postulated mechanisms for low CD4+ T-cell counts in cirrhosis, including splenic sequestration, impaired T-cell production (due to impaired thymopoiesis), increased T-cell consumption, and apoptosis (due to persistent immune system activation from bacterial translocation and an overall pro-infl­ammatory state).^16,17

Continue to: Predisposing factors guide treatment

Routine treatment for PCP in patients without HIV is a 21-day course of trimethoprim/­sulfamethoxazole (Bactrim). Dosing for patients with normal renal function is 15 to 20 mg/kg orally or intravenously per day. Patients with allergy to trimethoprim/sulfamethoxazole should ideally undergo desensitization, given its effectiveness against PCP.

Due to a sulfonamide allergy, our patient was started on primaquine 30 mg/d, clindamycin 600 mg tid, and prednisone 40 mg bid. (The corticosteroid was added because of the severity of the disease.) Three days after starting treatment—and 10 days into his hospital stay—the patient had significant improvement in his respiratory status and was successfully extubated. He underwent trimethoprim/sulfamethoxazole desensitization and completed a 21-day course of treatment for PCP with complete resolution of respiratory symptoms. Follow-up chest radiograph 2 months later (FIGURE 2) confirmed clearance of opacities.

THE TAKEAWAY

PCP remains a rare disease in patients without the typical immunosuppressive risk factors. However, it should be considered in patients with cirrhosis who develop respiratory failure, especially those with compatible radiographic findings and negative microbiologic evaluation for other, more typical, organisms.

CORRESPONDENCE
Tyler Albert, MD, VA Puget Sound Healthcare System, 1660 South Columbian Way, S-111-Pulm, Seattle, WA 98108; [email protected]

THE CASE

A 52-year-old man presented to the emergency department after vomiting a large volume of blood and was admitted to the intensive care unit. His past medical history was remarkable for untreated chronic hepatitis C resulting from injection drug use and cirrhosis without prior history of esophageal varices.

Due to ongoing hematemesis, he was intubated for airway protection and underwent esophagogastroduodenoscopy with banding of large esophageal varices on hospital day (HD) 1. He was extubated on HD 2 after clinical stability was achieved; however, he became encephalopathic over the subsequent days despite treatment with lactulose. On HD 4, the patient required re-intubation for progressive respiratory failure. Chest imaging revealed a large, simple-appearing right pleural effusion and extensive bilateral patchy ground-glass opacities (FIGURE 1).

Thoracentesis was ordered and revealed transudative pleural fluid; this finding, along with negative infectious studies, was consistent with hepatic hydrothorax. In the setting of initial decompensation, empiric treatment with vancomycin and meropenem was started for suspected hospital-acquired pneumonia.

The patient had persistent fevers that had developed during his hospital stay and pulmonary opacities, despite 72 hours of treatment with broad-spectrum antibiotics. Thus, a diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL cell count and differential revealed 363 nucleated cells/µL, with profound eosinophilia (42% eosinophils, 44% macrophages, 14% neutrophils).

Bacterial and fungal cultures and a viral polymerase chain reaction panel were negative. HIV antibody-antigen and RNA testing were also negative. The patient had no evidence or history of underlying malignancy, autoimmune disease, or recent immunosuppressive therapy, including corticosteroids. Due to consistent imaging findings and lack of improvement with appropriate treatment for bacterial pneumonia, further work-up was pursued.

THE DIAGNOSIS

Given the consistent radiographic pattern, the differential diagnosis for this patient included pneumocystis pneumonia (PCP), a potentially life-threatening opportunistic infection. Work-up therefore included direct fluorescent antibody testing, which was positive for Pneumocystis jirovecii, a fungus that can cause PCP.

Of note, the patient’s white blood cell count was elevated on admission (11.44 × 10³/µL) but low for much of his hospital stay (nadir = 1.97 × 10³/µL), with associated lymphopenia (nadir = 0.22 × 10³/µl). No peripheral eosinophilia was noted.

Continue to: DISCUSSION

PCP typically occurs in immunocompromised individuals and may be related to HIV infection, malignancy, or exposure to immunosuppressive therapies.^1,2 While rare cases of PCP have been described in adults without predisposing factors, many of these cases occurred at the beginning of the AIDS epidemic, prior to reliable HIV testing.^3-5

Uncharted territory. We were confident in our diagnosis because immunofluorescence testing has very few false-positives and a high specificity.^6-8 But there were informational gaps. The eosinophilia recorded on BAL is poorly described in HIV-negative patients with PCP but well-described in HIV-positive patients, with the level of eosinophilia associated with disease severity.^9,10 Eosinophils are thought to contribute to pulmonary inflammation, which may explain the severity of our patient’s course.¹⁰

A first of its kind case?

To our knowledge, this is the first report of PCP in a patient with cirrhosis from chronic hepatitis C virus infection and no other predisposing conditions or preceding immunosuppressive therapy. We suspect that his lymphopenia, which was noted during his critical illness, predisposed him to PCP.

Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of pneumocystis pneumonia.

Lymphocytes (in particular CD4+ T cells) have been shown to play an important role, along with alveolar macrophages and neutrophils, in directing the host defense against P jirovecii infection.^1,3,11 Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of PCP; risk increases markedly with CD4+ T cells below 200 cells/µL.^11-13

Typical risk factors for lymphopenia had not been observed in this patient. However, cirrhosis has been associated with low CD4+ T-cell counts and disruption of cell-mediated immunity, even in HIV-­seronegative patients.^14,15 There are several postulated mechanisms for low CD4+ T-cell counts in cirrhosis, including splenic sequestration, impaired T-cell production (due to impaired thymopoiesis), increased T-cell consumption, and apoptosis (due to persistent immune system activation from bacterial translocation and an overall pro-infl­ammatory state).^16,17

Continue to: Predisposing factors guide treatment

Routine treatment for PCP in patients without HIV is a 21-day course of trimethoprim/­sulfamethoxazole (Bactrim). Dosing for patients with normal renal function is 15 to 20 mg/kg orally or intravenously per day. Patients with allergy to trimethoprim/sulfamethoxazole should ideally undergo desensitization, given its effectiveness against PCP.

Due to a sulfonamide allergy, our patient was started on primaquine 30 mg/d, clindamycin 600 mg tid, and prednisone 40 mg bid. (The corticosteroid was added because of the severity of the disease.) Three days after starting treatment—and 10 days into his hospital stay—the patient had significant improvement in his respiratory status and was successfully extubated. He underwent trimethoprim/sulfamethoxazole desensitization and completed a 21-day course of treatment for PCP with complete resolution of respiratory symptoms. Follow-up chest radiograph 2 months later (FIGURE 2) confirmed clearance of opacities.

THE TAKEAWAY

PCP remains a rare disease in patients without the typical immunosuppressive risk factors. However, it should be considered in patients with cirrhosis who develop respiratory failure, especially those with compatible radiographic findings and negative microbiologic evaluation for other, more typical, organisms.

CORRESPONDENCE
Tyler Albert, MD, VA Puget Sound Healthcare System, 1660 South Columbian Way, S-111-Pulm, Seattle, WA 98108; [email protected]

THE CASE

A 52-year-old man presented to the emergency department after vomiting a large volume of blood and was admitted to the intensive care unit. His past medical history was remarkable for untreated chronic hepatitis C resulting from injection drug use and cirrhosis without prior history of esophageal varices.

Due to ongoing hematemesis, he was intubated for airway protection and underwent esophagogastroduodenoscopy with banding of large esophageal varices on hospital day (HD) 1. He was extubated on HD 2 after clinical stability was achieved; however, he became encephalopathic over the subsequent days despite treatment with lactulose. On HD 4, the patient required re-intubation for progressive respiratory failure. Chest imaging revealed a large, simple-appearing right pleural effusion and extensive bilateral patchy ground-glass opacities (FIGURE 1).

Thoracentesis was ordered and revealed transudative pleural fluid; this finding, along with negative infectious studies, was consistent with hepatic hydrothorax. In the setting of initial decompensation, empiric treatment with vancomycin and meropenem was started for suspected hospital-acquired pneumonia.

The patient had persistent fevers that had developed during his hospital stay and pulmonary opacities, despite 72 hours of treatment with broad-spectrum antibiotics. Thus, a diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL cell count and differential revealed 363 nucleated cells/µL, with profound eosinophilia (42% eosinophils, 44% macrophages, 14% neutrophils).

Bacterial and fungal cultures and a viral polymerase chain reaction panel were negative. HIV antibody-antigen and RNA testing were also negative. The patient had no evidence or history of underlying malignancy, autoimmune disease, or recent immunosuppressive therapy, including corticosteroids. Due to consistent imaging findings and lack of improvement with appropriate treatment for bacterial pneumonia, further work-up was pursued.

THE DIAGNOSIS

Given the consistent radiographic pattern, the differential diagnosis for this patient included pneumocystis pneumonia (PCP), a potentially life-threatening opportunistic infection. Work-up therefore included direct fluorescent antibody testing, which was positive for Pneumocystis jirovecii, a fungus that can cause PCP.

Of note, the patient’s white blood cell count was elevated on admission (11.44 × 10³/µL) but low for much of his hospital stay (nadir = 1.97 × 10³/µL), with associated lymphopenia (nadir = 0.22 × 10³/µl). No peripheral eosinophilia was noted.

Continue to: DISCUSSION

PCP typically occurs in immunocompromised individuals and may be related to HIV infection, malignancy, or exposure to immunosuppressive therapies.^1,2 While rare cases of PCP have been described in adults without predisposing factors, many of these cases occurred at the beginning of the AIDS epidemic, prior to reliable HIV testing.^3-5

Uncharted territory. We were confident in our diagnosis because immunofluorescence testing has very few false-positives and a high specificity.^6-8 But there were informational gaps. The eosinophilia recorded on BAL is poorly described in HIV-negative patients with PCP but well-described in HIV-positive patients, with the level of eosinophilia associated with disease severity.^9,10 Eosinophils are thought to contribute to pulmonary inflammation, which may explain the severity of our patient’s course.¹⁰

A first of its kind case?

To our knowledge, this is the first report of PCP in a patient with cirrhosis from chronic hepatitis C virus infection and no other predisposing conditions or preceding immunosuppressive therapy. We suspect that his lymphopenia, which was noted during his critical illness, predisposed him to PCP.

Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of pneumocystis pneumonia.

Lymphocytes (in particular CD4+ T cells) have been shown to play an important role, along with alveolar macrophages and neutrophils, in directing the host defense against P jirovecii infection.^1,3,11 Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of PCP; risk increases markedly with CD4+ T cells below 200 cells/µL.^11-13

Typical risk factors for lymphopenia had not been observed in this patient. However, cirrhosis has been associated with low CD4+ T-cell counts and disruption of cell-mediated immunity, even in HIV-­seronegative patients.^14,15 There are several postulated mechanisms for low CD4+ T-cell counts in cirrhosis, including splenic sequestration, impaired T-cell production (due to impaired thymopoiesis), increased T-cell consumption, and apoptosis (due to persistent immune system activation from bacterial translocation and an overall pro-infl­ammatory state).^16,17

Continue to: Predisposing factors guide treatment

Routine treatment for PCP in patients without HIV is a 21-day course of trimethoprim/­sulfamethoxazole (Bactrim). Dosing for patients with normal renal function is 15 to 20 mg/kg orally or intravenously per day. Patients with allergy to trimethoprim/sulfamethoxazole should ideally undergo desensitization, given its effectiveness against PCP.

Due to a sulfonamide allergy, our patient was started on primaquine 30 mg/d, clindamycin 600 mg tid, and prednisone 40 mg bid. (The corticosteroid was added because of the severity of the disease.) Three days after starting treatment—and 10 days into his hospital stay—the patient had significant improvement in his respiratory status and was successfully extubated. He underwent trimethoprim/sulfamethoxazole desensitization and completed a 21-day course of treatment for PCP with complete resolution of respiratory symptoms. Follow-up chest radiograph 2 months later (FIGURE 2) confirmed clearance of opacities.

THE TAKEAWAY

PCP remains a rare disease in patients without the typical immunosuppressive risk factors. However, it should be considered in patients with cirrhosis who develop respiratory failure, especially those with compatible radiographic findings and negative microbiologic evaluation for other, more typical, organisms.

CORRESPONDENCE
Tyler Albert, MD, VA Puget Sound Healthcare System, 1660 South Columbian Way, S-111-Pulm, Seattle, WA 98108; [email protected]

THE CASE

James R* is a 30-year-old man who presented for a primary care walk-in visit due to dizziness, 2 days after he visited an emergency department (ED) for the same concern. He reported episodic symptoms lasting seconds to minutes, specifically when lying down. He said he had not fallen or experienced other physical trauma, did not have blurred vision or hearing loss, and was taking no medications. He also reported panic attacks, during which he experienced palpitations, trembling, paresthesia, and fear of dying. He stated that dizziness did not occur exclusively during panic episodes. His medical history was significant for hypertension; however, he reported significant anxiety related to medical visits. All home blood pressure readings he reported were within normal limits. 

Upon examination, the patient had a blood pressure reading of 142/90 mm Hg and no evidence of nystagmus at rest. A neurologic exam was normal and a Dix-Hallpike maneuver reproduced subjective vertigo without nystagmus. Laboratory findings from the patient’s ED visit were negative for troponin and drug use, and blood oxygenation levels were within normal limits. At the time of this current visit, an electrocardiogram was unremarkable, with the exception of some tachycardia.

The presumptive diagnosis was benign paroxysmal positional vertigo (BPPV). An Epley maneuver was performed in the clinic and resulted in minimal symptom improvement. The physician taught Mr. R how to perform the Epley maneuver himself, prescribed a short course of meclizine, and referred him to the integrated mental health care service to address his panic attacks and anxiety.

Over the next few months, Mr. R continued to report significant distress about the dizzy spells, which persisted even after performing the Epley maneuver, and he reported that the meclizine was causing worsening vertigo. He received an ear-nose-and-throat consultation and cognitive behavioral therapy (CBT)–based consultation/interventions. He also reported avoiding multiple activities due to concerns about his dizziness.

● How would you proceed with this patient?

*The patient’s name and other personally identifying information have been changed to protect his identity.

