Federal Practitioner

Deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, has been approved by the Food and Drug Administration for treating adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy, the manufacturer announced on Sept. 9.

Deucravacitinib targets TYK2, which inhibits signaling of interleukin-23, interleukin-12, and type 1 interferons, key cytokines involved in the pathogenesis of multiple immune-mediated diseases, according to Bristol Myers Squibb (BMS). This is the first approval for deucravacitinib, which will be marketed as Sotyktu, and the first drug in this class to be approved.

It is also currently under review for the same indication in Europe and Japan, and elsewhere, and for treating pustular psoriasis and erythrodermic psoriasis in Japan.

FDA approval was based on the results of POETYK PSO-1 and POETYK PSO-2, phase 3 trials of almost 1,700 adults with moderate to severe plaque psoriasis. In these studies, treatment with once-daily deucravacitinib showed significant and clinically meaningful improvements in skin clearance and symptoms, compared with placebo and with apremilast (Otezla), according to the company.

In the two studies, patients were randomly assigned to receive 6 mg daily of deucravacitinib, placebo, or a 30-mg twice-daily dose of apremilast, the oral phosphodiesterase 4 inhibitor approved for psoriasis. The primary endpoints were the percentage of patients who achieved a Psoriasis Area and Severity Index (PASI) 75 response and a static Physician’s Global Assessment (sPGA) score of 0 or 1 (clear or almost clear) at 16 weeks.

At 16 weeks, 58% and 53% of patients receiving deucravacitinib in the POETYK PSO-1 and POETYK PSO-2 studies, respectively, achieved PASI 75 response, compared with 13% and 9% of those receiving placebo (P < .0001 for both) and 35% and 40% receiving apremilast (P < .0001, P = .0004, respectively), according to the company’s announcement of the approval. PASI 75 responses were maintained through 52 weeks among the patients who remained on treatment, in both studies, according to BMS.

In the POETYK PSO-1 and PSO-2 studies, respectively, 54% and 50% of those on deucravacitinib achieved an sPGA of 0/1 at 16 weeks, compared with 7% and 9% of those receiving placebo (P < .0001 for both) and 32% and 34% of those receiving apremilast (P < .0001 for both).

Across the two studies, at 16 weeks, the most common adverse events that affected at least 1% of patients on deucravacitinib and that occurred at higher rates than in the placebo group were upper respiratory infections (19.2%), increases in serum creatine phosphokinase (2.7%), herpes simplex (2%), mouth ulcers (1.9%), folliculitis (1.7%), and acne (1.4%). Adverse events resulting in discontinuation of treatment were reported in 2.4% of persons receiving deucravacitinib and 5.2% of those receiving apremilast, compared with 3.8% of those receiving placebo.

Up to 16 weeks, according to the BMS statement, 28% of persons receiving deucravacitinib had infections, most of which were mild to moderate and not serious and did not result in stopping treatment, compared with 22% of those receiving placebo. In addition, five patients treated with deucravacitinib and five patients receiving placebo had serious infections, and three patients receiving deucravacitinib had cancer (not including nonmelanoma skin cancer).

Deucravacitinib is also being evaluated in clinical trials for psoriatic arthritis, lupus, and inflammatory bowel disease. It is not recommended for use in combination with other potent immunosuppressants, according to BMS.

The prescribing information and patient medication guide are available online.

The POETYK PSO-1 and POETYK PSO-2 studies were funded by Bristol Myers Squibb.

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

Deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, has been approved by the Food and Drug Administration for treating adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy, the manufacturer announced on Sept. 9.

Deucravacitinib targets TYK2, which inhibits signaling of interleukin-23, interleukin-12, and type 1 interferons, key cytokines involved in the pathogenesis of multiple immune-mediated diseases, according to Bristol Myers Squibb (BMS). This is the first approval for deucravacitinib, which will be marketed as Sotyktu, and the first drug in this class to be approved.

It is also currently under review for the same indication in Europe and Japan, and elsewhere, and for treating pustular psoriasis and erythrodermic psoriasis in Japan.

FDA approval was based on the results of POETYK PSO-1 and POETYK PSO-2, phase 3 trials of almost 1,700 adults with moderate to severe plaque psoriasis. In these studies, treatment with once-daily deucravacitinib showed significant and clinically meaningful improvements in skin clearance and symptoms, compared with placebo and with apremilast (Otezla), according to the company.

In the two studies, patients were randomly assigned to receive 6 mg daily of deucravacitinib, placebo, or a 30-mg twice-daily dose of apremilast, the oral phosphodiesterase 4 inhibitor approved for psoriasis. The primary endpoints were the percentage of patients who achieved a Psoriasis Area and Severity Index (PASI) 75 response and a static Physician’s Global Assessment (sPGA) score of 0 or 1 (clear or almost clear) at 16 weeks.

At 16 weeks, 58% and 53% of patients receiving deucravacitinib in the POETYK PSO-1 and POETYK PSO-2 studies, respectively, achieved PASI 75 response, compared with 13% and 9% of those receiving placebo (P < .0001 for both) and 35% and 40% receiving apremilast (P < .0001, P = .0004, respectively), according to the company’s announcement of the approval. PASI 75 responses were maintained through 52 weeks among the patients who remained on treatment, in both studies, according to BMS.

In the POETYK PSO-1 and PSO-2 studies, respectively, 54% and 50% of those on deucravacitinib achieved an sPGA of 0/1 at 16 weeks, compared with 7% and 9% of those receiving placebo (P < .0001 for both) and 32% and 34% of those receiving apremilast (P < .0001 for both).

Across the two studies, at 16 weeks, the most common adverse events that affected at least 1% of patients on deucravacitinib and that occurred at higher rates than in the placebo group were upper respiratory infections (19.2%), increases in serum creatine phosphokinase (2.7%), herpes simplex (2%), mouth ulcers (1.9%), folliculitis (1.7%), and acne (1.4%). Adverse events resulting in discontinuation of treatment were reported in 2.4% of persons receiving deucravacitinib and 5.2% of those receiving apremilast, compared with 3.8% of those receiving placebo.

Up to 16 weeks, according to the BMS statement, 28% of persons receiving deucravacitinib had infections, most of which were mild to moderate and not serious and did not result in stopping treatment, compared with 22% of those receiving placebo. In addition, five patients treated with deucravacitinib and five patients receiving placebo had serious infections, and three patients receiving deucravacitinib had cancer (not including nonmelanoma skin cancer).

Deucravacitinib is also being evaluated in clinical trials for psoriatic arthritis, lupus, and inflammatory bowel disease. It is not recommended for use in combination with other potent immunosuppressants, according to BMS.

The prescribing information and patient medication guide are available online.

The POETYK PSO-1 and POETYK PSO-2 studies were funded by Bristol Myers Squibb.

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

Deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, has been approved by the Food and Drug Administration for treating adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy, the manufacturer announced on Sept. 9.

Deucravacitinib targets TYK2, which inhibits signaling of interleukin-23, interleukin-12, and type 1 interferons, key cytokines involved in the pathogenesis of multiple immune-mediated diseases, according to Bristol Myers Squibb (BMS). This is the first approval for deucravacitinib, which will be marketed as Sotyktu, and the first drug in this class to be approved.

It is also currently under review for the same indication in Europe and Japan, and elsewhere, and for treating pustular psoriasis and erythrodermic psoriasis in Japan.

FDA approval was based on the results of POETYK PSO-1 and POETYK PSO-2, phase 3 trials of almost 1,700 adults with moderate to severe plaque psoriasis. In these studies, treatment with once-daily deucravacitinib showed significant and clinically meaningful improvements in skin clearance and symptoms, compared with placebo and with apremilast (Otezla), according to the company.

In the two studies, patients were randomly assigned to receive 6 mg daily of deucravacitinib, placebo, or a 30-mg twice-daily dose of apremilast, the oral phosphodiesterase 4 inhibitor approved for psoriasis. The primary endpoints were the percentage of patients who achieved a Psoriasis Area and Severity Index (PASI) 75 response and a static Physician’s Global Assessment (sPGA) score of 0 or 1 (clear or almost clear) at 16 weeks.

At 16 weeks, 58% and 53% of patients receiving deucravacitinib in the POETYK PSO-1 and POETYK PSO-2 studies, respectively, achieved PASI 75 response, compared with 13% and 9% of those receiving placebo (P < .0001 for both) and 35% and 40% receiving apremilast (P < .0001, P = .0004, respectively), according to the company’s announcement of the approval. PASI 75 responses were maintained through 52 weeks among the patients who remained on treatment, in both studies, according to BMS.

In the POETYK PSO-1 and PSO-2 studies, respectively, 54% and 50% of those on deucravacitinib achieved an sPGA of 0/1 at 16 weeks, compared with 7% and 9% of those receiving placebo (P < .0001 for both) and 32% and 34% of those receiving apremilast (P < .0001 for both).

Across the two studies, at 16 weeks, the most common adverse events that affected at least 1% of patients on deucravacitinib and that occurred at higher rates than in the placebo group were upper respiratory infections (19.2%), increases in serum creatine phosphokinase (2.7%), herpes simplex (2%), mouth ulcers (1.9%), folliculitis (1.7%), and acne (1.4%). Adverse events resulting in discontinuation of treatment were reported in 2.4% of persons receiving deucravacitinib and 5.2% of those receiving apremilast, compared with 3.8% of those receiving placebo.

Up to 16 weeks, according to the BMS statement, 28% of persons receiving deucravacitinib had infections, most of which were mild to moderate and not serious and did not result in stopping treatment, compared with 22% of those receiving placebo. In addition, five patients treated with deucravacitinib and five patients receiving placebo had serious infections, and three patients receiving deucravacitinib had cancer (not including nonmelanoma skin cancer).

Deucravacitinib is also being evaluated in clinical trials for psoriatic arthritis, lupus, and inflammatory bowel disease. It is not recommended for use in combination with other potent immunosuppressants, according to BMS.

The prescribing information and patient medication guide are available online.

The POETYK PSO-1 and POETYK PSO-2 studies were funded by Bristol Myers Squibb.

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

PARIS – New results from a large prospective trial give a better idea of how a blood test that can detect multiple cancers performs in a “real-life” setting.

“As this technology develops, people must continue with their standard cancer screening, but this is a glimpse of what the future may hold,” commented study investigator Deborah Schrag, MD, MPH, chair, department of medicine, Memorial Sloan Kettering Cancer Center, New York.

For the PATHFINDER study, the Galleri blood test (developed by Grail) was used in 6,621 healthy individuals aged over 50, with or without additional cancer risk factors (such as history of smoking or genetic risk).

It found a positive cancer signal in 92 individuals (1.4%). 

None of the individuals who tested positive was known to have cancer at the time of testing. Subsequent workup, which could include scans and/or biopsy, found cancer in 38% of those with a positive test.

“When the test was positive, the workups were typically done in less than 3 months,” Dr. Schrag commented, adding that “the blood test typically predicted the origin of the cancer.”

Dr. Schrag presented the findings at the annual meeting of the European Society for Medical Oncology (ESMO).

Approached for comment, Anthony J. Olszanski, MD, RPh, vice chair of research at the Fox Chase Cancer Center, Philadelphia, noted that the use of a blood test to “find” cancer has long been on the minds of patients. “It is not uncommon to hear oncology patients ask: ‘Why didn’t my doctor find my cancer earlier, on blood tests?’ ”

As this study suggests, finding a malignancy before it becomes apparent on imaging or because of symptoms is one step closer to becoming a reality. “But although this is an important study, it must be noted that only about 40% of patients with a positive test result were actually found to have cancer,” Dr. Olszanski said. “Conversely, about 60% of patients with a positive test result likely suffered from a considerable amount of anxiety that may persist even after further testing did not reveal a malignancy.”

Another important issue is that such testing may incur substantial health care cost. “Less than 2 participants per 100 had a positive test result, and those patients underwent further testing to interrogate the result,” he added. “It also remains unclear if detecting cancer early will lead to better outcomes.”

Whether or not the test will be cost-effective remains unknown, as Dr. Schrag emphasized they do not have a formal cost analysis at this time. “This technology is not ready for population-wide screening, but as the technology improves, costs will go down,” she said.

Dr. Schrag also added that this is a new concept and the trial shows it is feasible to detect cancer using a blood test. “It was not designed to determine if the test can decrease cancer mortality, which is obviously the purpose of screening, but it’s premature for that,” she said.
 

Details of the results

The Galleri test uses cell-free DNA and machine learning to detect a common cancer signal across more than 50 cancer types as well as to predict cancer signal origin.

Overall, the test detected a cancer signal in 1.4% (n = 92) of participants with analyzable samples.

A total of 90 participants underwent diagnostic testing (33 true positives and 57 false positives). Of the true positives, 81.8% underwent more than one invasive diagnostic test, as did 29.8% of false positives.

Specificity was 99.1%, positive predictive value (PPV) was approximately 40%, and 73% of those who were true positives had diagnostic resolution in less than 3 months.

Of the cancers that were diagnosed, 19 were solid tumors and 17 were hematologic cancers; 7 were diagnosed in a person with a history of cancer, 26 were cancer types without standard screening, and 14 were diagnosed at an early stage.

“What is exciting about this new paradigm is that many of these were cancers for which we don’t have standard screening,” said Dr. Schrag.

Dr. Schrag noted that given the immense interest in this study, the manufacturer is working toward refining the assay and improving the test. A reanalysis was conducted on all specimens using a refined version of the test.

“Importantly, the new analysis identified fewer patients with having positive signals, from 1.4% to 0.9%,” she said. “Specificity improved to 99.5% as did PPV – from 38% to 43.1% – and more people need to be screened to find a cancer – up to 263 from 189.”
 

False positives concerning

Previous, and very similar, results from the PATHFINDER trial were presented last year at the annual meeting of the American Society of Clinical Oncology.

Max Diehn, MD, PhD, associate professor of radiation oncology at Stanford (Calif.) University, was an invited discussant for the study.