Somatic symptom disorder (SSD) is characterized by one or more physical symptoms associated with “excessive thoughts, feelings, or behaviors that result in distress and/or functional impairment.”¹ Individuals with SSD are preoccupied with symptom-related severity, experience high symptom-related anxiety, or devote significant time and energy to the symptoms or heath concerns. With a diagnosis of SSD, physical symptoms experienced by the patient may or may not be medically explained. The same symptom need not be continuously present as long as the overall symptomatic presentation lasts 6 months or longer.

The specifier “with predominant pain” is used when pain dominates the presentation.¹ Estimated prevalence of SSD in primary care ranges from 5% to 35%.² The true scope of SSD is difficult to assess accurately since research tends to focus on medically unexplained symptoms, rather than excessive symptom-related concerns. Furthermore, terms such as “medically unexplained symptoms” and “functional syndromes” (including fibromyalgia and irritable bowel syndrome) are frequently used when describing SSD.³

One or more factors may contribute to unexplained symptoms: limitations of medical procedures and techniques, partial clinical information, patients’ inability to follow management recommendations, challenges in differential diagnostics, and access-to-care limitations preventing regular care and appropriate diagnostic work up.

What’s important to remember is that it’s the patient’s reaction to physical symptoms, rather than the presence of symptoms per se, that defines SSD.

Considerations in the differential diagnosis

When making a diagnosis of SSD, symptoms cannot:⁴

• be feigned or deliberately produced as in malingering or factitious disorder.
• result from physiologic effects of a substance (eg, intoxication, withdrawal, or adverse medication effects).
• constitute somatic delusions, as occur in psychotic disorders.
• constitute symptoms or deficits affecting voluntary motor or sensory function that are better explained by neurologic, medical, or psychiatric conditions (consider conversion disorder).
• be preoccupations with physical appearance flaws, as in body dysmorphic disorder.
• be accounted for by an anxiety disorder (eg, palpitations associated with panic attacks).

Continue to: Illness anxiety disorder...

Illness anxiety disorder is also characterized by significant health-related concerns; however, physical symptoms are either mild or absent.

Ongoing elevated screening scores for anxiety and depression refractory to interventions may signal somatic symptom disorder.

Possible causes of SSD are varied and complex, including genetic and biological factors, family dynamics, behavioral modeling/learning, personality traits, difficulties with emotional regulation, and awareness.⁵ Patients may present with ongoing requests for symptom explanations, feelings of helplessness, fear of having concerns dismissed, and low motivation for change.³

Aids in supporting a diagnosis of SSD

It’s not appropriate to rely solely on questionnaires to make the diagnosis of SSD. However, brief screening tools are a time-efficient way to capture patients’ experiences and perceptions.⁶ Along with other components of clinical evaluation, brief symptom screens can both support the diagnosis and help in longitudinal symptom assessment.

Patient Health Questionnaire-15 (PHQ-15), developed for self-report screening in primary care, has desirable psychometric properties including appropriate internal reliability; convergent validity with measures of functional status, disability days, and symptom-related burden; and discriminant validity from measures of depressive symptoms.⁷ The PHQ-15 is an open access tool that is available in several languages. The respondent is asked to rate the extent of being bothered by a range of medical symptoms in the proceeding 4 weeks. Total scores range from 0 to 30, with higher scores indicating greater symptom aggravation. Cutoffs of 5, 10, and 15 correspond to mild, moderate, and severe symptom levels.⁸

Somatic Symptom Disorder - B Criteria Scale (SSD-12) aims to capture SSD symptoms in line with Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria. It assesses cognitive, affective, and behavioral aspects of SSD.⁹ The SSD-12 is copyrighted and its use requires registration and purchase. Cutoffs by age and gender are available. SSD-12 has demonstrated appropriate reliability and validity.⁹

Continue to: Structured Clinical Interview for DSM Disorders

Structured Clinical Interview for DSM Disorders (SCID)^10,11 is perhaps the most rigorous differential diagnostic tool. However, SCID administration requires training and skill; time for administration and cost of the materials may be prohibitive in primary care.

CBT is empirically supported as a treatment approach to medically unexplained symptoms and somatic symptom disorder.

Finally, SSD symptoms are highly associated with depression and anxiety. Ongoing elevated screening scores for anxiety and depression refractory to interventions may indicate the possibility of overlooked SSD. Furthermore, use of SSD screening tools with anxiety and depression screening tools can provide a more comprehensive picture of impairment, as well as symptom progress.

Treatment: Avoid a split approach

Diagnosing and treating SSD can be challenging for physicians who focus on biomedically based approaches in patient care. Additional tests, studies, and prescriptions are likely to fuel (rather than pacify) patients’ concerns, as such steps divert attention from the underlying psychological needs and mechanisms which maintain SSD. Avoid using a split biopsychosocial approach—ie, beginning the inquiry and treatment planning from a biomedical perspective, and then falling back on psychosocial formulation when treatment efforts have been ineffective. Such an approach leads to understandable patient dissatisfaction and can be interpreted by them as the caregiver suggesting that physical symptoms are “all in [their] head.”¹²

These 4 tips can help

1. Use a biopsychosocial formulation when initiating treatment. Be familiar with biopsychosocial factors in SSD and develop a narrative for discussing this formulation with patients. For example: “Mr. R, we are going to use the following [medical tests/studies/medications] to understand the cause of your symptoms and better manage them. We also need to think about the role of stress and distress in your symptoms because these can also be at play with dizziness.” This may be particularly beneficial for a functional disorder, such as chronic pain. Incorporating patient education resources is an important step toward shared understanding (see Hunter Integrated Pain Service for chronic pain educational videos; www.tga.gov.au/chronic-pain-­management-video-resource-brainman¹³).

2. Combine education about pathophysiology with patient-centered interviewing. Significant SSD symptom improvements were noted following a single 30-minute educational session, while motivational interviewing techniques were used to probe patients’ concerns.²

Continue to: Maintain professionalism and good clinical practice

3. Maintain professionalism and good clinical practice. Consider SSD a medical matter and address it accordingly: explore concerns fully, provide evidence-based responses, communicate empathy, and employ objective management strategies.¹⁴

4. Do not overlook the value of the relationship. A recent systematic review concluded that the relationship between the patient and care provider was central to the success of the interventions for symptom reduction.¹⁵

A controversial approach. Pharmacotherapy for SSD is controversial. While several trials of antidepressants and St. John’s wort have been positive and some authors have stated that all classes of antidepressants are effective for SSD, others maintain that questions regarding dosing, treatment duration, and sustainability of improvement have not been sufficiently addressed in research.^16,17

Coordination of care issues

Primary care continues to be the de facto mental health system, and specialty services may be unavailable or declined by patients.¹⁸ CBT delivered in person or online is empirically supported as a treatment approach to medically unexplained symptoms and SSD.^17,19-22

A recent meta-analysis of randomized controlled trials published by Jing and colleagues²³ reported that CBT was effective for SSD symptom reduction, and that treatment gains were maintained 3 to 12 months post treatment. However, concerns about the practical implementation of CBT in primary care were raised because CBT was not shown to be effective in improving social functioning or reducing the number of medical visits. Symptom improvement was maximized with longer durations of treatment (> 10 sessions) and greater session lengths (> 50 minutes). Additionally, Abbass and colleagues²⁴ brought up several methodologic (sampling and analysis) concerns related to Jing et al’s work.

Continue to: Overally, CBT's effect sizes...

Overall, CBT’s effect sizes are small, and patients who are open to biopsychosocial explanations for their symptoms and to receiving psychological services may differ from most patients seen in primary care practices.²¹ Furthermore, mental health providers may hesitate to diagnose SSD because they are concerned about missing a somatic illness.³ Therefore, when coordinating care with mental health providers, it may be beneficial to discuss the treatment approach, assess familiarity with the SSD diagnosis, and closely coordinate and collaborate on the treatment plan.

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for SSD treatment can be beneficial. Integrated mental health services may hold promise in addressing SSD in primary care. Onsite availability of a behavioral health provider competent in providing evidence-based care can target SSD symptoms and support both patients and physicians.

THE CASE

Mr. R’s treatment course included multiple primary care appointments (scheduled and walk in), ED visits, and specialist visits (ENT/­vestibular rehabilitation). He sought care as symptoms intensified, lasted longer, or occurred in new circumstances. He reported persistent fear of the symptoms and anxiety that serious medical causes had been overlooked. He also described distress associated with vertigo and his anxiety sensitivity (anxiety about being anxious).

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for somatic symptom disorder treatment can be beneficial.

The behavioral health consultant (BHC; psychologist) and physician talked to the patient about the biopsychosocial antecedents of his condition and the factors that perpetuate the anxiety and stress response. The BHC described the fight/flight/freeze response to the patient and explained its role in the physiologic stress response associated with somatic symptoms and panic. Educational materials (videos and handouts) were also provided to the patient to further illustrate these concepts. The BHC also discussed the role of interoceptive and situational avoidance and active coping (eg, engaging in safe activities); taught the patient relaxation and grounding techniques; and used cognitive disputation aimed at challenging catastrophic symptom interpretations.

The BHC and the patient’s physician established joint treatment goals that included improving functioning, promoting active coping, and decreasing distress associated with symptoms. After the initial medical and BHC visits, both vertigo and anxiety symptoms appeared to abate somewhat, but symptoms have been ongoing and distress and impairment have been variable. The patient’s family physician and BHC continue to work with him to optimize the care plan and treatment goals.

CORRESPONDENCE
Nataliya Pilipenko, PhD, ABPP, Center for Family and Community Medicine, Columbia University Vagelos College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032; [email protected]

ACKNOWLEDGEMENT
The author thanks Dr. Molly Warren for her collaboration and guidance.

THE CASE

James R* is a 30-year-old man who presented for a primary care walk-in visit due to dizziness, 2 days after he visited an emergency department (ED) for the same concern. He reported episodic symptoms lasting seconds to minutes, specifically when lying down. He said he had not fallen or experienced other physical trauma, did not have blurred vision or hearing loss, and was taking no medications. He also reported panic attacks, during which he experienced palpitations, trembling, paresthesia, and fear of dying. He stated that dizziness did not occur exclusively during panic episodes. His medical history was significant for hypertension; however, he reported significant anxiety related to medical visits. All home blood pressure readings he reported were within normal limits. 

Upon examination, the patient had a blood pressure reading of 142/90 mm Hg and no evidence of nystagmus at rest. A neurologic exam was normal and a Dix-Hallpike maneuver reproduced subjective vertigo without nystagmus. Laboratory findings from the patient’s ED visit were negative for troponin and drug use, and blood oxygenation levels were within normal limits. At the time of this current visit, an electrocardiogram was unremarkable, with the exception of some tachycardia.

The presumptive diagnosis was benign paroxysmal positional vertigo (BPPV). An Epley maneuver was performed in the clinic and resulted in minimal symptom improvement. The physician taught Mr. R how to perform the Epley maneuver himself, prescribed a short course of meclizine, and referred him to the integrated mental health care service to address his panic attacks and anxiety.

Over the next few months, Mr. R continued to report significant distress about the dizzy spells, which persisted even after performing the Epley maneuver, and he reported that the meclizine was causing worsening vertigo. He received an ear-nose-and-throat consultation and cognitive behavioral therapy (CBT)–based consultation/interventions. He also reported avoiding multiple activities due to concerns about his dizziness.

● How would you proceed with this patient?

*The patient’s name and other personally identifying information have been changed to protect his identity.

Somatic symptom disorder (SSD) is characterized by one or more physical symptoms associated with “excessive thoughts, feelings, or behaviors that result in distress and/or functional impairment.”¹ Individuals with SSD are preoccupied with symptom-related severity, experience high symptom-related anxiety, or devote significant time and energy to the symptoms or heath concerns. With a diagnosis of SSD, physical symptoms experienced by the patient may or may not be medically explained. The same symptom need not be continuously present as long as the overall symptomatic presentation lasts 6 months or longer.

The specifier “with predominant pain” is used when pain dominates the presentation.¹ Estimated prevalence of SSD in primary care ranges from 5% to 35%.² The true scope of SSD is difficult to assess accurately since research tends to focus on medically unexplained symptoms, rather than excessive symptom-related concerns. Furthermore, terms such as “medically unexplained symptoms” and “functional syndromes” (including fibromyalgia and irritable bowel syndrome) are frequently used when describing SSD.³

One or more factors may contribute to unexplained symptoms: limitations of medical procedures and techniques, partial clinical information, patients’ inability to follow management recommendations, challenges in differential diagnostics, and access-to-care limitations preventing regular care and appropriate diagnostic work up.

What’s important to remember is that it’s the patient’s reaction to physical symptoms, rather than the presence of symptoms per se, that defines SSD.

Considerations in the differential diagnosis

When making a diagnosis of SSD, symptoms cannot:⁴

• be feigned or deliberately produced as in malingering or factitious disorder.
• result from physiologic effects of a substance (eg, intoxication, withdrawal, or adverse medication effects).
• constitute somatic delusions, as occur in psychotic disorders.
• constitute symptoms or deficits affecting voluntary motor or sensory function that are better explained by neurologic, medical, or psychiatric conditions (consider conversion disorder).
• be preoccupations with physical appearance flaws, as in body dysmorphic disorder.
• be accounted for by an anxiety disorder (eg, palpitations associated with panic attacks).

Continue to: Illness anxiety disorder...

Illness anxiety disorder is also characterized by significant health-related concerns; however, physical symptoms are either mild or absent.

Ongoing elevated screening scores for anxiety and depression refractory to interventions may signal somatic symptom disorder.

Possible causes of SSD are varied and complex, including genetic and biological factors, family dynamics, behavioral modeling/learning, personality traits, difficulties with emotional regulation, and awareness.⁵ Patients may present with ongoing requests for symptom explanations, feelings of helplessness, fear of having concerns dismissed, and low motivation for change.³

Aids in supporting a diagnosis of SSD

It’s not appropriate to rely solely on questionnaires to make the diagnosis of SSD. However, brief screening tools are a time-efficient way to capture patients’ experiences and perceptions.⁶ Along with other components of clinical evaluation, brief symptom screens can both support the diagnosis and help in longitudinal symptom assessment.

Patient Health Questionnaire-15 (PHQ-15), developed for self-report screening in primary care, has desirable psychometric properties including appropriate internal reliability; convergent validity with measures of functional status, disability days, and symptom-related burden; and discriminant validity from measures of depressive symptoms.⁷ The PHQ-15 is an open access tool that is available in several languages. The respondent is asked to rate the extent of being bothered by a range of medical symptoms in the proceeding 4 weeks. Total scores range from 0 to 30, with higher scores indicating greater symptom aggravation. Cutoffs of 5, 10, and 15 correspond to mild, moderate, and severe symptom levels.⁸

Somatic Symptom Disorder - B Criteria Scale (SSD-12) aims to capture SSD symptoms in line with Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria. It assesses cognitive, affective, and behavioral aspects of SSD.⁹ The SSD-12 is copyrighted and its use requires registration and purchase. Cutoffs by age and gender are available. SSD-12 has demonstrated appropriate reliability and validity.⁹

Continue to: Structured Clinical Interview for DSM Disorders

Structured Clinical Interview for DSM Disorders (SCID)^10,11 is perhaps the most rigorous differential diagnostic tool. However, SCID administration requires training and skill; time for administration and cost of the materials may be prohibitive in primary care.

CBT is empirically supported as a treatment approach to medically unexplained symptoms and somatic symptom disorder.

Finally, SSD symptoms are highly associated with depression and anxiety. Ongoing elevated screening scores for anxiety and depression refractory to interventions may indicate the possibility of overlooked SSD. Furthermore, use of SSD screening tools with anxiety and depression screening tools can provide a more comprehensive picture of impairment, as well as symptom progress.

Treatment: Avoid a split approach

Diagnosing and treating SSD can be challenging for physicians who focus on biomedically based approaches in patient care. Additional tests, studies, and prescriptions are likely to fuel (rather than pacify) patients’ concerns, as such steps divert attention from the underlying psychological needs and mechanisms which maintain SSD. Avoid using a split biopsychosocial approach—ie, beginning the inquiry and treatment planning from a biomedical perspective, and then falling back on psychosocial formulation when treatment efforts have been ineffective. Such an approach leads to understandable patient dissatisfaction and can be interpreted by them as the caregiver suggesting that physical symptoms are “all in [their] head.”¹²

These 4 tips can help

1. Use a biopsychosocial formulation when initiating treatment. Be familiar with biopsychosocial factors in SSD and develop a narrative for discussing this formulation with patients. For example: “Mr. R, we are going to use the following [medical tests/studies/medications] to understand the cause of your symptoms and better manage them. We also need to think about the role of stress and distress in your symptoms because these can also be at play with dizziness.” This may be particularly beneficial for a functional disorder, such as chronic pain. Incorporating patient education resources is an important step toward shared understanding (see Hunter Integrated Pain Service for chronic pain educational videos; www.tga.gov.au/chronic-pain-­management-video-resource-brainman¹³).

2. Combine education about pathophysiology with patient-centered interviewing. Significant SSD symptom improvements were noted following a single 30-minute educational session, while motivational interviewing techniques were used to probe patients’ concerns.²

Continue to: Maintain professionalism and good clinical practice

3. Maintain professionalism and good clinical practice. Consider SSD a medical matter and address it accordingly: explore concerns fully, provide evidence-based responses, communicate empathy, and employ objective management strategies.¹⁴

4. Do not overlook the value of the relationship. A recent systematic review concluded that the relationship between the patient and care provider was central to the success of the interventions for symptom reduction.¹⁵

A controversial approach. Pharmacotherapy for SSD is controversial. While several trials of antidepressants and St. John’s wort have been positive and some authors have stated that all classes of antidepressants are effective for SSD, others maintain that questions regarding dosing, treatment duration, and sustainability of improvement have not been sufficiently addressed in research.^16,17

Coordination of care issues

Primary care continues to be the de facto mental health system, and specialty services may be unavailable or declined by patients.¹⁸ CBT delivered in person or online is empirically supported as a treatment approach to medically unexplained symptoms and SSD.^17,19-22

A recent meta-analysis of randomized controlled trials published by Jing and colleagues²³ reported that CBT was effective for SSD symptom reduction, and that treatment gains were maintained 3 to 12 months post treatment. However, concerns about the practical implementation of CBT in primary care were raised because CBT was not shown to be effective in improving social functioning or reducing the number of medical visits. Symptom improvement was maximized with longer durations of treatment (> 10 sessions) and greater session lengths (> 50 minutes). Additionally, Abbass and colleagues²⁴ brought up several methodologic (sampling and analysis) concerns related to Jing et al’s work.

Continue to: Overally, CBT's effect sizes...

Overall, CBT’s effect sizes are small, and patients who are open to biopsychosocial explanations for their symptoms and to receiving psychological services may differ from most patients seen in primary care practices.²¹ Furthermore, mental health providers may hesitate to diagnose SSD because they are concerned about missing a somatic illness.³ Therefore, when coordinating care with mental health providers, it may be beneficial to discuss the treatment approach, assess familiarity with the SSD diagnosis, and closely coordinate and collaborate on the treatment plan.

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for SSD treatment can be beneficial. Integrated mental health services may hold promise in addressing SSD in primary care. Onsite availability of a behavioral health provider competent in providing evidence-based care can target SSD symptoms and support both patients and physicians.

THE CASE

Mr. R’s treatment course included multiple primary care appointments (scheduled and walk in), ED visits, and specialist visits (ENT/­vestibular rehabilitation). He sought care as symptoms intensified, lasted longer, or occurred in new circumstances. He reported persistent fear of the symptoms and anxiety that serious medical causes had been overlooked. He also described distress associated with vertigo and his anxiety sensitivity (anxiety about being anxious).

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for somatic symptom disorder treatment can be beneficial.

The behavioral health consultant (BHC; psychologist) and physician talked to the patient about the biopsychosocial antecedents of his condition and the factors that perpetuate the anxiety and stress response. The BHC described the fight/flight/freeze response to the patient and explained its role in the physiologic stress response associated with somatic symptoms and panic. Educational materials (videos and handouts) were also provided to the patient to further illustrate these concepts. The BHC also discussed the role of interoceptive and situational avoidance and active coping (eg, engaging in safe activities); taught the patient relaxation and grounding techniques; and used cognitive disputation aimed at challenging catastrophic symptom interpretations.

The BHC and the patient’s physician established joint treatment goals that included improving functioning, promoting active coping, and decreasing distress associated with symptoms. After the initial medical and BHC visits, both vertigo and anxiety symptoms appeared to abate somewhat, but symptoms have been ongoing and distress and impairment have been variable. The patient’s family physician and BHC continue to work with him to optimize the care plan and treatment goals.

CORRESPONDENCE
Nataliya Pilipenko, PhD, ABPP, Center for Family and Community Medicine, Columbia University Vagelos College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032; [email protected]

ACKNOWLEDGEMENT
The author thanks Dr. Molly Warren for her collaboration and guidance.

THE CASE

James R* is a 30-year-old man who presented for a primary care walk-in visit due to dizziness, 2 days after he visited an emergency department (ED) for the same concern. He reported episodic symptoms lasting seconds to minutes, specifically when lying down. He said he had not fallen or experienced other physical trauma, did not have blurred vision or hearing loss, and was taking no medications. He also reported panic attacks, during which he experienced palpitations, trembling, paresthesia, and fear of dying. He stated that dizziness did not occur exclusively during panic episodes. His medical history was significant for hypertension; however, he reported significant anxiety related to medical visits. All home blood pressure readings he reported were within normal limits. 

Upon examination, the patient had a blood pressure reading of 142/90 mm Hg and no evidence of nystagmus at rest. A neurologic exam was normal and a Dix-Hallpike maneuver reproduced subjective vertigo without nystagmus. Laboratory findings from the patient’s ED visit were negative for troponin and drug use, and blood oxygenation levels were within normal limits. At the time of this current visit, an electrocardiogram was unremarkable, with the exception of some tachycardia.

The presumptive diagnosis was benign paroxysmal positional vertigo (BPPV). An Epley maneuver was performed in the clinic and resulted in minimal symptom improvement. The physician taught Mr. R how to perform the Epley maneuver himself, prescribed a short course of meclizine, and referred him to the integrated mental health care service to address his panic attacks and anxiety.

Over the next few months, Mr. R continued to report significant distress about the dizzy spells, which persisted even after performing the Epley maneuver, and he reported that the meclizine was causing worsening vertigo. He received an ear-nose-and-throat consultation and cognitive behavioral therapy (CBT)–based consultation/interventions. He also reported avoiding multiple activities due to concerns about his dizziness.

● How would you proceed with this patient?

*The patient’s name and other personally identifying information have been changed to protect his identity.

Somatic symptom disorder (SSD) is characterized by one or more physical symptoms associated with “excessive thoughts, feelings, or behaviors that result in distress and/or functional impairment.”¹ Individuals with SSD are preoccupied with symptom-related severity, experience high symptom-related anxiety, or devote significant time and energy to the symptoms or heath concerns. With a diagnosis of SSD, physical symptoms experienced by the patient may or may not be medically explained. The same symptom need not be continuously present as long as the overall symptomatic presentation lasts 6 months or longer.

The specifier “with predominant pain” is used when pain dominates the presentation.¹ Estimated prevalence of SSD in primary care ranges from 5% to 35%.² The true scope of SSD is difficult to assess accurately since research tends to focus on medically unexplained symptoms, rather than excessive symptom-related concerns. Furthermore, terms such as “medically unexplained symptoms” and “functional syndromes” (including fibromyalgia and irritable bowel syndrome) are frequently used when describing SSD.³

One or more factors may contribute to unexplained symptoms: limitations of medical procedures and techniques, partial clinical information, patients’ inability to follow management recommendations, challenges in differential diagnostics, and access-to-care limitations preventing regular care and appropriate diagnostic work up.

What’s important to remember is that it’s the patient’s reaction to physical symptoms, rather than the presence of symptoms per se, that defines SSD.

Considerations in the differential diagnosis

When making a diagnosis of SSD, symptoms cannot:⁴

• be feigned or deliberately produced as in malingering or factitious disorder.
• result from physiologic effects of a substance (eg, intoxication, withdrawal, or adverse medication effects).
• constitute somatic delusions, as occur in psychotic disorders.
• constitute symptoms or deficits affecting voluntary motor or sensory function that are better explained by neurologic, medical, or psychiatric conditions (consider conversion disorder).
• be preoccupations with physical appearance flaws, as in body dysmorphic disorder.
• be accounted for by an anxiety disorder (eg, palpitations associated with panic attacks).

Continue to: Illness anxiety disorder...

Illness anxiety disorder is also characterized by significant health-related concerns; however, physical symptoms are either mild or absent.

Ongoing elevated screening scores for anxiety and depression refractory to interventions may signal somatic symptom disorder.

Possible causes of SSD are varied and complex, including genetic and biological factors, family dynamics, behavioral modeling/learning, personality traits, difficulties with emotional regulation, and awareness.⁵ Patients may present with ongoing requests for symptom explanations, feelings of helplessness, fear of having concerns dismissed, and low motivation for change.³

Aids in supporting a diagnosis of SSD

It’s not appropriate to rely solely on questionnaires to make the diagnosis of SSD. However, brief screening tools are a time-efficient way to capture patients’ experiences and perceptions.⁶ Along with other components of clinical evaluation, brief symptom screens can both support the diagnosis and help in longitudinal symptom assessment.

Patient Health Questionnaire-15 (PHQ-15), developed for self-report screening in primary care, has desirable psychometric properties including appropriate internal reliability; convergent validity with measures of functional status, disability days, and symptom-related burden; and discriminant validity from measures of depressive symptoms.⁷ The PHQ-15 is an open access tool that is available in several languages. The respondent is asked to rate the extent of being bothered by a range of medical symptoms in the proceeding 4 weeks. Total scores range from 0 to 30, with higher scores indicating greater symptom aggravation. Cutoffs of 5, 10, and 15 correspond to mild, moderate, and severe symptom levels.⁸

Somatic Symptom Disorder - B Criteria Scale (SSD-12) aims to capture SSD symptoms in line with Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria. It assesses cognitive, affective, and behavioral aspects of SSD.⁹ The SSD-12 is copyrighted and its use requires registration and purchase. Cutoffs by age and gender are available. SSD-12 has demonstrated appropriate reliability and validity.⁹

Continue to: Structured Clinical Interview for DSM Disorders

Structured Clinical Interview for DSM Disorders (SCID)^10,11 is perhaps the most rigorous differential diagnostic tool. However, SCID administration requires training and skill; time for administration and cost of the materials may be prohibitive in primary care.

CBT is empirically supported as a treatment approach to medically unexplained symptoms and somatic symptom disorder.

Finally, SSD symptoms are highly associated with depression and anxiety. Ongoing elevated screening scores for anxiety and depression refractory to interventions may indicate the possibility of overlooked SSD. Furthermore, use of SSD screening tools with anxiety and depression screening tools can provide a more comprehensive picture of impairment, as well as symptom progress.

Treatment: Avoid a split approach

Diagnosing and treating SSD can be challenging for physicians who focus on biomedically based approaches in patient care. Additional tests, studies, and prescriptions are likely to fuel (rather than pacify) patients’ concerns, as such steps divert attention from the underlying psychological needs and mechanisms which maintain SSD. Avoid using a split biopsychosocial approach—ie, beginning the inquiry and treatment planning from a biomedical perspective, and then falling back on psychosocial formulation when treatment efforts have been ineffective. Such an approach leads to understandable patient dissatisfaction and can be interpreted by them as the caregiver suggesting that physical symptoms are “all in [their] head.”¹²

These 4 tips can help

1. Use a biopsychosocial formulation when initiating treatment. Be familiar with biopsychosocial factors in SSD and develop a narrative for discussing this formulation with patients. For example: “Mr. R, we are going to use the following [medical tests/studies/medications] to understand the cause of your symptoms and better manage them. We also need to think about the role of stress and distress in your symptoms because these can also be at play with dizziness.” This may be particularly beneficial for a functional disorder, such as chronic pain. Incorporating patient education resources is an important step toward shared understanding (see Hunter Integrated Pain Service for chronic pain educational videos; www.tga.gov.au/chronic-pain-­management-video-resource-brainman¹³).