He pointed out that there were more false positives than true positives and noted that “there were a significant number of invasive procedures in false positives, which could cause harm to these patients who don’t have cancer.”

Dr. Diehn also explained that most true positives were for lymphoid malignancies, not solid tumors, and it is not known whether early detection of lymphoid malignancy has clinical utility. 

The Galleri test is already available in the United States and is being offered by a number of U.S. health networks. However, it is not approved by the U.S. Food and Drug Administration and is not covered by medical insurance, so individuals have to pay around $950 for it out of pocket. 

Although some experts are excited by its potential, describing it as a “game-changer,” others are concerned that there are no clinical pathways in place yet to deal with the results of such a blood test, and say it is not ready for prime time. 

The study was funded by Grail, a subsidiary of Illumina. Dr. Shrag has reported relationships with Grail, the Journal of the American Medical Association, and Pfizer. Several coauthors also have disclosed relationships with industry. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and Instil Bio, and running trials for them.

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

PARIS – New results from a large prospective trial give a better idea of how a blood test that can detect multiple cancers performs in a “real-life” setting.

“As this technology develops, people must continue with their standard cancer screening, but this is a glimpse of what the future may hold,” commented study investigator Deborah Schrag, MD, MPH, chair, department of medicine, Memorial Sloan Kettering Cancer Center, New York.

For the PATHFINDER study, the Galleri blood test (developed by Grail) was used in 6,621 healthy individuals aged over 50, with or without additional cancer risk factors (such as history of smoking or genetic risk).

It found a positive cancer signal in 92 individuals (1.4%). 

None of the individuals who tested positive was known to have cancer at the time of testing. Subsequent workup, which could include scans and/or biopsy, found cancer in 38% of those with a positive test.

“When the test was positive, the workups were typically done in less than 3 months,” Dr. Schrag commented, adding that “the blood test typically predicted the origin of the cancer.”

Dr. Schrag presented the findings at the annual meeting of the European Society for Medical Oncology (ESMO).

Approached for comment, Anthony J. Olszanski, MD, RPh, vice chair of research at the Fox Chase Cancer Center, Philadelphia, noted that the use of a blood test to “find” cancer has long been on the minds of patients. “It is not uncommon to hear oncology patients ask: ‘Why didn’t my doctor find my cancer earlier, on blood tests?’ ”

As this study suggests, finding a malignancy before it becomes apparent on imaging or because of symptoms is one step closer to becoming a reality. “But although this is an important study, it must be noted that only about 40% of patients with a positive test result were actually found to have cancer,” Dr. Olszanski said. “Conversely, about 60% of patients with a positive test result likely suffered from a considerable amount of anxiety that may persist even after further testing did not reveal a malignancy.”

Another important issue is that such testing may incur substantial health care cost. “Less than 2 participants per 100 had a positive test result, and those patients underwent further testing to interrogate the result,” he added. “It also remains unclear if detecting cancer early will lead to better outcomes.”

Whether or not the test will be cost-effective remains unknown, as Dr. Schrag emphasized they do not have a formal cost analysis at this time. “This technology is not ready for population-wide screening, but as the technology improves, costs will go down,” she said.

Dr. Schrag also added that this is a new concept and the trial shows it is feasible to detect cancer using a blood test. “It was not designed to determine if the test can decrease cancer mortality, which is obviously the purpose of screening, but it’s premature for that,” she said.
 

Details of the results

The Galleri test uses cell-free DNA and machine learning to detect a common cancer signal across more than 50 cancer types as well as to predict cancer signal origin.

Overall, the test detected a cancer signal in 1.4% (n = 92) of participants with analyzable samples.

A total of 90 participants underwent diagnostic testing (33 true positives and 57 false positives). Of the true positives, 81.8% underwent more than one invasive diagnostic test, as did 29.8% of false positives.

Specificity was 99.1%, positive predictive value (PPV) was approximately 40%, and 73% of those who were true positives had diagnostic resolution in less than 3 months.

Of the cancers that were diagnosed, 19 were solid tumors and 17 were hematologic cancers; 7 were diagnosed in a person with a history of cancer, 26 were cancer types without standard screening, and 14 were diagnosed at an early stage.

“What is exciting about this new paradigm is that many of these were cancers for which we don’t have standard screening,” said Dr. Schrag.

Dr. Schrag noted that given the immense interest in this study, the manufacturer is working toward refining the assay and improving the test. A reanalysis was conducted on all specimens using a refined version of the test.

“Importantly, the new analysis identified fewer patients with having positive signals, from 1.4% to 0.9%,” she said. “Specificity improved to 99.5% as did PPV – from 38% to 43.1% – and more people need to be screened to find a cancer – up to 263 from 189.”
 

False positives concerning

Previous, and very similar, results from the PATHFINDER trial were presented last year at the annual meeting of the American Society of Clinical Oncology.

Max Diehn, MD, PhD, associate professor of radiation oncology at Stanford (Calif.) University, was an invited discussant for the study.

He pointed out that there were more false positives than true positives and noted that “there were a significant number of invasive procedures in false positives, which could cause harm to these patients who don’t have cancer.”

Dr. Diehn also explained that most true positives were for lymphoid malignancies, not solid tumors, and it is not known whether early detection of lymphoid malignancy has clinical utility. 

The Galleri test is already available in the United States and is being offered by a number of U.S. health networks. However, it is not approved by the U.S. Food and Drug Administration and is not covered by medical insurance, so individuals have to pay around $950 for it out of pocket. 

Although some experts are excited by its potential, describing it as a “game-changer,” others are concerned that there are no clinical pathways in place yet to deal with the results of such a blood test, and say it is not ready for prime time. 

The study was funded by Grail, a subsidiary of Illumina. Dr. Shrag has reported relationships with Grail, the Journal of the American Medical Association, and Pfizer. Several coauthors also have disclosed relationships with industry. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and Instil Bio, and running trials for them.

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

PARIS – New results from a large prospective trial give a better idea of how a blood test that can detect multiple cancers performs in a “real-life” setting.

“As this technology develops, people must continue with their standard cancer screening, but this is a glimpse of what the future may hold,” commented study investigator Deborah Schrag, MD, MPH, chair, department of medicine, Memorial Sloan Kettering Cancer Center, New York.

For the PATHFINDER study, the Galleri blood test (developed by Grail) was used in 6,621 healthy individuals aged over 50, with or without additional cancer risk factors (such as history of smoking or genetic risk).

It found a positive cancer signal in 92 individuals (1.4%). 

None of the individuals who tested positive was known to have cancer at the time of testing. Subsequent workup, which could include scans and/or biopsy, found cancer in 38% of those with a positive test.

“When the test was positive, the workups were typically done in less than 3 months,” Dr. Schrag commented, adding that “the blood test typically predicted the origin of the cancer.”

Dr. Schrag presented the findings at the annual meeting of the European Society for Medical Oncology (ESMO).

Approached for comment, Anthony J. Olszanski, MD, RPh, vice chair of research at the Fox Chase Cancer Center, Philadelphia, noted that the use of a blood test to “find” cancer has long been on the minds of patients. “It is not uncommon to hear oncology patients ask: ‘Why didn’t my doctor find my cancer earlier, on blood tests?’ ”

As this study suggests, finding a malignancy before it becomes apparent on imaging or because of symptoms is one step closer to becoming a reality. “But although this is an important study, it must be noted that only about 40% of patients with a positive test result were actually found to have cancer,” Dr. Olszanski said. “Conversely, about 60% of patients with a positive test result likely suffered from a considerable amount of anxiety that may persist even after further testing did not reveal a malignancy.”

Another important issue is that such testing may incur substantial health care cost. “Less than 2 participants per 100 had a positive test result, and those patients underwent further testing to interrogate the result,” he added. “It also remains unclear if detecting cancer early will lead to better outcomes.”

Whether or not the test will be cost-effective remains unknown, as Dr. Schrag emphasized they do not have a formal cost analysis at this time. “This technology is not ready for population-wide screening, but as the technology improves, costs will go down,” she said.

Dr. Schrag also added that this is a new concept and the trial shows it is feasible to detect cancer using a blood test. “It was not designed to determine if the test can decrease cancer mortality, which is obviously the purpose of screening, but it’s premature for that,” she said.
 

Details of the results

The Galleri test uses cell-free DNA and machine learning to detect a common cancer signal across more than 50 cancer types as well as to predict cancer signal origin.

Overall, the test detected a cancer signal in 1.4% (n = 92) of participants with analyzable samples.

A total of 90 participants underwent diagnostic testing (33 true positives and 57 false positives). Of the true positives, 81.8% underwent more than one invasive diagnostic test, as did 29.8% of false positives.

Specificity was 99.1%, positive predictive value (PPV) was approximately 40%, and 73% of those who were true positives had diagnostic resolution in less than 3 months.

Of the cancers that were diagnosed, 19 were solid tumors and 17 were hematologic cancers; 7 were diagnosed in a person with a history of cancer, 26 were cancer types without standard screening, and 14 were diagnosed at an early stage.

“What is exciting about this new paradigm is that many of these were cancers for which we don’t have standard screening,” said Dr. Schrag.

Dr. Schrag noted that given the immense interest in this study, the manufacturer is working toward refining the assay and improving the test. A reanalysis was conducted on all specimens using a refined version of the test.

“Importantly, the new analysis identified fewer patients with having positive signals, from 1.4% to 0.9%,” she said. “Specificity improved to 99.5% as did PPV – from 38% to 43.1% – and more people need to be screened to find a cancer – up to 263 from 189.”
 

False positives concerning

Previous, and very similar, results from the PATHFINDER trial were presented last year at the annual meeting of the American Society of Clinical Oncology.

Max Diehn, MD, PhD, associate professor of radiation oncology at Stanford (Calif.) University, was an invited discussant for the study.

He pointed out that there were more false positives than true positives and noted that “there were a significant number of invasive procedures in false positives, which could cause harm to these patients who don’t have cancer.”

Dr. Diehn also explained that most true positives were for lymphoid malignancies, not solid tumors, and it is not known whether early detection of lymphoid malignancy has clinical utility. 

The Galleri test is already available in the United States and is being offered by a number of U.S. health networks. However, it is not approved by the U.S. Food and Drug Administration and is not covered by medical insurance, so individuals have to pay around $950 for it out of pocket. 

Although some experts are excited by its potential, describing it as a “game-changer,” others are concerned that there are no clinical pathways in place yet to deal with the results of such a blood test, and say it is not ready for prime time. 

The study was funded by Grail, a subsidiary of Illumina. Dr. Shrag has reported relationships with Grail, the Journal of the American Medical Association, and Pfizer. Several coauthors also have disclosed relationships with industry. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and Instil Bio, and running trials for them.

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

Too often, when patients come to see Tejaswini Kulkarni, MD, with shortness of breath and cough and are diagnosed with interstitial lung disease (ILD), they are past the point when treatments would most benefit them.

“There is definitely a delay from the time of symptom onset to the time that they are even evaluated for ILD,” said Dr. Kulkarni of the department of pulmonary, allergy and critical care medicine at the University of Alabama, Birmingham. “Some patients have had a significant loss of lung function by the time they come to see us. By that point we are limited by what treatment options we can offer.”

Interstitial lung disease is an umbrella term for a group of disorders involving progressive scarring of the lungs – typically irreversible – usually caused by long-term exposure to hazardous materials or by autoimmune effects. It includes idiopathic pulmonary fibrosis (IPF), a disease that is fairly rare but which has therapy options that can be effective if caught early enough. The term pulmonary fibrosis refers to lung scarring. Another type of ILD is pulmonary sarcoidosis, in which small clumps of immune cells form in the lungs in an immune response sometimes following an environmental trigger, and can lead to lung scarring if it doesn’t resolve.

Cases of ILD appear to be on the rise, and COVID-19 has made diagnosing it more complicated. One study found the prevalence of ILD and pulmonary sarcoidosis in high-income countries was about 122 of every 100,000 people in 1990 and rose to about 198 of every 100,000 people in 2017. The data were pulled from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. Globally, the researchers found a prevalence of 62 per 100,000 in 1990, compared with 82 per 100,000 in 2017.

If all of a patient’s symptoms have appeared post COVID and a physician is seeing a patient within 4-6 weeks of COVID symptoms, it is likely that the symptoms are COVID related. But a full work-up is recommended if a patient has lung crackles, which are an indicator of lung scarring, she said.

“The patterns that are seen on CT scan for COVID pneumonia are very distinct from what we expect to see with idiopathic pulmonary fibrosis,” Dr. Kulkarni said. “Putting all this information together is what is important to differentiate it from COVID pneumonia, as well as other types of ILD.”

A study published earlier this year found similarities between COVID-19 and IPF in gene expression, their IL-15-heavy cytokine storms, and the type of damage to alveolar cells. Both might be driven by endoplasmic reticulum stress, they found.

“COVID-19 resembles IPF at a fundamental level,” they wrote.

Jeffrey Horowitz, MD, a pulmonologist and professor of medicine at the Ohio State University, said the need for early diagnosis is in part a function of the therapies available for ILD.

“They don’t make the lung function better,” he said. “So delays in diagnosis mean that there’s the possibility of underlying progression for months, or sometimes years, before the diagnosis is recognized.”

In an area in which diagnosis is delayed and the prognosis is dire – 3-5 years in untreated patients after diagnosis – “there’s a tremendous amount of nihilism out there” among patients, he said.

He said patients with long-term shortness of breath and unexplained cough are often told they have asthma and are prescribed inhalers, but then further assessment isn’t performed when those don’t work.
 

Diagnosing ILD in primary care

Many primary care physicians feel ill-equipped to discuss IPF. More than a dozen physicians contacted for this piece to talk about ILD either did not respond, or said they felt unqualified to respond to questions on the disease.

“Not my area of expertise” and “I don’t think I’m the right person for this discussion” were two of the responses provided to this news organization.

“For some reason, in the world of primary care, it seems like there’s an impediment to getting pulmonary function studies,” Dr. Horowitz said. “Anybody who has a persistent ongoing prolonged unexplained shortness of breath and cough should have pulmonary function studies done.”