2. Combine education about pathophysiology with patient-centered interviewing. Significant SSD symptom improvements were noted following a single 30-minute educational session, while motivational interviewing techniques were used to probe patients’ concerns.²

Continue to: Maintain professionalism and good clinical practice

3. Maintain professionalism and good clinical practice. Consider SSD a medical matter and address it accordingly: explore concerns fully, provide evidence-based responses, communicate empathy, and employ objective management strategies.¹⁴

4. Do not overlook the value of the relationship. A recent systematic review concluded that the relationship between the patient and care provider was central to the success of the interventions for symptom reduction.¹⁵

A controversial approach. Pharmacotherapy for SSD is controversial. While several trials of antidepressants and St. John’s wort have been positive and some authors have stated that all classes of antidepressants are effective for SSD, others maintain that questions regarding dosing, treatment duration, and sustainability of improvement have not been sufficiently addressed in research.^16,17

Coordination of care issues

Primary care continues to be the de facto mental health system, and specialty services may be unavailable or declined by patients.¹⁸ CBT delivered in person or online is empirically supported as a treatment approach to medically unexplained symptoms and SSD.^17,19-22

A recent meta-analysis of randomized controlled trials published by Jing and colleagues²³ reported that CBT was effective for SSD symptom reduction, and that treatment gains were maintained 3 to 12 months post treatment. However, concerns about the practical implementation of CBT in primary care were raised because CBT was not shown to be effective in improving social functioning or reducing the number of medical visits. Symptom improvement was maximized with longer durations of treatment (> 10 sessions) and greater session lengths (> 50 minutes). Additionally, Abbass and colleagues²⁴ brought up several methodologic (sampling and analysis) concerns related to Jing et al’s work.

Continue to: Overally, CBT's effect sizes...

Overall, CBT’s effect sizes are small, and patients who are open to biopsychosocial explanations for their symptoms and to receiving psychological services may differ from most patients seen in primary care practices.²¹ Furthermore, mental health providers may hesitate to diagnose SSD because they are concerned about missing a somatic illness.³ Therefore, when coordinating care with mental health providers, it may be beneficial to discuss the treatment approach, assess familiarity with the SSD diagnosis, and closely coordinate and collaborate on the treatment plan.

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for SSD treatment can be beneficial. Integrated mental health services may hold promise in addressing SSD in primary care. Onsite availability of a behavioral health provider competent in providing evidence-based care can target SSD symptoms and support both patients and physicians.

THE CASE

Mr. R’s treatment course included multiple primary care appointments (scheduled and walk in), ED visits, and specialist visits (ENT/­vestibular rehabilitation). He sought care as symptoms intensified, lasted longer, or occurred in new circumstances. He reported persistent fear of the symptoms and anxiety that serious medical causes had been overlooked. He also described distress associated with vertigo and his anxiety sensitivity (anxiety about being anxious).

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for somatic symptom disorder treatment can be beneficial.

The behavioral health consultant (BHC; psychologist) and physician talked to the patient about the biopsychosocial antecedents of his condition and the factors that perpetuate the anxiety and stress response. The BHC described the fight/flight/freeze response to the patient and explained its role in the physiologic stress response associated with somatic symptoms and panic. Educational materials (videos and handouts) were also provided to the patient to further illustrate these concepts. The BHC also discussed the role of interoceptive and situational avoidance and active coping (eg, engaging in safe activities); taught the patient relaxation and grounding techniques; and used cognitive disputation aimed at challenging catastrophic symptom interpretations.

The BHC and the patient’s physician established joint treatment goals that included improving functioning, promoting active coping, and decreasing distress associated with symptoms. After the initial medical and BHC visits, both vertigo and anxiety symptoms appeared to abate somewhat, but symptoms have been ongoing and distress and impairment have been variable. The patient’s family physician and BHC continue to work with him to optimize the care plan and treatment goals.

CORRESPONDENCE
Nataliya Pilipenko, PhD, ABPP, Center for Family and Community Medicine, Columbia University Vagelos College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032; [email protected]

ACKNOWLEDGEMENT
The author thanks Dr. Molly Warren for her collaboration and guidance.

ILLUSTRATIVE CASE

A 16-year-old girl with no chronic medical illness presents to your office with her parents after sustaining a head injury at a soccer game over the weekend. She collided with another player while attempting to head the ball. Immediately afterward, she was taken off the field and assessed. She was confused but had a normal level of consciousness and denied vision changes, weakness or tingling in her arms or legs, severe headache, or neck pain. Further testing revealed dizziness and abnormal balance. Her confusion and abnormal balance resolved after 1 day. She has had a mild headache and light sensitivity since the event. She otherwise feels well at rest in the office. She wants to recover quickly but safely and has heard conflicting statements about whether she should completely rest or start back to light activity now.

Sports-related concussions (SRCs) are highly prevalent in the United States, with as many as 3.8 million cases annually. Of those, 1.1 to 1.9 million cases are in children 18 years old or younger.^2,3 SRCs are defined by the Concussion in Sport Group (CISG) 2017 consensus statement as involving the following criteria: (1) direct or indirect trauma anywhere on the body with force transmitted to the head; (2) rapid or delayed symptom presentation, typically with spontaneous resolution; (3) functional rather than structural injury; and (4) occurrence with or without loss of consciousness with stepwise symptom resolution.⁴

SRCs do not have a proven, effective treatment and can have short- or long-term consequences. Initial treatment includes removing athletes from play immediately after an event. The American Academy of Neurology recommends that athletes not return to play until the concussion is resolved, as judged by a health care provider, and the athlete is asymptomatic when off medication.²

The CISG recommends a 6-step approach, with each step taking at least 24 hours.⁴ The final step is a return to normal activity.⁴ This working group recommended extensive study of rehabilitation programs involving subsymptom threshold exercise (ie, exercise performed at a level that does not exacerbate symptoms) before implementation as routine practice. Evidence from a 2015 study suggests that following strict rest for 5 days until complete symptom resolution may prolong recovery compared with rest for only 1 to 2 days.⁵ Additionally, strict rest did not show a difference in neurocognitive or balance outcomes in that study, and the authors noted it may also negatively impact academic, sports, and social function in adolescents.⁵ This study looked at the potential benefit of subsymptom threshold exercise during recovery from SRC.¹

STUDY SUMMARY

Light aerobic exercise may help speed recovery

This multicenter, prospective, parallel, randomized clinical trial compared subsymptom threshold aerobic exercise to ­placebo-like stretching. Patients were included if they were ages 13 to 18 years and presented within 10 days of an SRC, as diagnosed using the CISG criteria. Exclusion criteria included focal neurologic deficits; history of moderate or severe traumatic brain injury; inability to exercise due to orthopedic injury, cervical spine injury, diabetes, or heart disease; increased cardiac risk; or low postconcussion symptom severity. Patients with a diagnosis of and treatment with medication for ­attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, or learning disorder were excluded, as were patients with a history of more than 3 previous concussions.

It’s unclear whether subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with > 3 concussions were excluded from this study.

Patients in the aerobic exercise group were instructed to use a stationary bike or treadmill (or equivalent walking or jogging if they did not have access to this equipment) at a prescribed heart rate. The target heart rate was 80% of the heart rate achieved during initial assessment with the Buffalo Concussion Treadmill Test (BCTT).⁶ Patients in this group were instructed to exercise for 20 minutes or to the point at which their symptoms increased by 2 points (on a 10-point scale) from pre-exercise levels, whichever came first, with rest prescribed at all other times.

For the placebo-like group, a stretching instruction booklet was provided, with the goal of achieving a heart rate that was not significantly elevated. Participants in this group were told to perform the stretches for 20 minutes daily. Of note, researchers ensured the level of physician and research staff attention was similar for each patient, regardless of treatment group, to prevent intervention bias. Additionally, interventions were not initiated prior to 48 hours from the time of injury.

Continue to: The primary outcome...

The primary outcome was number of days to recovery since the date of injury. This was defined as symptom resolution to normal (as evaluated by a physician blinded to the study group) and by the patient’s ability to exercise to exhaustion without symptom exacerbation on the BCTT. Secondary outcomes measured the proportion of patients with delayed recovery (defined as recovery requiring > 30 days) and daily symptom scores.

Of 165 patients meeting the inclusion criteria, 52 patients were excluded prior to randomization (12 patients chose not to participate, 39 were excluded for lack of symptoms, and 1 withdrew due to severe symptoms on the BCTT). A total of 113 were randomized to either group, and 103 patients completed the study (10 patients did not complete the study or had another illness during the intervention). The study analysis included 52 patients in the aerobic exercise group and 51 in the placebo-like stretching group. The study was powered to detect a significant difference in recovery time.

Patients were about equally divided by sex, with a mean age of 15 years. Patients who had no previous concussion made up 50% of the aerobic group and 57% of the stretching group. The average time since injury was similar in the aerobic and stretching groups (4.9 days and 4.8 days, respectively). The aerobic exercise group recovered in a median of 13 days (interquartile range [IQR] = 10-18.5 days) compared with a median of 17 days (IQR = 13-23 days) for the stretching group (P = .009). The incidence of delayed recovery (> 30 days) was higher in the stretching group (n = 7) compared with the aerobic exercise group (n = 2) but was not statistically significant. Daily symptom reporting occurred at a high rate in both groups, with patients stating that they performed their prescribed exercise 89% of the time. No adverse events were reported.

WHAT’S NEW

First high-quality study to support evidence for early light activity

This is the first high-quality study of subsymptom threshold exercise for SRC. Its findings add to the growing body of evidence that early engagement in light aerobic activity that does not provoke symptoms (but not fully returning to sports activity) can aid in recovery from an SRC.

CAVEATS

Narrow study population limits application of findings

It is unclear if subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with more than 3 concussions were excluded from this study. Additionally, patients with comorbidities such as ADHD, depression, anxiety, or learning disorders were not included in this study, which limits the application of these findings. The generalizability of this study is limited in younger children, adults, those with increased cardiovascular risk, and in patients with concussions that are not sports related.

CHALLENGES TO IMPLEMENTATION

More real-world studies needed to confirm benefit

The majority of adolescent athletes in this study completed the subsymptom threshold exercise in a monitored environment with trainers, heart rate monitors, and access to equipment, limiting the study’s generalizability. Additionally, physicians need to be familiar with the BCTT to assign heart rate goals and assess improvement. The study environment may be feasible for some but not others. Studies evaluating real-world settings with athletes self-monitoring for symptom threshold with stepwise evaluations are needed and may be more broadly applicable.

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

A 16-year-old girl with no chronic medical illness presents to your office with her parents after sustaining a head injury at a soccer game over the weekend. She collided with another player while attempting to head the ball. Immediately afterward, she was taken off the field and assessed. She was confused but had a normal level of consciousness and denied vision changes, weakness or tingling in her arms or legs, severe headache, or neck pain. Further testing revealed dizziness and abnormal balance. Her confusion and abnormal balance resolved after 1 day. She has had a mild headache and light sensitivity since the event. She otherwise feels well at rest in the office. She wants to recover quickly but safely and has heard conflicting statements about whether she should completely rest or start back to light activity now.

Sports-related concussions (SRCs) are highly prevalent in the United States, with as many as 3.8 million cases annually. Of those, 1.1 to 1.9 million cases are in children 18 years old or younger.^2,3 SRCs are defined by the Concussion in Sport Group (CISG) 2017 consensus statement as involving the following criteria: (1) direct or indirect trauma anywhere on the body with force transmitted to the head; (2) rapid or delayed symptom presentation, typically with spontaneous resolution; (3) functional rather than structural injury; and (4) occurrence with or without loss of consciousness with stepwise symptom resolution.⁴

SRCs do not have a proven, effective treatment and can have short- or long-term consequences. Initial treatment includes removing athletes from play immediately after an event. The American Academy of Neurology recommends that athletes not return to play until the concussion is resolved, as judged by a health care provider, and the athlete is asymptomatic when off medication.²

The CISG recommends a 6-step approach, with each step taking at least 24 hours.⁴ The final step is a return to normal activity.⁴ This working group recommended extensive study of rehabilitation programs involving subsymptom threshold exercise (ie, exercise performed at a level that does not exacerbate symptoms) before implementation as routine practice. Evidence from a 2015 study suggests that following strict rest for 5 days until complete symptom resolution may prolong recovery compared with rest for only 1 to 2 days.⁵ Additionally, strict rest did not show a difference in neurocognitive or balance outcomes in that study, and the authors noted it may also negatively impact academic, sports, and social function in adolescents.⁵ This study looked at the potential benefit of subsymptom threshold exercise during recovery from SRC.¹

STUDY SUMMARY

Light aerobic exercise may help speed recovery

This multicenter, prospective, parallel, randomized clinical trial compared subsymptom threshold aerobic exercise to ­placebo-like stretching. Patients were included if they were ages 13 to 18 years and presented within 10 days of an SRC, as diagnosed using the CISG criteria. Exclusion criteria included focal neurologic deficits; history of moderate or severe traumatic brain injury; inability to exercise due to orthopedic injury, cervical spine injury, diabetes, or heart disease; increased cardiac risk; or low postconcussion symptom severity. Patients with a diagnosis of and treatment with medication for ­attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, or learning disorder were excluded, as were patients with a history of more than 3 previous concussions.

It’s unclear whether subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with > 3 concussions were excluded from this study.

Patients in the aerobic exercise group were instructed to use a stationary bike or treadmill (or equivalent walking or jogging if they did not have access to this equipment) at a prescribed heart rate. The target heart rate was 80% of the heart rate achieved during initial assessment with the Buffalo Concussion Treadmill Test (BCTT).⁶ Patients in this group were instructed to exercise for 20 minutes or to the point at which their symptoms increased by 2 points (on a 10-point scale) from pre-exercise levels, whichever came first, with rest prescribed at all other times.

For the placebo-like group, a stretching instruction booklet was provided, with the goal of achieving a heart rate that was not significantly elevated. Participants in this group were told to perform the stretches for 20 minutes daily. Of note, researchers ensured the level of physician and research staff attention was similar for each patient, regardless of treatment group, to prevent intervention bias. Additionally, interventions were not initiated prior to 48 hours from the time of injury.