Listening to the lungs alone might not be enough, he said. There might be no clear sign in the case of early pulmonary fibrosis, he said.

“There’s the textbook description of these Velcro-sounding crackles, but sometimes it’s very subtle,” he said. “And unless you’re listening very carefully it can easily be missed by somebody who has a busy practice, or it’s loud.”

William E. Golden, MD, professor of medicine and public health at the University of Arkansas, Little Rock, is the sole primary care physician contacted for this piece who spoke with authority on ILD.

For cases of suspected ILD, internist Dr. Golden, who also serves on the editorial advisory board of Internal Medicine News, suggested ordering a test for diffusing capacity for carbon monoxide (DLCO), which will be low in the case of IPF, along with a fine-cut lung CT scan to assess ongoing fibrotic changes.

It’s “not that difficult, but you need to have an index of suspicion for the diagnosis,” he said.
 

New initiative for helping diagnose ILD

Dr. Kulkarni is a committee member for a new effort under way to try to get patients with ILD diagnosed earlier.

The initiative, called Bridging Specialties: Timely Diagnosis for ILD Patients, has already produced an introductory podcast and a white paper on the effort, and its rationale is expected to be released soon, according to Dr. Kulkarni and her fellow committee members.

The American College of Chest Physicians and the Three Lakes Foundation – a foundation dedicated to pulmonary fibrosis awareness and research – are working together on this initiative. They plan to put together a suite of resources, to be gradually rolled out on the college’s website, to raise awareness about the importance of early diagnosis of ILD.

The full toolkit, expected to be rolled out over the next 12 months, will include a series of podcasts and resources on how to get patients diagnosed earlier and steps to take in cases of suspected ILD, Dr. Kulkarni said.

“The goal would be to try to increase awareness about the disease so that people start thinking more about it up front – and not after we’ve ruled out everything else,” she said. The main audience will be primary care providers, but patients and community pulmonologists would likely also benefit from the resources, the committee members said.

The urgency of the initiative stems from the way ILD treatments work. They are antifibrotic, meaning they help prevent scar tissue from forming, but they can’t reverse scar tissue that has already formed. If scarring is severe, the only option might be a lung transplant, and, since the average age at ILD diagnosis is in the 60s, many patients have comorbidities that make them ineligible for transplant. According to the Global Burden of Disease Study mentioned earlier, the death rate per 100,000 people with ILD was 1.93 in 2017.

“The longer we take to diagnose it, the more chance that inflammation will become scar tissue,” Dr. Kularni explained.

William Lago, MD, another member of the committee and a family physician, said identifying ILD early is not a straightforward matter .

“When they first present, it’s hard to pick up,” said Dr. Lago, who is also a staff physician at Cleveland Clinic’s Wooster Family Health Center and medical director of the COVID Recover Clinic there. “Many of them, even themselves, will discount the symptoms.”

Dr. Lago said that patients might resist having a work-up even when a primary care physician identifies symptoms as possible ILD. In rural settings, they might have to travel quite a distance for a CT scan or other necessary evaluations, or they might just not think the symptoms are serious enough.

“Most of the time when I’ve picked up some of my pulmonary fibrosis patients, it’s been incidentally while they’re in the office for other things,” he said. He often has to “push the issue” for further work-up, he said.

The overlap of shortness of breath and cough with other, much more common disorders, such as heart disease or chronic obstructive pulmonary disease (COPD), make ILD diagnosis a challenge, he said.

“For most of us, we’ve got sometimes 10 or 15 minutes with a patient who’s presenting with 5-6 different problems. And the shortness of breath or the occasional cough – that they think is nothing – is probably the least of those,” Dr. Lago said.

Dr. Golden said he suspected a tool like the one being developed by CHEST to be useful for some and not useful for others. He added that “no one has the time to spend on that kind of thing.”

Instead, he suggested just reinforcing what the core symptoms are and what the core testing is, “to make people think about it.”

Dr. Horowitiz seemed more optimistic about the likelihood of the CHEST tool being utilized to diagnose ILD.

Whether and how he would use the CHEST resource will depend on the final form it takes, Dr. Horowitz said. It’s encouraging that it’s being put together by a credible source, he added.

Dr. Kulkarni reported financial relationships with Boehringer Ingelheim, Aluda Pharmaceuticals and PureTech Lyt-100 Inc. Dr. Lago, Dr. Horowitz, and Dr. Golden reported no relevant disclosures.

Katie Lennon contributed to this report.

Too often, when patients come to see Tejaswini Kulkarni, MD, with shortness of breath and cough and are diagnosed with interstitial lung disease (ILD), they are past the point when treatments would most benefit them.

“There is definitely a delay from the time of symptom onset to the time that they are even evaluated for ILD,” said Dr. Kulkarni of the department of pulmonary, allergy and critical care medicine at the University of Alabama, Birmingham. “Some patients have had a significant loss of lung function by the time they come to see us. By that point we are limited by what treatment options we can offer.”

Interstitial lung disease is an umbrella term for a group of disorders involving progressive scarring of the lungs – typically irreversible – usually caused by long-term exposure to hazardous materials or by autoimmune effects. It includes idiopathic pulmonary fibrosis (IPF), a disease that is fairly rare but which has therapy options that can be effective if caught early enough. The term pulmonary fibrosis refers to lung scarring. Another type of ILD is pulmonary sarcoidosis, in which small clumps of immune cells form in the lungs in an immune response sometimes following an environmental trigger, and can lead to lung scarring if it doesn’t resolve.

Cases of ILD appear to be on the rise, and COVID-19 has made diagnosing it more complicated. One study found the prevalence of ILD and pulmonary sarcoidosis in high-income countries was about 122 of every 100,000 people in 1990 and rose to about 198 of every 100,000 people in 2017. The data were pulled from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. Globally, the researchers found a prevalence of 62 per 100,000 in 1990, compared with 82 per 100,000 in 2017.

If all of a patient’s symptoms have appeared post COVID and a physician is seeing a patient within 4-6 weeks of COVID symptoms, it is likely that the symptoms are COVID related. But a full work-up is recommended if a patient has lung crackles, which are an indicator of lung scarring, she said.

“The patterns that are seen on CT scan for COVID pneumonia are very distinct from what we expect to see with idiopathic pulmonary fibrosis,” Dr. Kulkarni said. “Putting all this information together is what is important to differentiate it from COVID pneumonia, as well as other types of ILD.”

A study published earlier this year found similarities between COVID-19 and IPF in gene expression, their IL-15-heavy cytokine storms, and the type of damage to alveolar cells. Both might be driven by endoplasmic reticulum stress, they found.

“COVID-19 resembles IPF at a fundamental level,” they wrote.

Jeffrey Horowitz, MD, a pulmonologist and professor of medicine at the Ohio State University, said the need for early diagnosis is in part a function of the therapies available for ILD.

“They don’t make the lung function better,” he said. “So delays in diagnosis mean that there’s the possibility of underlying progression for months, or sometimes years, before the diagnosis is recognized.”

In an area in which diagnosis is delayed and the prognosis is dire – 3-5 years in untreated patients after diagnosis – “there’s a tremendous amount of nihilism out there” among patients, he said.

He said patients with long-term shortness of breath and unexplained cough are often told they have asthma and are prescribed inhalers, but then further assessment isn’t performed when those don’t work.
 

Diagnosing ILD in primary care

Many primary care physicians feel ill-equipped to discuss IPF. More than a dozen physicians contacted for this piece to talk about ILD either did not respond, or said they felt unqualified to respond to questions on the disease.

“Not my area of expertise” and “I don’t think I’m the right person for this discussion” were two of the responses provided to this news organization.

“For some reason, in the world of primary care, it seems like there’s an impediment to getting pulmonary function studies,” Dr. Horowitz said. “Anybody who has a persistent ongoing prolonged unexplained shortness of breath and cough should have pulmonary function studies done.”

Listening to the lungs alone might not be enough, he said. There might be no clear sign in the case of early pulmonary fibrosis, he said.

“There’s the textbook description of these Velcro-sounding crackles, but sometimes it’s very subtle,” he said. “And unless you’re listening very carefully it can easily be missed by somebody who has a busy practice, or it’s loud.”

William E. Golden, MD, professor of medicine and public health at the University of Arkansas, Little Rock, is the sole primary care physician contacted for this piece who spoke with authority on ILD.

For cases of suspected ILD, internist Dr. Golden, who also serves on the editorial advisory board of Internal Medicine News, suggested ordering a test for diffusing capacity for carbon monoxide (DLCO), which will be low in the case of IPF, along with a fine-cut lung CT scan to assess ongoing fibrotic changes.

It’s “not that difficult, but you need to have an index of suspicion for the diagnosis,” he said.
 

New initiative for helping diagnose ILD

Dr. Kulkarni is a committee member for a new effort under way to try to get patients with ILD diagnosed earlier.

The initiative, called Bridging Specialties: Timely Diagnosis for ILD Patients, has already produced an introductory podcast and a white paper on the effort, and its rationale is expected to be released soon, according to Dr. Kulkarni and her fellow committee members.

The American College of Chest Physicians and the Three Lakes Foundation – a foundation dedicated to pulmonary fibrosis awareness and research – are working together on this initiative. They plan to put together a suite of resources, to be gradually rolled out on the college’s website, to raise awareness about the importance of early diagnosis of ILD.

The full toolkit, expected to be rolled out over the next 12 months, will include a series of podcasts and resources on how to get patients diagnosed earlier and steps to take in cases of suspected ILD, Dr. Kulkarni said.

“The goal would be to try to increase awareness about the disease so that people start thinking more about it up front – and not after we’ve ruled out everything else,” she said. The main audience will be primary care providers, but patients and community pulmonologists would likely also benefit from the resources, the committee members said.

The urgency of the initiative stems from the way ILD treatments work. They are antifibrotic, meaning they help prevent scar tissue from forming, but they can’t reverse scar tissue that has already formed. If scarring is severe, the only option might be a lung transplant, and, since the average age at ILD diagnosis is in the 60s, many patients have comorbidities that make them ineligible for transplant. According to the Global Burden of Disease Study mentioned earlier, the death rate per 100,000 people with ILD was 1.93 in 2017.

“The longer we take to diagnose it, the more chance that inflammation will become scar tissue,” Dr. Kularni explained.

William Lago, MD, another member of the committee and a family physician, said identifying ILD early is not a straightforward matter .

“When they first present, it’s hard to pick up,” said Dr. Lago, who is also a staff physician at Cleveland Clinic’s Wooster Family Health Center and medical director of the COVID Recover Clinic there. “Many of them, even themselves, will discount the symptoms.”

Dr. Lago said that patients might resist having a work-up even when a primary care physician identifies symptoms as possible ILD. In rural settings, they might have to travel quite a distance for a CT scan or other necessary evaluations, or they might just not think the symptoms are serious enough.

“Most of the time when I’ve picked up some of my pulmonary fibrosis patients, it’s been incidentally while they’re in the office for other things,” he said. He often has to “push the issue” for further work-up, he said.

The overlap of shortness of breath and cough with other, much more common disorders, such as heart disease or chronic obstructive pulmonary disease (COPD), make ILD diagnosis a challenge, he said.

“For most of us, we’ve got sometimes 10 or 15 minutes with a patient who’s presenting with 5-6 different problems. And the shortness of breath or the occasional cough – that they think is nothing – is probably the least of those,” Dr. Lago said.

Dr. Golden said he suspected a tool like the one being developed by CHEST to be useful for some and not useful for others. He added that “no one has the time to spend on that kind of thing.”

Instead, he suggested just reinforcing what the core symptoms are and what the core testing is, “to make people think about it.”

Dr. Horowitiz seemed more optimistic about the likelihood of the CHEST tool being utilized to diagnose ILD.

Whether and how he would use the CHEST resource will depend on the final form it takes, Dr. Horowitz said. It’s encouraging that it’s being put together by a credible source, he added.

Dr. Kulkarni reported financial relationships with Boehringer Ingelheim, Aluda Pharmaceuticals and PureTech Lyt-100 Inc. Dr. Lago, Dr. Horowitz, and Dr. Golden reported no relevant disclosures.

Katie Lennon contributed to this report.

Too often, when patients come to see Tejaswini Kulkarni, MD, with shortness of breath and cough and are diagnosed with interstitial lung disease (ILD), they are past the point when treatments would most benefit them.

“There is definitely a delay from the time of symptom onset to the time that they are even evaluated for ILD,” said Dr. Kulkarni of the department of pulmonary, allergy and critical care medicine at the University of Alabama, Birmingham. “Some patients have had a significant loss of lung function by the time they come to see us. By that point we are limited by what treatment options we can offer.”

Interstitial lung disease is an umbrella term for a group of disorders involving progressive scarring of the lungs – typically irreversible – usually caused by long-term exposure to hazardous materials or by autoimmune effects. It includes idiopathic pulmonary fibrosis (IPF), a disease that is fairly rare but which has therapy options that can be effective if caught early enough. The term pulmonary fibrosis refers to lung scarring. Another type of ILD is pulmonary sarcoidosis, in which small clumps of immune cells form in the lungs in an immune response sometimes following an environmental trigger, and can lead to lung scarring if it doesn’t resolve.

Cases of ILD appear to be on the rise, and COVID-19 has made diagnosing it more complicated. One study found the prevalence of ILD and pulmonary sarcoidosis in high-income countries was about 122 of every 100,000 people in 1990 and rose to about 198 of every 100,000 people in 2017. The data were pulled from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. Globally, the researchers found a prevalence of 62 per 100,000 in 1990, compared with 82 per 100,000 in 2017.

If all of a patient’s symptoms have appeared post COVID and a physician is seeing a patient within 4-6 weeks of COVID symptoms, it is likely that the symptoms are COVID related. But a full work-up is recommended if a patient has lung crackles, which are an indicator of lung scarring, she said.