Continue to: The primary outcome...

The primary outcome was number of days to recovery since the date of injury. This was defined as symptom resolution to normal (as evaluated by a physician blinded to the study group) and by the patient’s ability to exercise to exhaustion without symptom exacerbation on the BCTT. Secondary outcomes measured the proportion of patients with delayed recovery (defined as recovery requiring > 30 days) and daily symptom scores.

Of 165 patients meeting the inclusion criteria, 52 patients were excluded prior to randomization (12 patients chose not to participate, 39 were excluded for lack of symptoms, and 1 withdrew due to severe symptoms on the BCTT). A total of 113 were randomized to either group, and 103 patients completed the study (10 patients did not complete the study or had another illness during the intervention). The study analysis included 52 patients in the aerobic exercise group and 51 in the placebo-like stretching group. The study was powered to detect a significant difference in recovery time.

Patients were about equally divided by sex, with a mean age of 15 years. Patients who had no previous concussion made up 50% of the aerobic group and 57% of the stretching group. The average time since injury was similar in the aerobic and stretching groups (4.9 days and 4.8 days, respectively). The aerobic exercise group recovered in a median of 13 days (interquartile range [IQR] = 10-18.5 days) compared with a median of 17 days (IQR = 13-23 days) for the stretching group (P = .009). The incidence of delayed recovery (> 30 days) was higher in the stretching group (n = 7) compared with the aerobic exercise group (n = 2) but was not statistically significant. Daily symptom reporting occurred at a high rate in both groups, with patients stating that they performed their prescribed exercise 89% of the time. No adverse events were reported.

WHAT’S NEW

First high-quality study to support evidence for early light activity

This is the first high-quality study of subsymptom threshold exercise for SRC. Its findings add to the growing body of evidence that early engagement in light aerobic activity that does not provoke symptoms (but not fully returning to sports activity) can aid in recovery from an SRC.

CAVEATS

Narrow study population limits application of findings

It is unclear if subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with more than 3 concussions were excluded from this study. Additionally, patients with comorbidities such as ADHD, depression, anxiety, or learning disorders were not included in this study, which limits the application of these findings. The generalizability of this study is limited in younger children, adults, those with increased cardiovascular risk, and in patients with concussions that are not sports related.

CHALLENGES TO IMPLEMENTATION

More real-world studies needed to confirm benefit

The majority of adolescent athletes in this study completed the subsymptom threshold exercise in a monitored environment with trainers, heart rate monitors, and access to equipment, limiting the study’s generalizability. Additionally, physicians need to be familiar with the BCTT to assign heart rate goals and assess improvement. The study environment may be feasible for some but not others. Studies evaluating real-world settings with athletes self-monitoring for symptom threshold with stepwise evaluations are needed and may be more broadly applicable.

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

A 16-year-old girl with no chronic medical illness presents to your office with her parents after sustaining a head injury at a soccer game over the weekend. She collided with another player while attempting to head the ball. Immediately afterward, she was taken off the field and assessed. She was confused but had a normal level of consciousness and denied vision changes, weakness or tingling in her arms or legs, severe headache, or neck pain. Further testing revealed dizziness and abnormal balance. Her confusion and abnormal balance resolved after 1 day. She has had a mild headache and light sensitivity since the event. She otherwise feels well at rest in the office. She wants to recover quickly but safely and has heard conflicting statements about whether she should completely rest or start back to light activity now.

Sports-related concussions (SRCs) are highly prevalent in the United States, with as many as 3.8 million cases annually. Of those, 1.1 to 1.9 million cases are in children 18 years old or younger.^2,3 SRCs are defined by the Concussion in Sport Group (CISG) 2017 consensus statement as involving the following criteria: (1) direct or indirect trauma anywhere on the body with force transmitted to the head; (2) rapid or delayed symptom presentation, typically with spontaneous resolution; (3) functional rather than structural injury; and (4) occurrence with or without loss of consciousness with stepwise symptom resolution.⁴

SRCs do not have a proven, effective treatment and can have short- or long-term consequences. Initial treatment includes removing athletes from play immediately after an event. The American Academy of Neurology recommends that athletes not return to play until the concussion is resolved, as judged by a health care provider, and the athlete is asymptomatic when off medication.²

The CISG recommends a 6-step approach, with each step taking at least 24 hours.⁴ The final step is a return to normal activity.⁴ This working group recommended extensive study of rehabilitation programs involving subsymptom threshold exercise (ie, exercise performed at a level that does not exacerbate symptoms) before implementation as routine practice. Evidence from a 2015 study suggests that following strict rest for 5 days until complete symptom resolution may prolong recovery compared with rest for only 1 to 2 days.⁵ Additionally, strict rest did not show a difference in neurocognitive or balance outcomes in that study, and the authors noted it may also negatively impact academic, sports, and social function in adolescents.⁵ This study looked at the potential benefit of subsymptom threshold exercise during recovery from SRC.¹

STUDY SUMMARY

Light aerobic exercise may help speed recovery

This multicenter, prospective, parallel, randomized clinical trial compared subsymptom threshold aerobic exercise to ­placebo-like stretching. Patients were included if they were ages 13 to 18 years and presented within 10 days of an SRC, as diagnosed using the CISG criteria. Exclusion criteria included focal neurologic deficits; history of moderate or severe traumatic brain injury; inability to exercise due to orthopedic injury, cervical spine injury, diabetes, or heart disease; increased cardiac risk; or low postconcussion symptom severity. Patients with a diagnosis of and treatment with medication for ­attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, or learning disorder were excluded, as were patients with a history of more than 3 previous concussions.

It’s unclear whether subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with > 3 concussions were excluded from this study.

Patients in the aerobic exercise group were instructed to use a stationary bike or treadmill (or equivalent walking or jogging if they did not have access to this equipment) at a prescribed heart rate. The target heart rate was 80% of the heart rate achieved during initial assessment with the Buffalo Concussion Treadmill Test (BCTT).⁶ Patients in this group were instructed to exercise for 20 minutes or to the point at which their symptoms increased by 2 points (on a 10-point scale) from pre-exercise levels, whichever came first, with rest prescribed at all other times.

For the placebo-like group, a stretching instruction booklet was provided, with the goal of achieving a heart rate that was not significantly elevated. Participants in this group were told to perform the stretches for 20 minutes daily. Of note, researchers ensured the level of physician and research staff attention was similar for each patient, regardless of treatment group, to prevent intervention bias. Additionally, interventions were not initiated prior to 48 hours from the time of injury.

Continue to: The primary outcome...

The primary outcome was number of days to recovery since the date of injury. This was defined as symptom resolution to normal (as evaluated by a physician blinded to the study group) and by the patient’s ability to exercise to exhaustion without symptom exacerbation on the BCTT. Secondary outcomes measured the proportion of patients with delayed recovery (defined as recovery requiring > 30 days) and daily symptom scores.

Of 165 patients meeting the inclusion criteria, 52 patients were excluded prior to randomization (12 patients chose not to participate, 39 were excluded for lack of symptoms, and 1 withdrew due to severe symptoms on the BCTT). A total of 113 were randomized to either group, and 103 patients completed the study (10 patients did not complete the study or had another illness during the intervention). The study analysis included 52 patients in the aerobic exercise group and 51 in the placebo-like stretching group. The study was powered to detect a significant difference in recovery time.

Patients were about equally divided by sex, with a mean age of 15 years. Patients who had no previous concussion made up 50% of the aerobic group and 57% of the stretching group. The average time since injury was similar in the aerobic and stretching groups (4.9 days and 4.8 days, respectively). The aerobic exercise group recovered in a median of 13 days (interquartile range [IQR] = 10-18.5 days) compared with a median of 17 days (IQR = 13-23 days) for the stretching group (P = .009). The incidence of delayed recovery (> 30 days) was higher in the stretching group (n = 7) compared with the aerobic exercise group (n = 2) but was not statistically significant. Daily symptom reporting occurred at a high rate in both groups, with patients stating that they performed their prescribed exercise 89% of the time. No adverse events were reported.

WHAT’S NEW

First high-quality study to support evidence for early light activity

This is the first high-quality study of subsymptom threshold exercise for SRC. Its findings add to the growing body of evidence that early engagement in light aerobic activity that does not provoke symptoms (but not fully returning to sports activity) can aid in recovery from an SRC.

CAVEATS

Narrow study population limits application of findings

It is unclear if subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with more than 3 concussions were excluded from this study. Additionally, patients with comorbidities such as ADHD, depression, anxiety, or learning disorders were not included in this study, which limits the application of these findings. The generalizability of this study is limited in younger children, adults, those with increased cardiovascular risk, and in patients with concussions that are not sports related.

CHALLENGES TO IMPLEMENTATION

More real-world studies needed to confirm benefit

The majority of adolescent athletes in this study completed the subsymptom threshold exercise in a monitored environment with trainers, heart rate monitors, and access to equipment, limiting the study’s generalizability. Additionally, physicians need to be familiar with the BCTT to assign heart rate goals and assess improvement. The study environment may be feasible for some but not others. Studies evaluating real-world settings with athletes self-monitoring for symptom threshold with stepwise evaluations are needed and may be more broadly applicable.

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.

Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.

A brief history. BZDs are a subset of benzodiazepine receptor agonists (BZRAs), which enhance the inhibitory effect of centrally acting γ-amino butyric acid (GABA) at the GABA_A receptor through allosteric modulation. In 1960, the first BZD, chlordiazepoxide, was marketed for clinical use, and as other agents in the class became available, BZDs supplanted the more toxic barbiturates, another BZRA subset (TABLE 1). By the late 1970s, BZDs had risen to the top of most prescribed medications, with one agent in particular—diazepam (Valium)—earning a reputation as “mother’s little helper,” a phrase derived from a Rolling Stones' song with that title produced in 1966.¹

With recognition of the problems associated with BZDs, their popularity diminished somewhat but remained high. BZDs were listed under Schedule IV by the Drug Enforcement Administration in 1975 due to the risk for addiction, and on the American Geriatrics Society Beers Criteria list in 1991 because of significant adverse consequences in the elderly. Researchers began to question their use as early as the 1970s, and the landmark Ashton Manual, guidance for patients and clinicians alike, was published in 2002.²

Currently, there are 14 BZDs approved by the Food and Drug Administration (FDA) as well as 3 Z-hypnotics, termed such as they include the letter “z” in their generic names (TABLE 1). In recent years, BZD prescribing has risen; a 2019 study found that 1 of 8 American adults reported using a BZD in the previous year.³

Limited benefits of benzodiazepine receptor agonists

BZRAs can be of benefit in a limited range of medical conditions, including some for which they are first-line considerations. (See TABLE 2 for a list of indications for BZDs.) They are most often prescribed for anxiety and insomnia, although they are not first-line treatments for these conditions and should be prescribed only when symptoms limit a patient’s daily functioning.

BZRAs are not intended for long-term use. In recent decades, the percentage of patients prescribed BZRAs has doubled, and more than 80% of these patients indicate usage for more than 6 months.⁴ Evidence, however, does not support long-term daily use.

Observation periods in most studies are far shorter than the number of years over which BZDs are actually prescribed, and flawed research methodology has introduced the risk of bias. Specifically, the generalizability of reported outcomes must be qualified, since efficacy trials performed under ideal study conditions (eg, exclusion criteria to minimize confounders) differ from circumstances seen in clinical practice. Conclusions are also limited by the inherent bias of pharmaceutical industry sponsorship and unavailability of unpublished trials that may have demonstrated unfavorable results.

Continue to: Insomnia

Insomnia, a current (past 30 days) complaint in more than 40% of US adults, is associated with a variety of symptoms.⁵ About 20% of adults have an insomnia disorder, defined as a predominant problem for at least 1 month involving sleep initiation, maintenance, or nonrestorative sleep along with daytime function-limiting fatigue.⁵ Meta-­analyses indicate BZRAs can reduce sleep latency (BZDs, by 4 minutes; Z-hypnotics, 22 minutes) and may increase sleep duration (BZDs, 62 minutes per limited data; Z-hypnotics, data insufficient).^6,7 Definitive evidence for long-term (> 2-4 weeks) BZD benefit is lacking, and cognitive behavioral therapy for insomnia (CBT-I) is well established as first-line treatment yielding improvements that may last at least 18 months after completion of therapy. ^8,9

Although CBT-I is generally provided by behavioral health specialists, elements of CBT-I and sleep hygiene measures can be effectively used by primary care clinicians.¹⁰ Data indicate other nonpharmacologic interventions are also effective,¹¹ including acceptance and commitment therapy,¹² meditation,¹³ and acupuncture.¹⁴

Episodic fear and anxiety are universal and essential for survival. Fear is an alarm warning of an immediate hazard. Anxiety (the emotion) paired with worry (the thought) relate to a perceived future threat. Transient (state) anxiety should not be suppressed altogether if self-management can curb its intensity and thereby allow effective problem engagement. However, when individuals are incapacitated by crisis anxiety or sporadic specific phobias such as flight anxiety, episodic BZDs do have a role.

Ongoing anxiety is a more complex treatment situation. Obsessive-compulsive disorder and posttraumatic stress disorder are no longer categorized as anxiety disorders, but they often involve anxiety. Here, BZDs have no indication aside from exceptional acute crisis presentations. Anxiety disorders are defined by a core persistent (trait) anxiety disproportionate to the actual threat, limited daily functioning, and more than 6 months’ duration. One of 3 Americans older than 13 years meet the criteria for anxiety in their lifetime; 1 of 5 meet the criteria in any single year.¹⁵

BZDs are effective in treating anxiety disorders in the short term (2-4 weeks)^2,16,17; however, benefit may fade over time.^18-21 For some individuals, data suggest BZDs themselves might actually generate anxiety, as evidenced by reduced symptom intensity following discontinuation.^22,23 Recommended first-line medications for anxiety disorders include certain antidepressants and pregabalin, which exhibit efficacy similar to that of BZDs.²⁴ Mindfulness and various psychotherapies have value, as well.¹⁶ Among the latter, CBT is considered first line with benefit comparable to BZDs in the short term; yet unlike BZDs, CBT gains can last 12 months or longer after the conclusion of therapy. ^25,26 Because there may be a delay between the start of CBT and the onset of benefit, BZDs, which work quickly, may be used to bridge functionally impaired patients in the short term.

Continue to: Risks with benzodiazepine receptor agonists

Risks with benzodiazepine receptor agonists

Harms from BZRA use are common, tempering their utility. Sedation, dyscognition, and psychomotor impairments are often seen upon initiation of BZRA use. These adverse effects can—although not always—improve with continuous BZRA exposure, an effect known as tolerance, which is due to neuropharmacologic adaptation. 

Cognitive issues include problems with memory, judgment, and decision making. These may be unrecognized or, if noted, attributed to other issues such as aging, and may become clear only when BZRAs are discontinued. Anterograde amnesia and parasomnias occur less often.

Psychomotor impairment can result in falls, fractures, and other injuries, especially in the elderly. Decrements in mood, including emergent depression and paradoxical anxiety, can occur. Some individuals experience disinhibition that is expressed through irritability, agitation, aggression, and violence.

Misuse of BZRAs is not unusual and can be related to dosing errors or attempts to ease intrusive symptoms. Nonmedical use almost always occurs in the context of an underlying use disorder, whereby BZRAs serve to amplify euphoria or ameliorate withdrawal from opioids or alcohol. Addiction per se, which entails BZRA craving and compulsive use leading to adverse consequences, is unusual.

BZRAs are associated with increased mortality, including all-cause mortality and suicide. They are respiratory depressants, although when taken alone in excess rarely result in death. They are, however, strongly implicated in opioid-related overdose fatalities, as their presence has been identified in 1 of 3 such decedents.²⁷

Continue to: Physiologic dependence with BZRAs

Among the more important adverse outcomes with ongoing BZRA exposure is physiologic dependence. This occurs primarily because of neuroadaptation of GABA_A and glutaminergic receptors, but dependence probably also involves changes in the adenosine A_2A, serotonergic, and peripheral benzodiazepine receptors, the latter being present on mitochondrial membranes. The hypothalamic-pituitary-adrenal axis also appears to be involved.

Physiologic dependence is expressed through BZRA tolerance and characteristic physical and psychological symptoms upon withdrawal. Tolerance refers to a reduced effect with continued substance exposure or the need for an increased dose to get the same effect. Drug withdrawal can result in manifestations distinctive to addiction-prone substances, as well as to some medications without addiction liability, such as corticosteroids and antidepressants. Tolerance and withdrawal are not applicable criteria in the diagnosis of sedative-hypnotic use disorder when BZRAs are prescribed.²⁸

Withdrawal. Reported prevalence of BZRA physiologic dependence differs according to populations studied, criteria used, and the deprescribing process employed. Some researchers have found rates of one-third and others exceeding one-half among individuals using BZRAs for longer than a month.^23,29Physiologic dependence has also been seen in those exposed for as little as 1 week and at usual or even low dosages.^30,31 Moderate-to-severe withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology.^2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities.³⁴

Deprescribing BZRAs

Because benefits are limited and adverse outcomes including physiologic dependence are common, it is recommended that clinicians urge deprescribing of BZRAs for any patient taking them consistently for more than 1 month. Published deprescribing investigations and guidance are insufficient, heterogenous, and confusing. Still, some approaches can work well, and success rates as high as 80% have been achieved among the elderly, for example.³⁵ Brief interventions such as providing individualized advice, support, and management are effective.^36,37 Abrupt discontinuation is inappropriate and can be life threatening.³⁸ Forced cessation is also inappropriate unless significant respiratory depression is identified.

Physiologic dependence with benzodiazepine receptor agonists has been seen in those exposed for as little as 1 week and at usual or even low dosages.

The Ashton Manual is a useful guide, readable by patients. Proceed with tapering slowly at a rate led by the patient’s response.^2,39 Avoid discrediting patients’ reports of unusual withdrawal symptoms, as this can lead to misdiagnosis (eg, somatic symptom disorder) or ineffective treatment (eg, addiction recovery approaches). Adding CBT to tapering improves outcomes, and adjunctive medications may be helpful, although not without their own problems.²⁹ Consistent support of patients by others involved in treatment (prescriber, pharmacist, behavioral health specialists, peer coach, significant others) is essential. Complex challenges generally resolve through authentic listening and response but may require referral to others with necessary skills and experience. Complete cessation may take 12 to 18 months (or longer). Even if complete cessation is not possible, the least dose necessary can be achieved.

CORRESPONDENCE
Steven Wright, MD, 1975 Ashland Mine Road, Ashland, OR 97520; [email protected]

Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.

A brief history. BZDs are a subset of benzodiazepine receptor agonists (BZRAs), which enhance the inhibitory effect of centrally acting γ-amino butyric acid (GABA) at the GABA_A receptor through allosteric modulation. In 1960, the first BZD, chlordiazepoxide, was marketed for clinical use, and as other agents in the class became available, BZDs supplanted the more toxic barbiturates, another BZRA subset (TABLE 1). By the late 1970s, BZDs had risen to the top of most prescribed medications, with one agent in particular—diazepam (Valium)—earning a reputation as “mother’s little helper,” a phrase derived from a Rolling Stones' song with that title produced in 1966.¹

With recognition of the problems associated with BZDs, their popularity diminished somewhat but remained high. BZDs were listed under Schedule IV by the Drug Enforcement Administration in 1975 due to the risk for addiction, and on the American Geriatrics Society Beers Criteria list in 1991 because of significant adverse consequences in the elderly. Researchers began to question their use as early as the 1970s, and the landmark Ashton Manual, guidance for patients and clinicians alike, was published in 2002.²

Currently, there are 14 BZDs approved by the Food and Drug Administration (FDA) as well as 3 Z-hypnotics, termed such as they include the letter “z” in their generic names (TABLE 1). In recent years, BZD prescribing has risen; a 2019 study found that 1 of 8 American adults reported using a BZD in the previous year.³

Limited benefits of benzodiazepine receptor agonists

BZRAs can be of benefit in a limited range of medical conditions, including some for which they are first-line considerations. (See TABLE 2 for a list of indications for BZDs.) They are most often prescribed for anxiety and insomnia, although they are not first-line treatments for these conditions and should be prescribed only when symptoms limit a patient’s daily functioning.

BZRAs are not intended for long-term use. In recent decades, the percentage of patients prescribed BZRAs has doubled, and more than 80% of these patients indicate usage for more than 6 months.⁴ Evidence, however, does not support long-term daily use.

Observation periods in most studies are far shorter than the number of years over which BZDs are actually prescribed, and flawed research methodology has introduced the risk of bias. Specifically, the generalizability of reported outcomes must be qualified, since efficacy trials performed under ideal study conditions (eg, exclusion criteria to minimize confounders) differ from circumstances seen in clinical practice. Conclusions are also limited by the inherent bias of pharmaceutical industry sponsorship and unavailability of unpublished trials that may have demonstrated unfavorable results.

Continue to: Insomnia

Insomnia, a current (past 30 days) complaint in more than 40% of US adults, is associated with a variety of symptoms.⁵ About 20% of adults have an insomnia disorder, defined as a predominant problem for at least 1 month involving sleep initiation, maintenance, or nonrestorative sleep along with daytime function-limiting fatigue.⁵ Meta-­analyses indicate BZRAs can reduce sleep latency (BZDs, by 4 minutes; Z-hypnotics, 22 minutes) and may increase sleep duration (BZDs, 62 minutes per limited data; Z-hypnotics, data insufficient).^6,7 Definitive evidence for long-term (> 2-4 weeks) BZD benefit is lacking, and cognitive behavioral therapy for insomnia (CBT-I) is well established as first-line treatment yielding improvements that may last at least 18 months after completion of therapy. ^8,9

Although CBT-I is generally provided by behavioral health specialists, elements of CBT-I and sleep hygiene measures can be effectively used by primary care clinicians.¹⁰ Data indicate other nonpharmacologic interventions are also effective,¹¹ including acceptance and commitment therapy,¹² meditation,¹³ and acupuncture.¹⁴

Episodic fear and anxiety are universal and essential for survival. Fear is an alarm warning of an immediate hazard. Anxiety (the emotion) paired with worry (the thought) relate to a perceived future threat. Transient (state) anxiety should not be suppressed altogether if self-management can curb its intensity and thereby allow effective problem engagement. However, when individuals are incapacitated by crisis anxiety or sporadic specific phobias such as flight anxiety, episodic BZDs do have a role.

Ongoing anxiety is a more complex treatment situation. Obsessive-compulsive disorder and posttraumatic stress disorder are no longer categorized as anxiety disorders, but they often involve anxiety. Here, BZDs have no indication aside from exceptional acute crisis presentations. Anxiety disorders are defined by a core persistent (trait) anxiety disproportionate to the actual threat, limited daily functioning, and more than 6 months’ duration. One of 3 Americans older than 13 years meet the criteria for anxiety in their lifetime; 1 of 5 meet the criteria in any single year.¹⁵

BZDs are effective in treating anxiety disorders in the short term (2-4 weeks)^2,16,17; however, benefit may fade over time.^18-21 For some individuals, data suggest BZDs themselves might actually generate anxiety, as evidenced by reduced symptom intensity following discontinuation.^22,23 Recommended first-line medications for anxiety disorders include certain antidepressants and pregabalin, which exhibit efficacy similar to that of BZDs.²⁴ Mindfulness and various psychotherapies have value, as well.¹⁶ Among the latter, CBT is considered first line with benefit comparable to BZDs in the short term; yet unlike BZDs, CBT gains can last 12 months or longer after the conclusion of therapy. ^25,26 Because there may be a delay between the start of CBT and the onset of benefit, BZDs, which work quickly, may be used to bridge functionally impaired patients in the short term.

Continue to: Risks with benzodiazepine receptor agonists

Risks with benzodiazepine receptor agonists

Harms from BZRA use are common, tempering their utility. Sedation, dyscognition, and psychomotor impairments are often seen upon initiation of BZRA use. These adverse effects can—although not always—improve with continuous BZRA exposure, an effect known as tolerance, which is due to neuropharmacologic adaptation. 

Cognitive issues include problems with memory, judgment, and decision making. These may be unrecognized or, if noted, attributed to other issues such as aging, and may become clear only when BZRAs are discontinued. Anterograde amnesia and parasomnias occur less often.

Psychomotor impairment can result in falls, fractures, and other injuries, especially in the elderly. Decrements in mood, including emergent depression and paradoxical anxiety, can occur. Some individuals experience disinhibition that is expressed through irritability, agitation, aggression, and violence.

Misuse of BZRAs is not unusual and can be related to dosing errors or attempts to ease intrusive symptoms. Nonmedical use almost always occurs in the context of an underlying use disorder, whereby BZRAs serve to amplify euphoria or ameliorate withdrawal from opioids or alcohol. Addiction per se, which entails BZRA craving and compulsive use leading to adverse consequences, is unusual.

BZRAs are associated with increased mortality, including all-cause mortality and suicide. They are respiratory depressants, although when taken alone in excess rarely result in death. They are, however, strongly implicated in opioid-related overdose fatalities, as their presence has been identified in 1 of 3 such decedents.²⁷

Continue to: Physiologic dependence with BZRAs

Among the more important adverse outcomes with ongoing BZRA exposure is physiologic dependence. This occurs primarily because of neuroadaptation of GABA_A and glutaminergic receptors, but dependence probably also involves changes in the adenosine A_2A, serotonergic, and peripheral benzodiazepine receptors, the latter being present on mitochondrial membranes. The hypothalamic-pituitary-adrenal axis also appears to be involved.

Physiologic dependence is expressed through BZRA tolerance and characteristic physical and psychological symptoms upon withdrawal. Tolerance refers to a reduced effect with continued substance exposure or the need for an increased dose to get the same effect. Drug withdrawal can result in manifestations distinctive to addiction-prone substances, as well as to some medications without addiction liability, such as corticosteroids and antidepressants. Tolerance and withdrawal are not applicable criteria in the diagnosis of sedative-hypnotic use disorder when BZRAs are prescribed.²⁸

Withdrawal. Reported prevalence of BZRA physiologic dependence differs according to populations studied, criteria used, and the deprescribing process employed. Some researchers have found rates of one-third and others exceeding one-half among individuals using BZRAs for longer than a month.^23,29Physiologic dependence has also been seen in those exposed for as little as 1 week and at usual or even low dosages.^30,31 Moderate-to-severe withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology.^2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities.³⁴

Deprescribing BZRAs

Because benefits are limited and adverse outcomes including physiologic dependence are common, it is recommended that clinicians urge deprescribing of BZRAs for any patient taking them consistently for more than 1 month. Published deprescribing investigations and guidance are insufficient, heterogenous, and confusing. Still, some approaches can work well, and success rates as high as 80% have been achieved among the elderly, for example.³⁵ Brief interventions such as providing individualized advice, support, and management are effective.^36,37 Abrupt discontinuation is inappropriate and can be life threatening.³⁸ Forced cessation is also inappropriate unless significant respiratory depression is identified.

Physiologic dependence with benzodiazepine receptor agonists has been seen in those exposed for as little as 1 week and at usual or even low dosages.

The Ashton Manual is a useful guide, readable by patients. Proceed with tapering slowly at a rate led by the patient’s response.^2,39 Avoid discrediting patients’ reports of unusual withdrawal symptoms, as this can lead to misdiagnosis (eg, somatic symptom disorder) or ineffective treatment (eg, addiction recovery approaches). Adding CBT to tapering improves outcomes, and adjunctive medications may be helpful, although not without their own problems.²⁹ Consistent support of patients by others involved in treatment (prescriber, pharmacist, behavioral health specialists, peer coach, significant others) is essential. Complex challenges generally resolve through authentic listening and response but may require referral to others with necessary skills and experience. Complete cessation may take 12 to 18 months (or longer). Even if complete cessation is not possible, the least dose necessary can be achieved.

CORRESPONDENCE
Steven Wright, MD, 1975 Ashland Mine Road, Ashland, OR 97520; [email protected]

Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.