“The patterns that are seen on CT scan for COVID pneumonia are very distinct from what we expect to see with idiopathic pulmonary fibrosis,” Dr. Kulkarni said. “Putting all this information together is what is important to differentiate it from COVID pneumonia, as well as other types of ILD.”

A study published earlier this year found similarities between COVID-19 and IPF in gene expression, their IL-15-heavy cytokine storms, and the type of damage to alveolar cells. Both might be driven by endoplasmic reticulum stress, they found.

“COVID-19 resembles IPF at a fundamental level,” they wrote.

Jeffrey Horowitz, MD, a pulmonologist and professor of medicine at the Ohio State University, said the need for early diagnosis is in part a function of the therapies available for ILD.

“They don’t make the lung function better,” he said. “So delays in diagnosis mean that there’s the possibility of underlying progression for months, or sometimes years, before the diagnosis is recognized.”

In an area in which diagnosis is delayed and the prognosis is dire – 3-5 years in untreated patients after diagnosis – “there’s a tremendous amount of nihilism out there” among patients, he said.

He said patients with long-term shortness of breath and unexplained cough are often told they have asthma and are prescribed inhalers, but then further assessment isn’t performed when those don’t work.
 

Diagnosing ILD in primary care

Many primary care physicians feel ill-equipped to discuss IPF. More than a dozen physicians contacted for this piece to talk about ILD either did not respond, or said they felt unqualified to respond to questions on the disease.

“Not my area of expertise” and “I don’t think I’m the right person for this discussion” were two of the responses provided to this news organization.

“For some reason, in the world of primary care, it seems like there’s an impediment to getting pulmonary function studies,” Dr. Horowitz said. “Anybody who has a persistent ongoing prolonged unexplained shortness of breath and cough should have pulmonary function studies done.”

Listening to the lungs alone might not be enough, he said. There might be no clear sign in the case of early pulmonary fibrosis, he said.

“There’s the textbook description of these Velcro-sounding crackles, but sometimes it’s very subtle,” he said. “And unless you’re listening very carefully it can easily be missed by somebody who has a busy practice, or it’s loud.”

William E. Golden, MD, professor of medicine and public health at the University of Arkansas, Little Rock, is the sole primary care physician contacted for this piece who spoke with authority on ILD.

For cases of suspected ILD, internist Dr. Golden, who also serves on the editorial advisory board of Internal Medicine News, suggested ordering a test for diffusing capacity for carbon monoxide (DLCO), which will be low in the case of IPF, along with a fine-cut lung CT scan to assess ongoing fibrotic changes.

It’s “not that difficult, but you need to have an index of suspicion for the diagnosis,” he said.
 

New initiative for helping diagnose ILD

Dr. Kulkarni is a committee member for a new effort under way to try to get patients with ILD diagnosed earlier.

The initiative, called Bridging Specialties: Timely Diagnosis for ILD Patients, has already produced an introductory podcast and a white paper on the effort, and its rationale is expected to be released soon, according to Dr. Kulkarni and her fellow committee members.

The American College of Chest Physicians and the Three Lakes Foundation – a foundation dedicated to pulmonary fibrosis awareness and research – are working together on this initiative. They plan to put together a suite of resources, to be gradually rolled out on the college’s website, to raise awareness about the importance of early diagnosis of ILD.

The full toolkit, expected to be rolled out over the next 12 months, will include a series of podcasts and resources on how to get patients diagnosed earlier and steps to take in cases of suspected ILD, Dr. Kulkarni said.

“The goal would be to try to increase awareness about the disease so that people start thinking more about it up front – and not after we’ve ruled out everything else,” she said. The main audience will be primary care providers, but patients and community pulmonologists would likely also benefit from the resources, the committee members said.

The urgency of the initiative stems from the way ILD treatments work. They are antifibrotic, meaning they help prevent scar tissue from forming, but they can’t reverse scar tissue that has already formed. If scarring is severe, the only option might be a lung transplant, and, since the average age at ILD diagnosis is in the 60s, many patients have comorbidities that make them ineligible for transplant. According to the Global Burden of Disease Study mentioned earlier, the death rate per 100,000 people with ILD was 1.93 in 2017.

“The longer we take to diagnose it, the more chance that inflammation will become scar tissue,” Dr. Kularni explained.

William Lago, MD, another member of the committee and a family physician, said identifying ILD early is not a straightforward matter .

“When they first present, it’s hard to pick up,” said Dr. Lago, who is also a staff physician at Cleveland Clinic’s Wooster Family Health Center and medical director of the COVID Recover Clinic there. “Many of them, even themselves, will discount the symptoms.”

Dr. Lago said that patients might resist having a work-up even when a primary care physician identifies symptoms as possible ILD. In rural settings, they might have to travel quite a distance for a CT scan or other necessary evaluations, or they might just not think the symptoms are serious enough.

“Most of the time when I’ve picked up some of my pulmonary fibrosis patients, it’s been incidentally while they’re in the office for other things,” he said. He often has to “push the issue” for further work-up, he said.

The overlap of shortness of breath and cough with other, much more common disorders, such as heart disease or chronic obstructive pulmonary disease (COPD), make ILD diagnosis a challenge, he said.

“For most of us, we’ve got sometimes 10 or 15 minutes with a patient who’s presenting with 5-6 different problems. And the shortness of breath or the occasional cough – that they think is nothing – is probably the least of those,” Dr. Lago said.

Dr. Golden said he suspected a tool like the one being developed by CHEST to be useful for some and not useful for others. He added that “no one has the time to spend on that kind of thing.”

Instead, he suggested just reinforcing what the core symptoms are and what the core testing is, “to make people think about it.”

Dr. Horowitiz seemed more optimistic about the likelihood of the CHEST tool being utilized to diagnose ILD.

Whether and how he would use the CHEST resource will depend on the final form it takes, Dr. Horowitz said. It’s encouraging that it’s being put together by a credible source, he added.

Dr. Kulkarni reported financial relationships with Boehringer Ingelheim, Aluda Pharmaceuticals and PureTech Lyt-100 Inc. Dr. Lago, Dr. Horowitz, and Dr. Golden reported no relevant disclosures.

Katie Lennon contributed to this report.

Levels of calprotectin, a biomarker used to detect intestinal inflammation, may vary in fecal samples based on an individual’s microbiome composition, according to researchers. The results, if confirmed, might help refine its use in monitoring inflammatory bowel disease (IBD).

Researchers used a new ex vivo functional assay to identify specific bacteria that degrade calprotectin and may play a role in variations found in vivo. “Microbiome-based calibration could improve sensitivity and specificity of fecal calprotectin readouts, thereby facilitating more reliable real-time monitoring and ultimately enabling more timely interventions,” the authors wrote in their research letter, which was published in Gastro Hep Advances.

The standard for diagnosing ulcerative colitis (UC) and Crohn’s disease (CD) is endoscopy and biopsy because it allows both visual and histological examination of the severity and extent of intestinal inflammation, but this cannot be used to monitor patients on an ongoing basis.

Calprotectin is a promising biomarker for intestinal inflammation, but a meta-analysis found that it has a pooled sensitivity of 85% and a pooled specificity of 75% for the diagnosis of endoscopically active inflammatory bowel disease.

The researchers investigated whether an individual’s microbiome can metabolize calprotectin, which would complicate measurement of fecal calprotectin. They recruited 22 individuals with IBD (64% female, 73% with colonic disease), who provided stool samples. They completed a symptom questionnaire in advance of a colonoscopy. Overall, 64% had endoscopically inactive disease, and 82% had clinically inactive disease.

At a cutoff of 50 mcg/g, 9 patients had normal fecal calprotectin levels, and 13 had elevated levels. Those with clinically or endoscopically active disease had higher levels of fecal calprotectin (P < .0001).

There was a significant but poor correlation between disease activity measures and fecal calprotectin levels in CD (r = 0.62; P = .008), but there was no statistically significant association for UC (r = –0.29; P = .6). Endoscopic disease activity was also significantly correlated with fecal calprotectin in CD (r = 0.83; P < .001), but not UC (r = 0.50; P = .4).

The researchers created an ex vivo functional assay to measure calprotectin metabolism by the microbiome. They anaerobically cultured fecal samples in the presence of calprotectin and measured levels of calprotectin after 24 hours. Control samples were grown without microbes, without calprotectin, or lacking both. The researchers tested samples in both standard media and in media with low levels of amino acids, reasoning that the latter condition might encourage catabolism of calprotectin. The cultures with low amino acid content had lower calprotectin levels than those with normal amino acid content (P < .0007).

The researchers found greater calprotectin degradation in the low amino acid media, and the difference was more pronounced among samples taken from individuals with UC than CD (P < .02).

They used metagenomic sequencing data from fecal samples to identify bacterial species associated with calprotectin metabolism. Similarly to previous reports, the researchers found that Firmicutes was dominant, while Subdoligranulum correlated with calprotectin degradation in low amino acid media (P = .04).

For 5 days, they cultured Subdoligranulum variabile in low amino acid media that also contained calprotectin. Calprotectin levels were lower than a control sample with cultured Akkermansia muciniphila, which was previously shown to not be associated with calprotectin degradation in low amino acid media (P = .03). Because Subdoligranulum species were not detectable in 5 of 22 fecal samples, the authors say they are unlikely to be the only species capable of metabolizing calprotectin.

Among IBD patients, only one had both endoscopically active colitis and a low fecal calprotectin level. The patient’s micobiome had Subdoligranulum present, and their fecal sample was able to metabolize calprotectin in the functional assay.

The study was limited by its small sample size, which prevented development of a calibration model for fecal calprotectin, and the researchers called for additional studies among individuals with active colitis.

Levels of calprotectin, a biomarker used to detect intestinal inflammation, may vary in fecal samples based on an individual’s microbiome composition, according to researchers. The results, if confirmed, might help refine its use in monitoring inflammatory bowel disease (IBD).

Researchers used a new ex vivo functional assay to identify specific bacteria that degrade calprotectin and may play a role in variations found in vivo. “Microbiome-based calibration could improve sensitivity and specificity of fecal calprotectin readouts, thereby facilitating more reliable real-time monitoring and ultimately enabling more timely interventions,” the authors wrote in their research letter, which was published in Gastro Hep Advances.

The standard for diagnosing ulcerative colitis (UC) and Crohn’s disease (CD) is endoscopy and biopsy because it allows both visual and histological examination of the severity and extent of intestinal inflammation, but this cannot be used to monitor patients on an ongoing basis.

Calprotectin is a promising biomarker for intestinal inflammation, but a meta-analysis found that it has a pooled sensitivity of 85% and a pooled specificity of 75% for the diagnosis of endoscopically active inflammatory bowel disease.

The researchers investigated whether an individual’s microbiome can metabolize calprotectin, which would complicate measurement of fecal calprotectin. They recruited 22 individuals with IBD (64% female, 73% with colonic disease), who provided stool samples. They completed a symptom questionnaire in advance of a colonoscopy. Overall, 64% had endoscopically inactive disease, and 82% had clinically inactive disease.

At a cutoff of 50 mcg/g, 9 patients had normal fecal calprotectin levels, and 13 had elevated levels. Those with clinically or endoscopically active disease had higher levels of fecal calprotectin (P < .0001).

There was a significant but poor correlation between disease activity measures and fecal calprotectin levels in CD (r = 0.62; P = .008), but there was no statistically significant association for UC (r = –0.29; P = .6). Endoscopic disease activity was also significantly correlated with fecal calprotectin in CD (r = 0.83; P < .001), but not UC (r = 0.50; P = .4).

The researchers created an ex vivo functional assay to measure calprotectin metabolism by the microbiome. They anaerobically cultured fecal samples in the presence of calprotectin and measured levels of calprotectin after 24 hours. Control samples were grown without microbes, without calprotectin, or lacking both. The researchers tested samples in both standard media and in media with low levels of amino acids, reasoning that the latter condition might encourage catabolism of calprotectin. The cultures with low amino acid content had lower calprotectin levels than those with normal amino acid content (P < .0007).

The researchers found greater calprotectin degradation in the low amino acid media, and the difference was more pronounced among samples taken from individuals with UC than CD (P < .02).

They used metagenomic sequencing data from fecal samples to identify bacterial species associated with calprotectin metabolism. Similarly to previous reports, the researchers found that Firmicutes was dominant, while Subdoligranulum correlated with calprotectin degradation in low amino acid media (P = .04).

For 5 days, they cultured Subdoligranulum variabile in low amino acid media that also contained calprotectin. Calprotectin levels were lower than a control sample with cultured Akkermansia muciniphila, which was previously shown to not be associated with calprotectin degradation in low amino acid media (P = .03). Because Subdoligranulum species were not detectable in 5 of 22 fecal samples, the authors say they are unlikely to be the only species capable of metabolizing calprotectin.

Among IBD patients, only one had both endoscopically active colitis and a low fecal calprotectin level. The patient’s micobiome had Subdoligranulum present, and their fecal sample was able to metabolize calprotectin in the functional assay.

The study was limited by its small sample size, which prevented development of a calibration model for fecal calprotectin, and the researchers called for additional studies among individuals with active colitis.

Levels of calprotectin, a biomarker used to detect intestinal inflammation, may vary in fecal samples based on an individual’s microbiome composition, according to researchers. The results, if confirmed, might help refine its use in monitoring inflammatory bowel disease (IBD).

Researchers used a new ex vivo functional assay to identify specific bacteria that degrade calprotectin and may play a role in variations found in vivo. “Microbiome-based calibration could improve sensitivity and specificity of fecal calprotectin readouts, thereby facilitating more reliable real-time monitoring and ultimately enabling more timely interventions,” the authors wrote in their research letter, which was published in Gastro Hep Advances.

The standard for diagnosing ulcerative colitis (UC) and Crohn’s disease (CD) is endoscopy and biopsy because it allows both visual and histological examination of the severity and extent of intestinal inflammation, but this cannot be used to monitor patients on an ongoing basis.

Calprotectin is a promising biomarker for intestinal inflammation, but a meta-analysis found that it has a pooled sensitivity of 85% and a pooled specificity of 75% for the diagnosis of endoscopically active inflammatory bowel disease.