A brief history. BZDs are a subset of benzodiazepine receptor agonists (BZRAs), which enhance the inhibitory effect of centrally acting γ-amino butyric acid (GABA) at the GABA_A receptor through allosteric modulation. In 1960, the first BZD, chlordiazepoxide, was marketed for clinical use, and as other agents in the class became available, BZDs supplanted the more toxic barbiturates, another BZRA subset (TABLE 1). By the late 1970s, BZDs had risen to the top of most prescribed medications, with one agent in particular—diazepam (Valium)—earning a reputation as “mother’s little helper,” a phrase derived from a Rolling Stones' song with that title produced in 1966.¹

With recognition of the problems associated with BZDs, their popularity diminished somewhat but remained high. BZDs were listed under Schedule IV by the Drug Enforcement Administration in 1975 due to the risk for addiction, and on the American Geriatrics Society Beers Criteria list in 1991 because of significant adverse consequences in the elderly. Researchers began to question their use as early as the 1970s, and the landmark Ashton Manual, guidance for patients and clinicians alike, was published in 2002.²

Currently, there are 14 BZDs approved by the Food and Drug Administration (FDA) as well as 3 Z-hypnotics, termed such as they include the letter “z” in their generic names (TABLE 1). In recent years, BZD prescribing has risen; a 2019 study found that 1 of 8 American adults reported using a BZD in the previous year.³

Limited benefits of benzodiazepine receptor agonists

BZRAs can be of benefit in a limited range of medical conditions, including some for which they are first-line considerations. (See TABLE 2 for a list of indications for BZDs.) They are most often prescribed for anxiety and insomnia, although they are not first-line treatments for these conditions and should be prescribed only when symptoms limit a patient’s daily functioning.

BZRAs are not intended for long-term use. In recent decades, the percentage of patients prescribed BZRAs has doubled, and more than 80% of these patients indicate usage for more than 6 months.⁴ Evidence, however, does not support long-term daily use.

Observation periods in most studies are far shorter than the number of years over which BZDs are actually prescribed, and flawed research methodology has introduced the risk of bias. Specifically, the generalizability of reported outcomes must be qualified, since efficacy trials performed under ideal study conditions (eg, exclusion criteria to minimize confounders) differ from circumstances seen in clinical practice. Conclusions are also limited by the inherent bias of pharmaceutical industry sponsorship and unavailability of unpublished trials that may have demonstrated unfavorable results.

Continue to: Insomnia

Insomnia, a current (past 30 days) complaint in more than 40% of US adults, is associated with a variety of symptoms.⁵ About 20% of adults have an insomnia disorder, defined as a predominant problem for at least 1 month involving sleep initiation, maintenance, or nonrestorative sleep along with daytime function-limiting fatigue.⁵ Meta-­analyses indicate BZRAs can reduce sleep latency (BZDs, by 4 minutes; Z-hypnotics, 22 minutes) and may increase sleep duration (BZDs, 62 minutes per limited data; Z-hypnotics, data insufficient).^6,7 Definitive evidence for long-term (> 2-4 weeks) BZD benefit is lacking, and cognitive behavioral therapy for insomnia (CBT-I) is well established as first-line treatment yielding improvements that may last at least 18 months after completion of therapy. ^8,9

Although CBT-I is generally provided by behavioral health specialists, elements of CBT-I and sleep hygiene measures can be effectively used by primary care clinicians.¹⁰ Data indicate other nonpharmacologic interventions are also effective,¹¹ including acceptance and commitment therapy,¹² meditation,¹³ and acupuncture.¹⁴

Episodic fear and anxiety are universal and essential for survival. Fear is an alarm warning of an immediate hazard. Anxiety (the emotion) paired with worry (the thought) relate to a perceived future threat. Transient (state) anxiety should not be suppressed altogether if self-management can curb its intensity and thereby allow effective problem engagement. However, when individuals are incapacitated by crisis anxiety or sporadic specific phobias such as flight anxiety, episodic BZDs do have a role.

Ongoing anxiety is a more complex treatment situation. Obsessive-compulsive disorder and posttraumatic stress disorder are no longer categorized as anxiety disorders, but they often involve anxiety. Here, BZDs have no indication aside from exceptional acute crisis presentations. Anxiety disorders are defined by a core persistent (trait) anxiety disproportionate to the actual threat, limited daily functioning, and more than 6 months’ duration. One of 3 Americans older than 13 years meet the criteria for anxiety in their lifetime; 1 of 5 meet the criteria in any single year.¹⁵

BZDs are effective in treating anxiety disorders in the short term (2-4 weeks)^2,16,17; however, benefit may fade over time.^18-21 For some individuals, data suggest BZDs themselves might actually generate anxiety, as evidenced by reduced symptom intensity following discontinuation.^22,23 Recommended first-line medications for anxiety disorders include certain antidepressants and pregabalin, which exhibit efficacy similar to that of BZDs.²⁴ Mindfulness and various psychotherapies have value, as well.¹⁶ Among the latter, CBT is considered first line with benefit comparable to BZDs in the short term; yet unlike BZDs, CBT gains can last 12 months or longer after the conclusion of therapy. ^25,26 Because there may be a delay between the start of CBT and the onset of benefit, BZDs, which work quickly, may be used to bridge functionally impaired patients in the short term.

Continue to: Risks with benzodiazepine receptor agonists

Risks with benzodiazepine receptor agonists

Harms from BZRA use are common, tempering their utility. Sedation, dyscognition, and psychomotor impairments are often seen upon initiation of BZRA use. These adverse effects can—although not always—improve with continuous BZRA exposure, an effect known as tolerance, which is due to neuropharmacologic adaptation. 

Cognitive issues include problems with memory, judgment, and decision making. These may be unrecognized or, if noted, attributed to other issues such as aging, and may become clear only when BZRAs are discontinued. Anterograde amnesia and parasomnias occur less often.

Psychomotor impairment can result in falls, fractures, and other injuries, especially in the elderly. Decrements in mood, including emergent depression and paradoxical anxiety, can occur. Some individuals experience disinhibition that is expressed through irritability, agitation, aggression, and violence.

Misuse of BZRAs is not unusual and can be related to dosing errors or attempts to ease intrusive symptoms. Nonmedical use almost always occurs in the context of an underlying use disorder, whereby BZRAs serve to amplify euphoria or ameliorate withdrawal from opioids or alcohol. Addiction per se, which entails BZRA craving and compulsive use leading to adverse consequences, is unusual.

BZRAs are associated with increased mortality, including all-cause mortality and suicide. They are respiratory depressants, although when taken alone in excess rarely result in death. They are, however, strongly implicated in opioid-related overdose fatalities, as their presence has been identified in 1 of 3 such decedents.²⁷

Continue to: Physiologic dependence with BZRAs

Among the more important adverse outcomes with ongoing BZRA exposure is physiologic dependence. This occurs primarily because of neuroadaptation of GABA_A and glutaminergic receptors, but dependence probably also involves changes in the adenosine A_2A, serotonergic, and peripheral benzodiazepine receptors, the latter being present on mitochondrial membranes. The hypothalamic-pituitary-adrenal axis also appears to be involved.

Physiologic dependence is expressed through BZRA tolerance and characteristic physical and psychological symptoms upon withdrawal. Tolerance refers to a reduced effect with continued substance exposure or the need for an increased dose to get the same effect. Drug withdrawal can result in manifestations distinctive to addiction-prone substances, as well as to some medications without addiction liability, such as corticosteroids and antidepressants. Tolerance and withdrawal are not applicable criteria in the diagnosis of sedative-hypnotic use disorder when BZRAs are prescribed.²⁸

Withdrawal. Reported prevalence of BZRA physiologic dependence differs according to populations studied, criteria used, and the deprescribing process employed. Some researchers have found rates of one-third and others exceeding one-half among individuals using BZRAs for longer than a month.^23,29Physiologic dependence has also been seen in those exposed for as little as 1 week and at usual or even low dosages.^30,31 Moderate-to-severe withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology.^2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities.³⁴

Deprescribing BZRAs

Because benefits are limited and adverse outcomes including physiologic dependence are common, it is recommended that clinicians urge deprescribing of BZRAs for any patient taking them consistently for more than 1 month. Published deprescribing investigations and guidance are insufficient, heterogenous, and confusing. Still, some approaches can work well, and success rates as high as 80% have been achieved among the elderly, for example.³⁵ Brief interventions such as providing individualized advice, support, and management are effective.^36,37 Abrupt discontinuation is inappropriate and can be life threatening.³⁸ Forced cessation is also inappropriate unless significant respiratory depression is identified.

Physiologic dependence with benzodiazepine receptor agonists has been seen in those exposed for as little as 1 week and at usual or even low dosages.

The Ashton Manual is a useful guide, readable by patients. Proceed with tapering slowly at a rate led by the patient’s response.^2,39 Avoid discrediting patients’ reports of unusual withdrawal symptoms, as this can lead to misdiagnosis (eg, somatic symptom disorder) or ineffective treatment (eg, addiction recovery approaches). Adding CBT to tapering improves outcomes, and adjunctive medications may be helpful, although not without their own problems.²⁹ Consistent support of patients by others involved in treatment (prescriber, pharmacist, behavioral health specialists, peer coach, significant others) is essential. Complex challenges generally resolve through authentic listening and response but may require referral to others with necessary skills and experience. Complete cessation may take 12 to 18 months (or longer). Even if complete cessation is not possible, the least dose necessary can be achieved.

CORRESPONDENCE
Steven Wright, MD, 1975 Ashland Mine Road, Ashland, OR 97520; [email protected]

Evidence summary

Bicarbonate therapy demonstrates benefit in 2 meta-analyses

Two recent meta-analyses evaluated studies of bicarbonate therapy in patients with CKD, and both found benefit.^1,2

A 2020 meta-analysis included 15 RCTs (N = 2445) of adults (mean age, 61 years; range, 40.5-73.9 years) with CKD.¹ Most trials enrolled patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²; however, 1 study (N = 80) enrolled patients who had an eGFR of 60 to 90 mL/min/1.73 m² and albuminuria, and another (N = 74) enrolled patients with an eGFR of 15 to 89 mL/min/1.73 m². Four studies included patients with normal baseline bicarbonate levels, while the rest enrolled patients with metabolic acidosis. The primary outcome was CKD progression at study conclusion, which ranged from 3 to 60 months (median, 12 months).

Compared to placebo or no therapy, sodium bicarbonate (variously dosed) resulted in a small reduction in the rate of loss of kidney function (defined by eGFR or creatinine clearance) from baseline to trial completion (14 trials, N = 2073; standardized mean difference [SMD] = 0.26; 95% CI, 0.13-0.40; P = .018; I² = 50%).¹Sodium bicarbonate therapy also resulted in a moderate reduction in the risk of end-stage renal disease (7 trials, N = 1526; risk ratio [RR] = 0.53; 95% CI, 0.30-0.89; P = .011; I² = 69%; number needed to treat [NNT] = 14).¹ There was no difference in hospitalizations for heart failure, risk of worsening blood pressure, or all-cause mortality between the sodium bicarbonate and control groups.

Subgroup analysis by follow-up time found a significant preservation of eGFR only in studies with follow-up > 12 months (4 trials, N = 392; weighted mean difference = 3.71 mL/min/1.73 m²; 95% CI, 0.18-7.24; P = .042; I² = 63%).¹ Duration of therapy did not affect initiation of dialysis. Another subgroup analysis found that low- and moderate-quality studies were more likely than high-quality studies to find a change in the primary outcome. Overall, there was significant heterogeneity among the trials (control intervention, follow-up duration, methods of assessment of kidney function, dosage of sodium bicarbonate), as well as underrepresentation of female, pediatric, and elderly patients.

Another meta-analysis, published in 2019 by a different research group, analyzed 7 RCTs (N = 815) that comprised a subset of those in the newer analysis.² The 2019 analysis similarly found that, compared to placebo or usual care, oral bicarbonate therapy resulted in statistically significantly higher eGFRs at 3 to 60 months’ follow-up (mean difference = 3.1 mL/min/1.73 m²; 95% CI, 1.3-4.9).² The authors noted that the protective effect on eGFR was not seen in studies reporting outcomes at 1 year. Progression to end-stage renal disease or initiation of dialysis were not used as outcomes.

Significant outcomes seen in 1 large study

The largest study (N = 740) included in the 2020 meta-analysis (and discussed separately due to its size and duration) was a multicenter, unblinded, pragmatic trial investigating bicarbonate therapy in CKD.³ Patients were adults (mean age, 67.8 years) with CKD stages 3 to 5 and metabolic acidosis (serum bicarbonate level of 18-24 mmol/L); mean serum creatinine was 2.3 mg/dL, and mean serum bicarbonate was 21.5 mmol/L. Patients with severe heart failure or uncontrolled hypertension were excluded.

Compared to placebo or no therapy, sodium bicarbonate (variously dosed) resulted in a small reduction in the rate of loss of kidney function.

Researchers randomized patients to oral sodium bicarbonate (titrated to a target serum concentration of 24-28 mmol/L) or standard care for a median duration of 30 months. The primary endpoint was time to doubling of serum creatinine, and secondary endpoints included all-cause mortality, time to initiation of dialysis, hospitalization rate, and hospital length of stay.

Continue to: Patients treated with...

Patients treated with bicarbonate therapy had a 64% lower risk of doubling their serum creatinine compared to those treated with standard care (hazard ratio [HR] = 0.36; 95% CI, 0.22-0.58; P < .001; NNT = 9.6).³ Bicarbonate therapy also significantly reduced the risk of dialysis (HR = 0.5; 95% CI, 0.31-0.81; P = .005; NNT = 19); all-cause mortality (HR = 0.43; 95% CI, 0.22-0.87; P = .01; NNT = 27); hospitalization rates (34.6% vs 14.2% by end of study in standard care and bicarbonate groups, respectively; P < .001); and hospital length of stay (1160 total d/y vs 400 total d/y; P < .0001).³ Inspection of Kaplan Meier curves shows outcomes beginning to diverge after 1 to 2 years of treatment. This trial was limited by the lack of blinding, placebo control, and standardization of care protocols.

Recommendations from others

The National Kidney Foundation’s 2012 Kidney Disease Outcomes Quality Initiative guidelines for the management of CKD recommend oral bicarbonate therapy for patients with CKD and serum bicarbonate concentrations < 22 mmol/L.⁴ The guidelines state that serum bicarbonate levels < 22 mmol/L correlate with an increased risk of CKD progression and death, whereas high bicarbonate levels (> 32 mmol/L) correlate with increased risk of death independent of level of kidney function. These guidelines cite small studies of alkali therapy slowing progression of CKD, although it was noted that the evidence base was not strong.