The researchers investigated whether an individual’s microbiome can metabolize calprotectin, which would complicate measurement of fecal calprotectin. They recruited 22 individuals with IBD (64% female, 73% with colonic disease), who provided stool samples. They completed a symptom questionnaire in advance of a colonoscopy. Overall, 64% had endoscopically inactive disease, and 82% had clinically inactive disease.

At a cutoff of 50 mcg/g, 9 patients had normal fecal calprotectin levels, and 13 had elevated levels. Those with clinically or endoscopically active disease had higher levels of fecal calprotectin (P < .0001).

There was a significant but poor correlation between disease activity measures and fecal calprotectin levels in CD (r = 0.62; P = .008), but there was no statistically significant association for UC (r = –0.29; P = .6). Endoscopic disease activity was also significantly correlated with fecal calprotectin in CD (r = 0.83; P < .001), but not UC (r = 0.50; P = .4).

The researchers created an ex vivo functional assay to measure calprotectin metabolism by the microbiome. They anaerobically cultured fecal samples in the presence of calprotectin and measured levels of calprotectin after 24 hours. Control samples were grown without microbes, without calprotectin, or lacking both. The researchers tested samples in both standard media and in media with low levels of amino acids, reasoning that the latter condition might encourage catabolism of calprotectin. The cultures with low amino acid content had lower calprotectin levels than those with normal amino acid content (P < .0007).

The researchers found greater calprotectin degradation in the low amino acid media, and the difference was more pronounced among samples taken from individuals with UC than CD (P < .02).

They used metagenomic sequencing data from fecal samples to identify bacterial species associated with calprotectin metabolism. Similarly to previous reports, the researchers found that Firmicutes was dominant, while Subdoligranulum correlated with calprotectin degradation in low amino acid media (P = .04).

For 5 days, they cultured Subdoligranulum variabile in low amino acid media that also contained calprotectin. Calprotectin levels were lower than a control sample with cultured Akkermansia muciniphila, which was previously shown to not be associated with calprotectin degradation in low amino acid media (P = .03). Because Subdoligranulum species were not detectable in 5 of 22 fecal samples, the authors say they are unlikely to be the only species capable of metabolizing calprotectin.

Among IBD patients, only one had both endoscopically active colitis and a low fecal calprotectin level. The patient’s micobiome had Subdoligranulum present, and their fecal sample was able to metabolize calprotectin in the functional assay.

The study was limited by its small sample size, which prevented development of a calibration model for fecal calprotectin, and the researchers called for additional studies among individuals with active colitis.

Experiencing psychological distress prior to becoming infected with SARS-CoV-2 is tied to an increased risk for post-COVID conditions often called “long COVID,” new research suggests.

In an analysis of almost 55,000 adult participants in three ongoing studies, having depression, anxiety, worry, perceived stress, or loneliness early in the pandemic, before SARS-CoV-2 infection, was associated with a 50% increased risk for developing long COVID. These types of psychological distress were also associated with a 15% to 51% greater risk for impairment in daily life among individuals with long COVID.

Psychological distress was even more strongly associated with developing long COVID than were physical health risk factors, and the increased risk was not explained by health behaviors such as smoking or physical comorbidities, researchers note.

“Our findings suggest the need to consider psychological health in addition to physical health as risk factors of long COVID-19,” lead author Siwen Wang, MD, postdoctoral fellow, department of nutrition, Harvard T. H. Chan School of Public Health, Boston, said in an interview.

“We need to increase public awareness of the importance of mental health and focus on getting mental health care for people who need it, increasing the supply of mental health clinicians and improving access to care,” she said.

The findings were published online in JAMA Psychiatry.
 

‘Poorly understood’

Postacute sequelae of SARS-CoV-2 (“long COVID”), which are “signs and symptoms consistent with COVID-19 that extend beyond 4 weeks from onset of infection” constitute “an emerging health issue,” the investigators write.

Dr. Wang noted that it has been estimated that 8-23 million Americans have developed long COVID. However, “despite the high prevalence and daily life impairment associated with long COVID, it is still poorly understood, and few risk factors have been established,” she said.

Although psychological distress may be implicated in long COVID, only three previous studies investigated psychological factors as potential contributors, the researchers note. Also, no study has investigated the potential role of other common manifestations of distress that have increased during the pandemic, such as loneliness and perceived stress, they add.

To investigate these issues, the researchers turned to three large ongoing longitudinal studies: the Nurses’ Health Study II (NSHII), the Nurses’ Health study 3 (NHS3), and the Growing Up Today Study (GUTS).

They analyzed data on 54,960 total participants (96.6% women; mean age, 57.5 years). Of the full group, 38% were active health care workers.

Participants completed an online COVID-19 questionnaire from April 2020 to Sept. 1, 2020 (baseline), and monthly surveys thereafter. Beginning in August 2020, surveys were administered quarterly. The end of follow-up was in November 2021.

The COVID questionnaires included questions about positive SARS-CoV-2 test results, COVID symptoms and hospitalization since March 1, 2020, and the presence of long-term COVID symptoms, such as fatigue, respiratory problems, persistent cough, muscle/joint/chest pain, smell/taste problems, confusion/disorientation/brain fog, depression/anxiety/changes in mood, headache, and memory problems.

Participants who reported these post-COVID conditions were asked about the frequency of symptoms and the degree of impairment in daily life.
 

Inflammation, immune dysregulation implicated?

The Patient Health Questionnaire–4 (PHQ-4) was used to assess for anxiety and depressive symptoms in the past 2 weeks. It consists of a two-item depression measure (PHQ-2) and a two-item Generalized Anxiety Disorder Scale (GAD-2).

Non–health care providers completed two additional assessments of psychological distress: the four-item Perceived Stress Scale and the three-item UCLA Loneliness Scale.

The researchers included demographic factors, weight, smoking status, marital status, and medical conditions, including diabetes, hypertension, hypercholesterolemia, asthma, and cancer, and socioeconomic factors as covariates.

For each participant, the investigators calculated the number of types of distress experienced at a high level, including probable depression, probable anxiety, worry about COVID-19, being in the top quartile of perceived stress, and loneliness.

During the 19 months of follow-up (1-47 weeks after baseline), 6% of respondents reported a positive result on a SARS-CoV-2 antibody, antigen, or polymerase chain reaction test.

Of these, 43.9% reported long-COVID conditions, with most reporting that symptoms lasted 2 months or longer; 55.8% reported at least occasional daily life impairment.

The most common post-COVID conditions were fatigue (reported by 56%), loss of smell or taste problems (44.6%), shortness of breath (25.5%), confusion/disorientation/ brain fog (24.5%), and memory issues (21.8%).

Among patients who had been infected, there was a considerably higher rate of preinfection psychological distress after adjusting for sociodemographic factors, health behaviors, and comorbidities. Each type of distress was associated with post-COVID conditions.

In addition, participants who had experienced at least two types of distress prior to infection were at nearly 50% increased risk for post–COVID conditions (risk ratio, 1.49; 95% confidence interval, 1.23-1.80).

Among those with post-COVID conditions, all types of distress were associated with increased risk for daily life impairment (RR range, 1.15-1.51).

Senior author Andrea Roberts, PhD, senior research scientist at the Harvard T. H. Chan School of Public Health, Boston, noted that the investigators did not examine biological mechanisms potentially underlying the association they found.

However, “based on prior research, it may be that inflammation and immune dysregulation related to psychological distress play a role in the association of distress with long COVID, but we can’t be sure,” Dr. Roberts said.
 

Contributes to the field

Commenting for this article, Yapeng Su, PhD, a postdoctoral researcher at the Fred Hutchinson Cancer Research Center in Seattle, called the study “great work contributing to the long-COVID research field and revealing important connections” with psychological stress prior to infection.

Dr. Su, who was not involved with the study, was previously at the Institute for Systems Biology, also in Seattle, and has written about long COVID.

He noted that the “biological mechanism of such intriguing linkage is definitely the important next step, which will likely require deep phenotyping of biological specimens from these patients longitudinally.”

Dr. Wang pointed to past research suggesting that some patients with mental illness “sometimes develop autoantibodies that have also been associated with increased risk of long COVID.” In addition, depression “affects the brain in ways that may explain certain cognitive symptoms in long COVID,” she added.

More studies are now needed to understand how psychological distress increases the risk for long COVID, said Dr. Wang.

The research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, the Dean’s Fund for Scientific Advancement Acceleration Award from the Harvard T. H. Chan School of Public Health, the Massachusetts Consortium on Pathogen Readiness Evergrande COVID-19 Response Fund Award, and the Veterans Affairs Health Services Research and Development Service funds. Dr. Wang and Dr. Roberts have reported no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Su reports no relevant financial relationships.

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

Experiencing psychological distress prior to becoming infected with SARS-CoV-2 is tied to an increased risk for post-COVID conditions often called “long COVID,” new research suggests.

In an analysis of almost 55,000 adult participants in three ongoing studies, having depression, anxiety, worry, perceived stress, or loneliness early in the pandemic, before SARS-CoV-2 infection, was associated with a 50% increased risk for developing long COVID. These types of psychological distress were also associated with a 15% to 51% greater risk for impairment in daily life among individuals with long COVID.

Psychological distress was even more strongly associated with developing long COVID than were physical health risk factors, and the increased risk was not explained by health behaviors such as smoking or physical comorbidities, researchers note.

“Our findings suggest the need to consider psychological health in addition to physical health as risk factors of long COVID-19,” lead author Siwen Wang, MD, postdoctoral fellow, department of nutrition, Harvard T. H. Chan School of Public Health, Boston, said in an interview.

“We need to increase public awareness of the importance of mental health and focus on getting mental health care for people who need it, increasing the supply of mental health clinicians and improving access to care,” she said.

The findings were published online in JAMA Psychiatry.
 

‘Poorly understood’

Postacute sequelae of SARS-CoV-2 (“long COVID”), which are “signs and symptoms consistent with COVID-19 that extend beyond 4 weeks from onset of infection” constitute “an emerging health issue,” the investigators write.

Dr. Wang noted that it has been estimated that 8-23 million Americans have developed long COVID. However, “despite the high prevalence and daily life impairment associated with long COVID, it is still poorly understood, and few risk factors have been established,” she said.

Although psychological distress may be implicated in long COVID, only three previous studies investigated psychological factors as potential contributors, the researchers note. Also, no study has investigated the potential role of other common manifestations of distress that have increased during the pandemic, such as loneliness and perceived stress, they add.

To investigate these issues, the researchers turned to three large ongoing longitudinal studies: the Nurses’ Health Study II (NSHII), the Nurses’ Health study 3 (NHS3), and the Growing Up Today Study (GUTS).

They analyzed data on 54,960 total participants (96.6% women; mean age, 57.5 years). Of the full group, 38% were active health care workers.

Participants completed an online COVID-19 questionnaire from April 2020 to Sept. 1, 2020 (baseline), and monthly surveys thereafter. Beginning in August 2020, surveys were administered quarterly. The end of follow-up was in November 2021.

The COVID questionnaires included questions about positive SARS-CoV-2 test results, COVID symptoms and hospitalization since March 1, 2020, and the presence of long-term COVID symptoms, such as fatigue, respiratory problems, persistent cough, muscle/joint/chest pain, smell/taste problems, confusion/disorientation/brain fog, depression/anxiety/changes in mood, headache, and memory problems.

Participants who reported these post-COVID conditions were asked about the frequency of symptoms and the degree of impairment in daily life.
 

Inflammation, immune dysregulation implicated?

The Patient Health Questionnaire–4 (PHQ-4) was used to assess for anxiety and depressive symptoms in the past 2 weeks. It consists of a two-item depression measure (PHQ-2) and a two-item Generalized Anxiety Disorder Scale (GAD-2).

Non–health care providers completed two additional assessments of psychological distress: the four-item Perceived Stress Scale and the three-item UCLA Loneliness Scale.

The researchers included demographic factors, weight, smoking status, marital status, and medical conditions, including diabetes, hypertension, hypercholesterolemia, asthma, and cancer, and socioeconomic factors as covariates.

For each participant, the investigators calculated the number of types of distress experienced at a high level, including probable depression, probable anxiety, worry about COVID-19, being in the top quartile of perceived stress, and loneliness.

During the 19 months of follow-up (1-47 weeks after baseline), 6% of respondents reported a positive result on a SARS-CoV-2 antibody, antigen, or polymerase chain reaction test.

Of these, 43.9% reported long-COVID conditions, with most reporting that symptoms lasted 2 months or longer; 55.8% reported at least occasional daily life impairment.

The most common post-COVID conditions were fatigue (reported by 56%), loss of smell or taste problems (44.6%), shortness of breath (25.5%), confusion/disorientation/ brain fog (24.5%), and memory issues (21.8%).

Among patients who had been infected, there was a considerably higher rate of preinfection psychological distress after adjusting for sociodemographic factors, health behaviors, and comorbidities. Each type of distress was associated with post-COVID conditions.

In addition, participants who had experienced at least two types of distress prior to infection were at nearly 50% increased risk for post–COVID conditions (risk ratio, 1.49; 95% confidence interval, 1.23-1.80).

Among those with post-COVID conditions, all types of distress were associated with increased risk for daily life impairment (RR range, 1.15-1.51).

Senior author Andrea Roberts, PhD, senior research scientist at the Harvard T. H. Chan School of Public Health, Boston, noted that the investigators did not examine biological mechanisms potentially underlying the association they found.

However, “based on prior research, it may be that inflammation and immune dysregulation related to psychological distress play a role in the association of distress with long COVID, but we can’t be sure,” Dr. Roberts said.
 

Contributes to the field

Commenting for this article, Yapeng Su, PhD, a postdoctoral researcher at the Fred Hutchinson Cancer Research Center in Seattle, called the study “great work contributing to the long-COVID research field and revealing important connections” with psychological stress prior to infection.

Dr. Su, who was not involved with the study, was previously at the Institute for Systems Biology, also in Seattle, and has written about long COVID.

He noted that the “biological mechanism of such intriguing linkage is definitely the important next step, which will likely require deep phenotyping of biological specimens from these patients longitudinally.”

Dr. Wang pointed to past research suggesting that some patients with mental illness “sometimes develop autoantibodies that have also been associated with increased risk of long COVID.” In addition, depression “affects the brain in ways that may explain certain cognitive symptoms in long COVID,” she added.

More studies are now needed to understand how psychological distress increases the risk for long COVID, said Dr. Wang.

The research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, the Dean’s Fund for Scientific Advancement Acceleration Award from the Harvard T. H. Chan School of Public Health, the Massachusetts Consortium on Pathogen Readiness Evergrande COVID-19 Response Fund Award, and the Veterans Affairs Health Services Research and Development Service funds. Dr. Wang and Dr. Roberts have reported no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Su reports no relevant financial relationships.

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

Experiencing psychological distress prior to becoming infected with SARS-CoV-2 is tied to an increased risk for post-COVID conditions often called “long COVID,” new research suggests.

In an analysis of almost 55,000 adult participants in three ongoing studies, having depression, anxiety, worry, perceived stress, or loneliness early in the pandemic, before SARS-CoV-2 infection, was associated with a 50% increased risk for developing long COVID. These types of psychological distress were also associated with a 15% to 51% greater risk for impairment in daily life among individuals with long COVID.

Psychological distress was even more strongly associated with developing long COVID than were physical health risk factors, and the increased risk was not explained by health behaviors such as smoking or physical comorbidities, researchers note.

“Our findings suggest the need to consider psychological health in addition to physical health as risk factors of long COVID-19,” lead author Siwen Wang, MD, postdoctoral fellow, department of nutrition, Harvard T. H. Chan School of Public Health, Boston, said in an interview.

“We need to increase public awareness of the importance of mental health and focus on getting mental health care for people who need it, increasing the supply of mental health clinicians and improving access to care,” she said.

The findings were published online in JAMA Psychiatry.
 

‘Poorly understood’

Postacute sequelae of SARS-CoV-2 (“long COVID”), which are “signs and symptoms consistent with COVID-19 that extend beyond 4 weeks from onset of infection” constitute “an emerging health issue,” the investigators write.

Dr. Wang noted that it has been estimated that 8-23 million Americans have developed long COVID. However, “despite the high prevalence and daily life impairment associated with long COVID, it is still poorly understood, and few risk factors have been established,” she said.

Although psychological distress may be implicated in long COVID, only three previous studies investigated psychological factors as potential contributors, the researchers note. Also, no study has investigated the potential role of other common manifestations of distress that have increased during the pandemic, such as loneliness and perceived stress, they add.

To investigate these issues, the researchers turned to three large ongoing longitudinal studies: the Nurses’ Health Study II (NSHII), the Nurses’ Health study 3 (NHS3), and the Growing Up Today Study (GUTS).

They analyzed data on 54,960 total participants (96.6% women; mean age, 57.5 years). Of the full group, 38% were active health care workers.

Participants completed an online COVID-19 questionnaire from April 2020 to Sept. 1, 2020 (baseline), and monthly surveys thereafter. Beginning in August 2020, surveys were administered quarterly. The end of follow-up was in November 2021.

The COVID questionnaires included questions about positive SARS-CoV-2 test results, COVID symptoms and hospitalization since March 1, 2020, and the presence of long-term COVID symptoms, such as fatigue, respiratory problems, persistent cough, muscle/joint/chest pain, smell/taste problems, confusion/disorientation/brain fog, depression/anxiety/changes in mood, headache, and memory problems.

Participants who reported these post-COVID conditions were asked about the frequency of symptoms and the degree of impairment in daily life.
 

Inflammation, immune dysregulation implicated?

The Patient Health Questionnaire–4 (PHQ-4) was used to assess for anxiety and depressive symptoms in the past 2 weeks. It consists of a two-item depression measure (PHQ-2) and a two-item Generalized Anxiety Disorder Scale (GAD-2).

Non–health care providers completed two additional assessments of psychological distress: the four-item Perceived Stress Scale and the three-item UCLA Loneliness Scale.

The researchers included demographic factors, weight, smoking status, marital status, and medical conditions, including diabetes, hypertension, hypercholesterolemia, asthma, and cancer, and socioeconomic factors as covariates.

For each participant, the investigators calculated the number of types of distress experienced at a high level, including probable depression, probable anxiety, worry about COVID-19, being in the top quartile of perceived stress, and loneliness.

During the 19 months of follow-up (1-47 weeks after baseline), 6% of respondents reported a positive result on a SARS-CoV-2 antibody, antigen, or polymerase chain reaction test.

Of these, 43.9% reported long-COVID conditions, with most reporting that symptoms lasted 2 months or longer; 55.8% reported at least occasional daily life impairment.

The most common post-COVID conditions were fatigue (reported by 56%), loss of smell or taste problems (44.6%), shortness of breath (25.5%), confusion/disorientation/ brain fog (24.5%), and memory issues (21.8%).

Among patients who had been infected, there was a considerably higher rate of preinfection psychological distress after adjusting for sociodemographic factors, health behaviors, and comorbidities. Each type of distress was associated with post-COVID conditions.

In addition, participants who had experienced at least two types of distress prior to infection were at nearly 50% increased risk for post–COVID conditions (risk ratio, 1.49; 95% confidence interval, 1.23-1.80).

Among those with post-COVID conditions, all types of distress were associated with increased risk for daily life impairment (RR range, 1.15-1.51).

Senior author Andrea Roberts, PhD, senior research scientist at the Harvard T. H. Chan School of Public Health, Boston, noted that the investigators did not examine biological mechanisms potentially underlying the association they found.

However, “based on prior research, it may be that inflammation and immune dysregulation related to psychological distress play a role in the association of distress with long COVID, but we can’t be sure,” Dr. Roberts said.
 

Contributes to the field

Commenting for this article, Yapeng Su, PhD, a postdoctoral researcher at the Fred Hutchinson Cancer Research Center in Seattle, called the study “great work contributing to the long-COVID research field and revealing important connections” with psychological stress prior to infection.

Dr. Su, who was not involved with the study, was previously at the Institute for Systems Biology, also in Seattle, and has written about long COVID.

He noted that the “biological mechanism of such intriguing linkage is definitely the important next step, which will likely require deep phenotyping of biological specimens from these patients longitudinally.”

Dr. Wang pointed to past research suggesting that some patients with mental illness “sometimes develop autoantibodies that have also been associated with increased risk of long COVID.” In addition, depression “affects the brain in ways that may explain certain cognitive symptoms in long COVID,” she added.

More studies are now needed to understand how psychological distress increases the risk for long COVID, said Dr. Wang.

The research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, the Dean’s Fund for Scientific Advancement Acceleration Award from the Harvard T. H. Chan School of Public Health, the Massachusetts Consortium on Pathogen Readiness Evergrande COVID-19 Response Fund Award, and the Veterans Affairs Health Services Research and Development Service funds. Dr. Wang and Dr. Roberts have reported no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Su reports no relevant financial relationships.

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

Cigarette smoking is an independent risk factor for lung cancer and atherosclerotic cardiovascular disease (ASCVD).^1-3 The National Lung Screening Trial (NLST) demonstrated both lung cancer mortality reduction with the use of surveillance low-dose computed tomography (LDCT) and ASCVD as the most common cause of death among smokers.^4,5 ASCVD remains the leading cause of death in the lung cancer screening (LCS) population.^2,3 After publication of the NLST results, the US Preventive Services Task Force (USPSTF) established LCS eligibility among smokers and the Center for Medicare and Medicaid Services approved payment for annual LDCT in this group.^1,6,7

Recently LDCT has been proposed as an adjunct diagnostic tool for detecting coronary artery calcium (CAC), which is independently associated with ASCVD and mortality.^8-13 CAC scores have been recommended by the 2019 American College of Cardiology/American Heart Association cholesterol treatment guidelines and shown to be cost-effective in guiding statin therapy for patients with borderline to intermediate ASCVD risk.^14-16 While CAC is conventionally quantified using electrocardiogram (ECG)-gated CT, these scans are not routinely performed in clinical practice because preventive CAC screening is neither recommended by the USPSTF nor covered by most insurance providers.^17,18 LDCT, conversely, is reimbursable and a well-validated ASCVD risk predictor.^18,19

In this study, we aimed to determine the validity of LDCT in identifying CAC among the military LCS population and whether it would impact statin recommendations based on 10-year ASCVD risk.

Methods

Participants were recruited from a retrospective cohort of 563 Military Health System (MHS) beneficiaries who received LCS with LDCT at Naval Medical Center Portsmouth (NMCP) in Virginia between January 1, 2019, and December 31, 2020. The 2013 USPSTF LCS guidelines were followed as the 2021 guidelines had not been published before the start of the study; thus, eligible participants included adults aged 55 to 80 years with at least a 30-pack-year smoking history and currently smoked or had quit within 15 years from the date of study consent.^6,7

Between November 2020 and May 2021, study investigators screened 287 patient records and recruited 190 participants by telephone, starting with individuals who had the most recent LDCT and working backward until reaching the predetermined 170 subjects who had undergone in-office consents before ECG-gated CT scans. Since LDCT was not obtained simultaneously with the ECG-gated CT, participants were required to complete their gated CT within 24 months of their last LDCT. Of the 190 subjects initially recruited, those who were ineligible for LCS (n = 4), had a history of angioplasty, stent, or bypass revascularization procedure (n = 4), did not complete their ECG-gated CT within the specified time frame (n = 8), or withdrew from the study (n = 4) were excluded. While gated CT scans were scored for CAC in the present time, LDCT (previously only read for general lung pathology) was not scored until after participant consent. Patients were peripherally followed, via health record reviews, for 3 months after their gated CT to document any additional imaging ordered by their primary care practitioners. The study was approved by the NMCP Institutional Review Board.

Coronary Artery Calcification Scoring

We performed CT scans using Siemens SOMATOM Flash, a second-generation dual-source scanner; and GE LightSpeed VCT, a single-source, 64-slice scanner. A step-and-shoot prospective trigger technique was used, and contiguous axial images were reconstructed at 2.5-mm or 3-mm intervals for CAC quantification using the Agatston method.²⁰ ECG-gated CT scans were electrocardiographically triggered at mid-diastole (70% of the R-R interval). Radiation dose reduction techniques involved adjustments of the mA according to body mass index and iterative reconstruction. LDCT scans were performed without ECG gating. We reconstructed contiguous axial images at 1-mm intervals for evaluation of the lung parenchyma. Similar dose-reduction techniques were used, to limit radiation exposure for each LDCT scan to < 1.5 mSv, per established guidelines.²¹ CAC on LDCT was also scored using the Agatston method. CAC was scored on the 2 scan types by different blinded reviewers.

Covariates

We reviewed outpatient health records to obtain participants’ age, sex, medical history, statin use, smoking status (current or former), and pack-years. International Classification of Diseases, Tenth Revision codes within medical encounters were used to document prevalent hypertension, hyperlipidemia, and diabetes mellitus. Participants’ most recent low-density lipoprotein value (within 24 months of ECG-gated CT) was recorded and 10-year ASCVD risk scores were calculated using the pooled cohorts equation.

Statistical Analysis

A power analysis performed before study initiation determined that a prospective sample size of 170 would be sufficient to provide strength of correlation between CAC scores calculated from ECG-gated CT and LDCT and achieve a statistical power of at least 80%. The Wilcoxon rank sum and Fisher exact tests were used to evaluate differences in continuous and categorical CAC scores, respectively. Given skewed distributions, Spearman rank correlations and Kendall W coefficient of concordance were respectively used to evaluate correlation and concordance of CAC scores between the 2 scan types. κ statistics were used to rate agreement between categorical CAC scores. Bland-Altman analysis was performed to determine the bias and limits of agreement between ECG-gated CT and LDCT.²² For categorical CAC score analysis, participants were categorized into 5 groups according to standard Agatston score cut-off points. We defined the 5 categories of CAC for both scan types based on previous analysis from Rumberger and colleagues: CAC = 0 (absent), CAC = 1-10 (minimal), CAC = 11-100 (mild), CAC = 101-400 (moderate), CAC > 400 (severe).²³ Of note, LDCT reports at NMCP include a visual CAC score using these qualitative descriptors that were available to LDCT reviewers. Analyses were conducted using SAS version 9.4 and Microsoft Excel; P values < .05 were considered statistically significant.

Results

The 170 participants had a mean (SD) age of 62.1 (4.6) years and were 70.6% male (Table 1). Hyperlipidemia was the most prevalent cardiac risk factor with almost 70% of participants on a statin. There was no incidence of ischemic ASCVD during follow-up, although 1 participant was later diagnosed with lung cancer after evaluation of suspicious pulmonary findings on ECG-gated CT. CAC was identified on both scan types in 126 participants; however, LDCT was discordant with gated CT in identifying CAC in 24 subjects (P < .001).

The correlation between CAC scores on ECG-gated CT and LDCT was 0.945 (P < .001) and the concordance was 0.643, indicating moderate agreement between CAC scores on the 2 different scans (Figure 1). Median CAC scores were significantly higher on ECG-gated CT when compared with LDCT (107.5 vs 48.1 Agatston units, respectively; P < .05). Table 2 shows the CAC score characteristics for both scan types. The κ statistic for agreement between categorical CAC scores on ECG-gated CT compared with LDCT was 0.49 (SEκ= 0.05; 95% CI, -0.73-1.71), and the weighted κ statistic was 0.71, indicating moderate to substantial agreement between the 2 scans using the specified cutoff points. The Bland-Altman analysis presented a mean bias of 111.45 Agatston units, with limits of agreement between -268.64 and 491.54, as shown in Figure 2, suggesting that CAC scores on ECG-gated CT were, on average, about 111 units higher than those on LDCT. Finally, there were 24 participants with CAC seen on ECG-gated CT but none identified on LDCT (P < .001); of this cohort 20 were already on a statin, and of the remaining 4 individuals, 1 met statin criteria based on a > 20% ASCVD risk score alone (regardless of CAC score), 1 with an intermediate risk score met statin criteria based on CAC score reporting, 1 did not meet criteria due to a low-risk score, and the last had no reportable ASCVD risk score.