Editor’s takeaway

The evidence shows a small but consistent effect of bicarbonate therapy on CKD progression. For patients with CKD stages 3 to 5 and metabolic acidosis (defined by serum bicarbonate levels < 22 mmol/L), the use of supplemental oral sodium bicarbonate, which is inexpensive and safe, can delay or prevent progression of serious disease.

Evidence summary

Bicarbonate therapy demonstrates benefit in 2 meta-analyses

Two recent meta-analyses evaluated studies of bicarbonate therapy in patients with CKD, and both found benefit.^1,2

A 2020 meta-analysis included 15 RCTs (N = 2445) of adults (mean age, 61 years; range, 40.5-73.9 years) with CKD.¹ Most trials enrolled patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²; however, 1 study (N = 80) enrolled patients who had an eGFR of 60 to 90 mL/min/1.73 m² and albuminuria, and another (N = 74) enrolled patients with an eGFR of 15 to 89 mL/min/1.73 m². Four studies included patients with normal baseline bicarbonate levels, while the rest enrolled patients with metabolic acidosis. The primary outcome was CKD progression at study conclusion, which ranged from 3 to 60 months (median, 12 months).

Compared to placebo or no therapy, sodium bicarbonate (variously dosed) resulted in a small reduction in the rate of loss of kidney function (defined by eGFR or creatinine clearance) from baseline to trial completion (14 trials, N = 2073; standardized mean difference [SMD] = 0.26; 95% CI, 0.13-0.40; P = .018; I² = 50%).¹Sodium bicarbonate therapy also resulted in a moderate reduction in the risk of end-stage renal disease (7 trials, N = 1526; risk ratio [RR] = 0.53; 95% CI, 0.30-0.89; P = .011; I² = 69%; number needed to treat [NNT] = 14).¹ There was no difference in hospitalizations for heart failure, risk of worsening blood pressure, or all-cause mortality between the sodium bicarbonate and control groups.

Subgroup analysis by follow-up time found a significant preservation of eGFR only in studies with follow-up > 12 months (4 trials, N = 392; weighted mean difference = 3.71 mL/min/1.73 m²; 95% CI, 0.18-7.24; P = .042; I² = 63%).¹ Duration of therapy did not affect initiation of dialysis. Another subgroup analysis found that low- and moderate-quality studies were more likely than high-quality studies to find a change in the primary outcome. Overall, there was significant heterogeneity among the trials (control intervention, follow-up duration, methods of assessment of kidney function, dosage of sodium bicarbonate), as well as underrepresentation of female, pediatric, and elderly patients.

Another meta-analysis, published in 2019 by a different research group, analyzed 7 RCTs (N = 815) that comprised a subset of those in the newer analysis.² The 2019 analysis similarly found that, compared to placebo or usual care, oral bicarbonate therapy resulted in statistically significantly higher eGFRs at 3 to 60 months’ follow-up (mean difference = 3.1 mL/min/1.73 m²; 95% CI, 1.3-4.9).² The authors noted that the protective effect on eGFR was not seen in studies reporting outcomes at 1 year. Progression to end-stage renal disease or initiation of dialysis were not used as outcomes.

Significant outcomes seen in 1 large study

The largest study (N = 740) included in the 2020 meta-analysis (and discussed separately due to its size and duration) was a multicenter, unblinded, pragmatic trial investigating bicarbonate therapy in CKD.³ Patients were adults (mean age, 67.8 years) with CKD stages 3 to 5 and metabolic acidosis (serum bicarbonate level of 18-24 mmol/L); mean serum creatinine was 2.3 mg/dL, and mean serum bicarbonate was 21.5 mmol/L. Patients with severe heart failure or uncontrolled hypertension were excluded.

Compared to placebo or no therapy, sodium bicarbonate (variously dosed) resulted in a small reduction in the rate of loss of kidney function.

Researchers randomized patients to oral sodium bicarbonate (titrated to a target serum concentration of 24-28 mmol/L) or standard care for a median duration of 30 months. The primary endpoint was time to doubling of serum creatinine, and secondary endpoints included all-cause mortality, time to initiation of dialysis, hospitalization rate, and hospital length of stay.

Continue to: Patients treated with...

Patients treated with bicarbonate therapy had a 64% lower risk of doubling their serum creatinine compared to those treated with standard care (hazard ratio [HR] = 0.36; 95% CI, 0.22-0.58; P < .001; NNT = 9.6).³ Bicarbonate therapy also significantly reduced the risk of dialysis (HR = 0.5; 95% CI, 0.31-0.81; P = .005; NNT = 19); all-cause mortality (HR = 0.43; 95% CI, 0.22-0.87; P = .01; NNT = 27); hospitalization rates (34.6% vs 14.2% by end of study in standard care and bicarbonate groups, respectively; P < .001); and hospital length of stay (1160 total d/y vs 400 total d/y; P < .0001).³ Inspection of Kaplan Meier curves shows outcomes beginning to diverge after 1 to 2 years of treatment. This trial was limited by the lack of blinding, placebo control, and standardization of care protocols.

Recommendations from others

The National Kidney Foundation’s 2012 Kidney Disease Outcomes Quality Initiative guidelines for the management of CKD recommend oral bicarbonate therapy for patients with CKD and serum bicarbonate concentrations < 22 mmol/L.⁴ The guidelines state that serum bicarbonate levels < 22 mmol/L correlate with an increased risk of CKD progression and death, whereas high bicarbonate levels (> 32 mmol/L) correlate with increased risk of death independent of level of kidney function. These guidelines cite small studies of alkali therapy slowing progression of CKD, although it was noted that the evidence base was not strong.

Editor’s takeaway

The evidence shows a small but consistent effect of bicarbonate therapy on CKD progression. For patients with CKD stages 3 to 5 and metabolic acidosis (defined by serum bicarbonate levels < 22 mmol/L), the use of supplemental oral sodium bicarbonate, which is inexpensive and safe, can delay or prevent progression of serious disease.

Evidence summary

Bicarbonate therapy demonstrates benefit in 2 meta-analyses

Two recent meta-analyses evaluated studies of bicarbonate therapy in patients with CKD, and both found benefit.^1,2

A 2020 meta-analysis included 15 RCTs (N = 2445) of adults (mean age, 61 years; range, 40.5-73.9 years) with CKD.¹ Most trials enrolled patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²; however, 1 study (N = 80) enrolled patients who had an eGFR of 60 to 90 mL/min/1.73 m² and albuminuria, and another (N = 74) enrolled patients with an eGFR of 15 to 89 mL/min/1.73 m². Four studies included patients with normal baseline bicarbonate levels, while the rest enrolled patients with metabolic acidosis. The primary outcome was CKD progression at study conclusion, which ranged from 3 to 60 months (median, 12 months).

Compared to placebo or no therapy, sodium bicarbonate (variously dosed) resulted in a small reduction in the rate of loss of kidney function (defined by eGFR or creatinine clearance) from baseline to trial completion (14 trials, N = 2073; standardized mean difference [SMD] = 0.26; 95% CI, 0.13-0.40; P = .018; I² = 50%).¹Sodium bicarbonate therapy also resulted in a moderate reduction in the risk of end-stage renal disease (7 trials, N = 1526; risk ratio [RR] = 0.53; 95% CI, 0.30-0.89; P = .011; I² = 69%; number needed to treat [NNT] = 14).¹ There was no difference in hospitalizations for heart failure, risk of worsening blood pressure, or all-cause mortality between the sodium bicarbonate and control groups.

Subgroup analysis by follow-up time found a significant preservation of eGFR only in studies with follow-up > 12 months (4 trials, N = 392; weighted mean difference = 3.71 mL/min/1.73 m²; 95% CI, 0.18-7.24; P = .042; I² = 63%).¹ Duration of therapy did not affect initiation of dialysis. Another subgroup analysis found that low- and moderate-quality studies were more likely than high-quality studies to find a change in the primary outcome. Overall, there was significant heterogeneity among the trials (control intervention, follow-up duration, methods of assessment of kidney function, dosage of sodium bicarbonate), as well as underrepresentation of female, pediatric, and elderly patients.

Another meta-analysis, published in 2019 by a different research group, analyzed 7 RCTs (N = 815) that comprised a subset of those in the newer analysis.² The 2019 analysis similarly found that, compared to placebo or usual care, oral bicarbonate therapy resulted in statistically significantly higher eGFRs at 3 to 60 months’ follow-up (mean difference = 3.1 mL/min/1.73 m²; 95% CI, 1.3-4.9).² The authors noted that the protective effect on eGFR was not seen in studies reporting outcomes at 1 year. Progression to end-stage renal disease or initiation of dialysis were not used as outcomes.

Significant outcomes seen in 1 large study

The largest study (N = 740) included in the 2020 meta-analysis (and discussed separately due to its size and duration) was a multicenter, unblinded, pragmatic trial investigating bicarbonate therapy in CKD.³ Patients were adults (mean age, 67.8 years) with CKD stages 3 to 5 and metabolic acidosis (serum bicarbonate level of 18-24 mmol/L); mean serum creatinine was 2.3 mg/dL, and mean serum bicarbonate was 21.5 mmol/L. Patients with severe heart failure or uncontrolled hypertension were excluded.

Compared to placebo or no therapy, sodium bicarbonate (variously dosed) resulted in a small reduction in the rate of loss of kidney function.

Researchers randomized patients to oral sodium bicarbonate (titrated to a target serum concentration of 24-28 mmol/L) or standard care for a median duration of 30 months. The primary endpoint was time to doubling of serum creatinine, and secondary endpoints included all-cause mortality, time to initiation of dialysis, hospitalization rate, and hospital length of stay.

Continue to: Patients treated with...

Patients treated with bicarbonate therapy had a 64% lower risk of doubling their serum creatinine compared to those treated with standard care (hazard ratio [HR] = 0.36; 95% CI, 0.22-0.58; P < .001; NNT = 9.6).³ Bicarbonate therapy also significantly reduced the risk of dialysis (HR = 0.5; 95% CI, 0.31-0.81; P = .005; NNT = 19); all-cause mortality (HR = 0.43; 95% CI, 0.22-0.87; P = .01; NNT = 27); hospitalization rates (34.6% vs 14.2% by end of study in standard care and bicarbonate groups, respectively; P < .001); and hospital length of stay (1160 total d/y vs 400 total d/y; P < .0001).³ Inspection of Kaplan Meier curves shows outcomes beginning to diverge after 1 to 2 years of treatment. This trial was limited by the lack of blinding, placebo control, and standardization of care protocols.

Recommendations from others

The National Kidney Foundation’s 2012 Kidney Disease Outcomes Quality Initiative guidelines for the management of CKD recommend oral bicarbonate therapy for patients with CKD and serum bicarbonate concentrations < 22 mmol/L.⁴ The guidelines state that serum bicarbonate levels < 22 mmol/L correlate with an increased risk of CKD progression and death, whereas high bicarbonate levels (> 32 mmol/L) correlate with increased risk of death independent of level of kidney function. These guidelines cite small studies of alkali therapy slowing progression of CKD, although it was noted that the evidence base was not strong.

Editor’s takeaway

The evidence shows a small but consistent effect of bicarbonate therapy on CKD progression. For patients with CKD stages 3 to 5 and metabolic acidosis (defined by serum bicarbonate levels < 22 mmol/L), the use of supplemental oral sodium bicarbonate, which is inexpensive and safe, can delay or prevent progression of serious disease.

Key clinical point: Colchicine use in patients with gout is associated with a lower risk for type 2 diabetes mellitus (T2D).

Major finding: Colchicine users vs. nonusers had a lower cumulative incidence of T2D (18.8% vs. 25.0%) and a significantly lower risk for T2D (adjusted hazard ratio 0.74; 95% CI 0.36-0.87), with the inverse association remaining significant across both sexes and different age groups.

Study details: The data come from a retrospective cohort study including patients newly diagnosed with gout who used (n = 3841) and did not use (n = 7682) colchicine.

Disclosures: The study received no external funding. The authors declared no conflict of interests.

Source: Chu C-C et al. Association between clinical use of colchicine and risk of type 2 diabetes mellitus among gouty patients: A nationwide cohort study. Int J Environ Res Public Health. 2022;19(6):3395 (Mar 14). Doi: 10.3390/ijerph19063395

Key clinical point: Colchicine use in patients with gout is associated with a lower risk for type 2 diabetes mellitus (T2D).

Major finding: Colchicine users vs. nonusers had a lower cumulative incidence of T2D (18.8% vs. 25.0%) and a significantly lower risk for T2D (adjusted hazard ratio 0.74; 95% CI 0.36-0.87), with the inverse association remaining significant across both sexes and different age groups.

Study details: The data come from a retrospective cohort study including patients newly diagnosed with gout who used (n = 3841) and did not use (n = 7682) colchicine.

Disclosures: The study received no external funding. The authors declared no conflict of interests.

Source: Chu C-C et al. Association between clinical use of colchicine and risk of type 2 diabetes mellitus among gouty patients: A nationwide cohort study. Int J Environ Res Public Health. 2022;19(6):3395 (Mar 14). Doi: 10.3390/ijerph19063395

Key clinical point: Colchicine use in patients with gout is associated with a lower risk for type 2 diabetes mellitus (T2D).

Major finding: Colchicine users vs. nonusers had a lower cumulative incidence of T2D (18.8% vs. 25.0%) and a significantly lower risk for T2D (adjusted hazard ratio 0.74; 95% CI 0.36-0.87), with the inverse association remaining significant across both sexes and different age groups.

Study details: The data come from a retrospective cohort study including patients newly diagnosed with gout who used (n = 3841) and did not use (n = 7682) colchicine.

Disclosures: The study received no external funding. The authors declared no conflict of interests.

Source: Chu C-C et al. Association between clinical use of colchicine and risk of type 2 diabetes mellitus among gouty patients: A nationwide cohort study. Int J Environ Res Public Health. 2022;19(6):3395 (Mar 14). Doi: 10.3390/ijerph19063395