Discussion

In this study population of recruited MHS beneficiaries, there was a strong correlation and moderate to substantial agreement between CAC scores calculated from LDCT and conventional ECG-gated CT. The number of nonstatin participants who met statin criteria and would have benefited from additional CAC score reporting was statistically significant as compared to their statin counterparts who no longer met the criteria.

CAC screening using nongated CT has become an increasingly available and consistently reproducible means for stratifying ASCVD risk and guiding statin therapy in individuals with equivocal ASCVD risk scores.^24-26 As has been demonstrated in previous studies, our study additionally highlights the effective use of LDCT in not only identifying CAC, but also in beneficially impacting statin decisions in the high-risk smoking population.^24-26 Our results also showed LDCT missed CAC in participants, the majority of which were already on a statin, and only 1 nonstatin individual benefited from additional CAC reporting. CAC scoring on LDCT should be an adjunct, not a substitute, for ASCVD risk stratification to help guide statin management.^25,27

Our results may provide cost considerate implications for preventive CAC screening. While TRICARE covers the cost of ECG-gated CT for MHS beneficiaries, the same is not true of most nonmilitary insurance providers. Concerns about cancer risk from radiation exposure may also lead to hesitation about receiving additional CTs in the smoking population. Since the LCS population already receives annual LDCT, these scans can also be used for CAC scoring to help primary care professionals risk stratify their patients, as has been previously shown.^28-31 Clinicians should consider implementing CAC scoring with annual LDCT scans, which would curtail further risks and expenses from CAC-specified scans.

Although CAC is scored visually and routinely reported in the body of LDCT reports at our facility, this is not a universal practice and was performed in only 44% of subjects with known CAC by a previous study.³² In 2007, there were 600,000 CAC scoring scans and > 9 million routine chest CTs performed in the United States.³³ Based on our results and the growing consensus in the existing literature, CAC scoring on nongated CT is not only valid and reliable, but also can estimate ASCVD risk and subsequent mortality.^34-36 Routine chest CTs remain an available resource for providing additional ASCVD risk stratification.

As we demonstrated, median CAC scores on LDCT were on average significantly lower than those from gated CT. This could be due to slice thickness variability between the GE and Siemens scanners or CAC progression between the time of the retrospective LDCT and prospective ECG-gated CT. Aside from this potential limitation, LDCT has been shown to have a high level of agreement with gated CT in predicting CAC, both visually and by the Agatston technique.^37-39 Our results further support previous recommendations of utilizing CAC score categories when determining ASCVD risk from LDCT and that establishing scoring cutoff points warrants further development for potential standardization.^37-39 Readers should be mindful that LDCT may still be less sensitive and underestimate low CAC levels and that ECG-gated CT may occasionally be more optimal in determining ASCVD risk when considering the negative predictive value of CAC.⁴⁰

Limitations

Our study cohort was composed of MHS beneficiaries. Compared with the general population, these individuals may have greater access to care and be more likely to receive statins after preventive screenings. Additional studies may be required to assess CAC-associated statin eligibility among the general population. As discussed previously LDCT was not performed concomitantly with the ECG-gated CT. Although there was moderate to substantial CAC agreement between the 2 scan types, the timing difference could have led to absolute differences in CAC scores across both scan types and impacted the ability to detect low-level CAC on LDCT. CAC values should be interpreted based on the respective scan type.

Conclusions

LDCT is a reliable diagnostic alternative to ECG-gated CT in predicting CAC. CAC scores from LDCT are highly correlated and concordant with those from gated CT and can help guide statin management in individuals with intermediate ASCVD risk. The proposed duality of LDCT to assess ASCVD risk in addition to lung cancer can reduce the need for unnecessary scans while optimizing preventive clinical care. While coronary calcium and elevated CAC scores can facilitate clinical decision making to initiate statin therapy for intermediate-risk patients, physicians must still determine whether additional cardiac testing is warranted to avoid unnecessary procedures and health care costs. Smokers undergoing annual LDCT may benefit from standardized CAC scoring to help further stratify ASCVD risk while limiting the expense and radiation of additional scans.

Acknowledgments

The authors thank Ms. Lorie Gower for her contributions to the study.

Cigarette smoking is an independent risk factor for lung cancer and atherosclerotic cardiovascular disease (ASCVD).^1-3 The National Lung Screening Trial (NLST) demonstrated both lung cancer mortality reduction with the use of surveillance low-dose computed tomography (LDCT) and ASCVD as the most common cause of death among smokers.^4,5 ASCVD remains the leading cause of death in the lung cancer screening (LCS) population.^2,3 After publication of the NLST results, the US Preventive Services Task Force (USPSTF) established LCS eligibility among smokers and the Center for Medicare and Medicaid Services approved payment for annual LDCT in this group.^1,6,7

Recently LDCT has been proposed as an adjunct diagnostic tool for detecting coronary artery calcium (CAC), which is independently associated with ASCVD and mortality.^8-13 CAC scores have been recommended by the 2019 American College of Cardiology/American Heart Association cholesterol treatment guidelines and shown to be cost-effective in guiding statin therapy for patients with borderline to intermediate ASCVD risk.^14-16 While CAC is conventionally quantified using electrocardiogram (ECG)-gated CT, these scans are not routinely performed in clinical practice because preventive CAC screening is neither recommended by the USPSTF nor covered by most insurance providers.^17,18 LDCT, conversely, is reimbursable and a well-validated ASCVD risk predictor.^18,19

In this study, we aimed to determine the validity of LDCT in identifying CAC among the military LCS population and whether it would impact statin recommendations based on 10-year ASCVD risk.

Methods

Participants were recruited from a retrospective cohort of 563 Military Health System (MHS) beneficiaries who received LCS with LDCT at Naval Medical Center Portsmouth (NMCP) in Virginia between January 1, 2019, and December 31, 2020. The 2013 USPSTF LCS guidelines were followed as the 2021 guidelines had not been published before the start of the study; thus, eligible participants included adults aged 55 to 80 years with at least a 30-pack-year smoking history and currently smoked or had quit within 15 years from the date of study consent.^6,7

Between November 2020 and May 2021, study investigators screened 287 patient records and recruited 190 participants by telephone, starting with individuals who had the most recent LDCT and working backward until reaching the predetermined 170 subjects who had undergone in-office consents before ECG-gated CT scans. Since LDCT was not obtained simultaneously with the ECG-gated CT, participants were required to complete their gated CT within 24 months of their last LDCT. Of the 190 subjects initially recruited, those who were ineligible for LCS (n = 4), had a history of angioplasty, stent, or bypass revascularization procedure (n = 4), did not complete their ECG-gated CT within the specified time frame (n = 8), or withdrew from the study (n = 4) were excluded. While gated CT scans were scored for CAC in the present time, LDCT (previously only read for general lung pathology) was not scored until after participant consent. Patients were peripherally followed, via health record reviews, for 3 months after their gated CT to document any additional imaging ordered by their primary care practitioners. The study was approved by the NMCP Institutional Review Board.

Coronary Artery Calcification Scoring

We performed CT scans using Siemens SOMATOM Flash, a second-generation dual-source scanner; and GE LightSpeed VCT, a single-source, 64-slice scanner. A step-and-shoot prospective trigger technique was used, and contiguous axial images were reconstructed at 2.5-mm or 3-mm intervals for CAC quantification using the Agatston method.²⁰ ECG-gated CT scans were electrocardiographically triggered at mid-diastole (70% of the R-R interval). Radiation dose reduction techniques involved adjustments of the mA according to body mass index and iterative reconstruction. LDCT scans were performed without ECG gating. We reconstructed contiguous axial images at 1-mm intervals for evaluation of the lung parenchyma. Similar dose-reduction techniques were used, to limit radiation exposure for each LDCT scan to < 1.5 mSv, per established guidelines.²¹ CAC on LDCT was also scored using the Agatston method. CAC was scored on the 2 scan types by different blinded reviewers.

Covariates

We reviewed outpatient health records to obtain participants’ age, sex, medical history, statin use, smoking status (current or former), and pack-years. International Classification of Diseases, Tenth Revision codes within medical encounters were used to document prevalent hypertension, hyperlipidemia, and diabetes mellitus. Participants’ most recent low-density lipoprotein value (within 24 months of ECG-gated CT) was recorded and 10-year ASCVD risk scores were calculated using the pooled cohorts equation.

Statistical Analysis

A power analysis performed before study initiation determined that a prospective sample size of 170 would be sufficient to provide strength of correlation between CAC scores calculated from ECG-gated CT and LDCT and achieve a statistical power of at least 80%. The Wilcoxon rank sum and Fisher exact tests were used to evaluate differences in continuous and categorical CAC scores, respectively. Given skewed distributions, Spearman rank correlations and Kendall W coefficient of concordance were respectively used to evaluate correlation and concordance of CAC scores between the 2 scan types. κ statistics were used to rate agreement between categorical CAC scores. Bland-Altman analysis was performed to determine the bias and limits of agreement between ECG-gated CT and LDCT.²² For categorical CAC score analysis, participants were categorized into 5 groups according to standard Agatston score cut-off points. We defined the 5 categories of CAC for both scan types based on previous analysis from Rumberger and colleagues: CAC = 0 (absent), CAC = 1-10 (minimal), CAC = 11-100 (mild), CAC = 101-400 (moderate), CAC > 400 (severe).²³ Of note, LDCT reports at NMCP include a visual CAC score using these qualitative descriptors that were available to LDCT reviewers. Analyses were conducted using SAS version 9.4 and Microsoft Excel; P values < .05 were considered statistically significant.

Results

The 170 participants had a mean (SD) age of 62.1 (4.6) years and were 70.6% male (Table 1). Hyperlipidemia was the most prevalent cardiac risk factor with almost 70% of participants on a statin. There was no incidence of ischemic ASCVD during follow-up, although 1 participant was later diagnosed with lung cancer after evaluation of suspicious pulmonary findings on ECG-gated CT. CAC was identified on both scan types in 126 participants; however, LDCT was discordant with gated CT in identifying CAC in 24 subjects (P < .001).

The correlation between CAC scores on ECG-gated CT and LDCT was 0.945 (P < .001) and the concordance was 0.643, indicating moderate agreement between CAC scores on the 2 different scans (Figure 1). Median CAC scores were significantly higher on ECG-gated CT when compared with LDCT (107.5 vs 48.1 Agatston units, respectively; P < .05). Table 2 shows the CAC score characteristics for both scan types. The κ statistic for agreement between categorical CAC scores on ECG-gated CT compared with LDCT was 0.49 (SEκ= 0.05; 95% CI, -0.73-1.71), and the weighted κ statistic was 0.71, indicating moderate to substantial agreement between the 2 scans using the specified cutoff points. The Bland-Altman analysis presented a mean bias of 111.45 Agatston units, with limits of agreement between -268.64 and 491.54, as shown in Figure 2, suggesting that CAC scores on ECG-gated CT were, on average, about 111 units higher than those on LDCT. Finally, there were 24 participants with CAC seen on ECG-gated CT but none identified on LDCT (P < .001); of this cohort 20 were already on a statin, and of the remaining 4 individuals, 1 met statin criteria based on a > 20% ASCVD risk score alone (regardless of CAC score), 1 with an intermediate risk score met statin criteria based on CAC score reporting, 1 did not meet criteria due to a low-risk score, and the last had no reportable ASCVD risk score.

Discussion

In this study population of recruited MHS beneficiaries, there was a strong correlation and moderate to substantial agreement between CAC scores calculated from LDCT and conventional ECG-gated CT. The number of nonstatin participants who met statin criteria and would have benefited from additional CAC score reporting was statistically significant as compared to their statin counterparts who no longer met the criteria.

CAC screening using nongated CT has become an increasingly available and consistently reproducible means for stratifying ASCVD risk and guiding statin therapy in individuals with equivocal ASCVD risk scores.^24-26 As has been demonstrated in previous studies, our study additionally highlights the effective use of LDCT in not only identifying CAC, but also in beneficially impacting statin decisions in the high-risk smoking population.^24-26 Our results also showed LDCT missed CAC in participants, the majority of which were already on a statin, and only 1 nonstatin individual benefited from additional CAC reporting. CAC scoring on LDCT should be an adjunct, not a substitute, for ASCVD risk stratification to help guide statin management.^25,27

Our results may provide cost considerate implications for preventive CAC screening. While TRICARE covers the cost of ECG-gated CT for MHS beneficiaries, the same is not true of most nonmilitary insurance providers. Concerns about cancer risk from radiation exposure may also lead to hesitation about receiving additional CTs in the smoking population. Since the LCS population already receives annual LDCT, these scans can also be used for CAC scoring to help primary care professionals risk stratify their patients, as has been previously shown.^28-31 Clinicians should consider implementing CAC scoring with annual LDCT scans, which would curtail further risks and expenses from CAC-specified scans.

Although CAC is scored visually and routinely reported in the body of LDCT reports at our facility, this is not a universal practice and was performed in only 44% of subjects with known CAC by a previous study.³² In 2007, there were 600,000 CAC scoring scans and > 9 million routine chest CTs performed in the United States.³³ Based on our results and the growing consensus in the existing literature, CAC scoring on nongated CT is not only valid and reliable, but also can estimate ASCVD risk and subsequent mortality.^34-36 Routine chest CTs remain an available resource for providing additional ASCVD risk stratification.

As we demonstrated, median CAC scores on LDCT were on average significantly lower than those from gated CT. This could be due to slice thickness variability between the GE and Siemens scanners or CAC progression between the time of the retrospective LDCT and prospective ECG-gated CT. Aside from this potential limitation, LDCT has been shown to have a high level of agreement with gated CT in predicting CAC, both visually and by the Agatston technique.^37-39 Our results further support previous recommendations of utilizing CAC score categories when determining ASCVD risk from LDCT and that establishing scoring cutoff points warrants further development for potential standardization.^37-39 Readers should be mindful that LDCT may still be less sensitive and underestimate low CAC levels and that ECG-gated CT may occasionally be more optimal in determining ASCVD risk when considering the negative predictive value of CAC.⁴⁰

Limitations

Our study cohort was composed of MHS beneficiaries. Compared with the general population, these individuals may have greater access to care and be more likely to receive statins after preventive screenings. Additional studies may be required to assess CAC-associated statin eligibility among the general population. As discussed previously LDCT was not performed concomitantly with the ECG-gated CT. Although there was moderate to substantial CAC agreement between the 2 scan types, the timing difference could have led to absolute differences in CAC scores across both scan types and impacted the ability to detect low-level CAC on LDCT. CAC values should be interpreted based on the respective scan type.

Conclusions

LDCT is a reliable diagnostic alternative to ECG-gated CT in predicting CAC. CAC scores from LDCT are highly correlated and concordant with those from gated CT and can help guide statin management in individuals with intermediate ASCVD risk. The proposed duality of LDCT to assess ASCVD risk in addition to lung cancer can reduce the need for unnecessary scans while optimizing preventive clinical care. While coronary calcium and elevated CAC scores can facilitate clinical decision making to initiate statin therapy for intermediate-risk patients, physicians must still determine whether additional cardiac testing is warranted to avoid unnecessary procedures and health care costs. Smokers undergoing annual LDCT may benefit from standardized CAC scoring to help further stratify ASCVD risk while limiting the expense and radiation of additional scans.

Acknowledgments

The authors thank Ms. Lorie Gower for her contributions to the study.

Cigarette smoking is an independent risk factor for lung cancer and atherosclerotic cardiovascular disease (ASCVD).^1-3 The National Lung Screening Trial (NLST) demonstrated both lung cancer mortality reduction with the use of surveillance low-dose computed tomography (LDCT) and ASCVD as the most common cause of death among smokers.^4,5 ASCVD remains the leading cause of death in the lung cancer screening (LCS) population.^2,3 After publication of the NLST results, the US Preventive Services Task Force (USPSTF) established LCS eligibility among smokers and the Center for Medicare and Medicaid Services approved payment for annual LDCT in this group.^1,6,7

Recently LDCT has been proposed as an adjunct diagnostic tool for detecting coronary artery calcium (CAC), which is independently associated with ASCVD and mortality.^8-13 CAC scores have been recommended by the 2019 American College of Cardiology/American Heart Association cholesterol treatment guidelines and shown to be cost-effective in guiding statin therapy for patients with borderline to intermediate ASCVD risk.^14-16 While CAC is conventionally quantified using electrocardiogram (ECG)-gated CT, these scans are not routinely performed in clinical practice because preventive CAC screening is neither recommended by the USPSTF nor covered by most insurance providers.^17,18 LDCT, conversely, is reimbursable and a well-validated ASCVD risk predictor.^18,19

In this study, we aimed to determine the validity of LDCT in identifying CAC among the military LCS population and whether it would impact statin recommendations based on 10-year ASCVD risk.

Methods

Participants were recruited from a retrospective cohort of 563 Military Health System (MHS) beneficiaries who received LCS with LDCT at Naval Medical Center Portsmouth (NMCP) in Virginia between January 1, 2019, and December 31, 2020. The 2013 USPSTF LCS guidelines were followed as the 2021 guidelines had not been published before the start of the study; thus, eligible participants included adults aged 55 to 80 years with at least a 30-pack-year smoking history and currently smoked or had quit within 15 years from the date of study consent.^6,7

Between November 2020 and May 2021, study investigators screened 287 patient records and recruited 190 participants by telephone, starting with individuals who had the most recent LDCT and working backward until reaching the predetermined 170 subjects who had undergone in-office consents before ECG-gated CT scans. Since LDCT was not obtained simultaneously with the ECG-gated CT, participants were required to complete their gated CT within 24 months of their last LDCT. Of the 190 subjects initially recruited, those who were ineligible for LCS (n = 4), had a history of angioplasty, stent, or bypass revascularization procedure (n = 4), did not complete their ECG-gated CT within the specified time frame (n = 8), or withdrew from the study (n = 4) were excluded. While gated CT scans were scored for CAC in the present time, LDCT (previously only read for general lung pathology) was not scored until after participant consent. Patients were peripherally followed, via health record reviews, for 3 months after their gated CT to document any additional imaging ordered by their primary care practitioners. The study was approved by the NMCP Institutional Review Board.

Coronary Artery Calcification Scoring

We performed CT scans using Siemens SOMATOM Flash, a second-generation dual-source scanner; and GE LightSpeed VCT, a single-source, 64-slice scanner. A step-and-shoot prospective trigger technique was used, and contiguous axial images were reconstructed at 2.5-mm or 3-mm intervals for CAC quantification using the Agatston method.²⁰ ECG-gated CT scans were electrocardiographically triggered at mid-diastole (70% of the R-R interval). Radiation dose reduction techniques involved adjustments of the mA according to body mass index and iterative reconstruction. LDCT scans were performed without ECG gating. We reconstructed contiguous axial images at 1-mm intervals for evaluation of the lung parenchyma. Similar dose-reduction techniques were used, to limit radiation exposure for each LDCT scan to < 1.5 mSv, per established guidelines.²¹ CAC on LDCT was also scored using the Agatston method. CAC was scored on the 2 scan types by different blinded reviewers.

Covariates

We reviewed outpatient health records to obtain participants’ age, sex, medical history, statin use, smoking status (current or former), and pack-years. International Classification of Diseases, Tenth Revision codes within medical encounters were used to document prevalent hypertension, hyperlipidemia, and diabetes mellitus. Participants’ most recent low-density lipoprotein value (within 24 months of ECG-gated CT) was recorded and 10-year ASCVD risk scores were calculated using the pooled cohorts equation.

Statistical Analysis

A power analysis performed before study initiation determined that a prospective sample size of 170 would be sufficient to provide strength of correlation between CAC scores calculated from ECG-gated CT and LDCT and achieve a statistical power of at least 80%. The Wilcoxon rank sum and Fisher exact tests were used to evaluate differences in continuous and categorical CAC scores, respectively. Given skewed distributions, Spearman rank correlations and Kendall W coefficient of concordance were respectively used to evaluate correlation and concordance of CAC scores between the 2 scan types. κ statistics were used to rate agreement between categorical CAC scores. Bland-Altman analysis was performed to determine the bias and limits of agreement between ECG-gated CT and LDCT.²² For categorical CAC score analysis, participants were categorized into 5 groups according to standard Agatston score cut-off points. We defined the 5 categories of CAC for both scan types based on previous analysis from Rumberger and colleagues: CAC = 0 (absent), CAC = 1-10 (minimal), CAC = 11-100 (mild), CAC = 101-400 (moderate), CAC > 400 (severe).²³ Of note, LDCT reports at NMCP include a visual CAC score using these qualitative descriptors that were available to LDCT reviewers. Analyses were conducted using SAS version 9.4 and Microsoft Excel; P values < .05 were considered statistically significant.

Results

The 170 participants had a mean (SD) age of 62.1 (4.6) years and were 70.6% male (Table 1). Hyperlipidemia was the most prevalent cardiac risk factor with almost 70% of participants on a statin. There was no incidence of ischemic ASCVD during follow-up, although 1 participant was later diagnosed with lung cancer after evaluation of suspicious pulmonary findings on ECG-gated CT. CAC was identified on both scan types in 126 participants; however, LDCT was discordant with gated CT in identifying CAC in 24 subjects (P < .001).

The correlation between CAC scores on ECG-gated CT and LDCT was 0.945 (P < .001) and the concordance was 0.643, indicating moderate agreement between CAC scores on the 2 different scans (Figure 1). Median CAC scores were significantly higher on ECG-gated CT when compared with LDCT (107.5 vs 48.1 Agatston units, respectively; P < .05). Table 2 shows the CAC score characteristics for both scan types. The κ statistic for agreement between categorical CAC scores on ECG-gated CT compared with LDCT was 0.49 (SEκ= 0.05; 95% CI, -0.73-1.71), and the weighted κ statistic was 0.71, indicating moderate to substantial agreement between the 2 scans using the specified cutoff points. The Bland-Altman analysis presented a mean bias of 111.45 Agatston units, with limits of agreement between -268.64 and 491.54, as shown in Figure 2, suggesting that CAC scores on ECG-gated CT were, on average, about 111 units higher than those on LDCT. Finally, there were 24 participants with CAC seen on ECG-gated CT but none identified on LDCT (P < .001); of this cohort 20 were already on a statin, and of the remaining 4 individuals, 1 met statin criteria based on a > 20% ASCVD risk score alone (regardless of CAC score), 1 with an intermediate risk score met statin criteria based on CAC score reporting, 1 did not meet criteria due to a low-risk score, and the last had no reportable ASCVD risk score.

Discussion

In this study population of recruited MHS beneficiaries, there was a strong correlation and moderate to substantial agreement between CAC scores calculated from LDCT and conventional ECG-gated CT. The number of nonstatin participants who met statin criteria and would have benefited from additional CAC score reporting was statistically significant as compared to their statin counterparts who no longer met the criteria.

CAC screening using nongated CT has become an increasingly available and consistently reproducible means for stratifying ASCVD risk and guiding statin therapy in individuals with equivocal ASCVD risk scores.^24-26 As has been demonstrated in previous studies, our study additionally highlights the effective use of LDCT in not only identifying CAC, but also in beneficially impacting statin decisions in the high-risk smoking population.^24-26 Our results also showed LDCT missed CAC in participants, the majority of which were already on a statin, and only 1 nonstatin individual benefited from additional CAC reporting. CAC scoring on LDCT should be an adjunct, not a substitute, for ASCVD risk stratification to help guide statin management.^25,27

Our results may provide cost considerate implications for preventive CAC screening. While TRICARE covers the cost of ECG-gated CT for MHS beneficiaries, the same is not true of most nonmilitary insurance providers. Concerns about cancer risk from radiation exposure may also lead to hesitation about receiving additional CTs in the smoking population. Since the LCS population already receives annual LDCT, these scans can also be used for CAC scoring to help primary care professionals risk stratify their patients, as has been previously shown.^28-31 Clinicians should consider implementing CAC scoring with annual LDCT scans, which would curtail further risks and expenses from CAC-specified scans.

Although CAC is scored visually and routinely reported in the body of LDCT reports at our facility, this is not a universal practice and was performed in only 44% of subjects with known CAC by a previous study.³² In 2007, there were 600,000 CAC scoring scans and > 9 million routine chest CTs performed in the United States.³³ Based on our results and the growing consensus in the existing literature, CAC scoring on nongated CT is not only valid and reliable, but also can estimate ASCVD risk and subsequent mortality.^34-36 Routine chest CTs remain an available resource for providing additional ASCVD risk stratification.

As we demonstrated, median CAC scores on LDCT were on average significantly lower than those from gated CT. This could be due to slice thickness variability between the GE and Siemens scanners or CAC progression between the time of the retrospective LDCT and prospective ECG-gated CT. Aside from this potential limitation, LDCT has been shown to have a high level of agreement with gated CT in predicting CAC, both visually and by the Agatston technique.^37-39 Our results further support previous recommendations of utilizing CAC score categories when determining ASCVD risk from LDCT and that establishing scoring cutoff points warrants further development for potential standardization.^37-39 Readers should be mindful that LDCT may still be less sensitive and underestimate low CAC levels and that ECG-gated CT may occasionally be more optimal in determining ASCVD risk when considering the negative predictive value of CAC.⁴⁰

Limitations

Our study cohort was composed of MHS beneficiaries. Compared with the general population, these individuals may have greater access to care and be more likely to receive statins after preventive screenings. Additional studies may be required to assess CAC-associated statin eligibility among the general population. As discussed previously LDCT was not performed concomitantly with the ECG-gated CT. Although there was moderate to substantial CAC agreement between the 2 scan types, the timing difference could have led to absolute differences in CAC scores across both scan types and impacted the ability to detect low-level CAC on LDCT. CAC values should be interpreted based on the respective scan type.

Conclusions

LDCT is a reliable diagnostic alternative to ECG-gated CT in predicting CAC. CAC scores from LDCT are highly correlated and concordant with those from gated CT and can help guide statin management in individuals with intermediate ASCVD risk. The proposed duality of LDCT to assess ASCVD risk in addition to lung cancer can reduce the need for unnecessary scans while optimizing preventive clinical care. While coronary calcium and elevated CAC scores can facilitate clinical decision making to initiate statin therapy for intermediate-risk patients, physicians must still determine whether additional cardiac testing is warranted to avoid unnecessary procedures and health care costs. Smokers undergoing annual LDCT may benefit from standardized CAC scoring to help further stratify ASCVD risk while limiting the expense and radiation of additional scans.

Acknowledgments

The authors thank Ms. Lorie Gower for her contributions to the study.

People with serious mental illness (SMI) are at substantial risk for premature mortality, dying on average 10 to 20 years earlier than others.¹ The reasons for this disparity are complex; however, the high prevalence of chronic disease and physical comorbidities in the SMI population have been identified as prominent factors.² Engagement and reengagement in care, including primary care for medical comorbidities, can mitigate these mortality risks.^2-4 Among veterans with SMI lost to follow-up care for more than 12 months, those not successfully reengaged in care were more likely to die compared with those reengaged in care.^2,3

Given this evidence, health care systems, including the US Department of Veterans Affairs (VA), have looked to better engage these patients in care. These efforts have included mental health population health management, colocation of mental health with primary care, designation of primary care teams specializing in SMI, and integration of mental health and primary care services for patients experiencing homelessness.^5-8

As part of a national approach to encourage locally driven quality improvement (QI), the VA compiles performance metrics for each facility, across a gamut of care settings, conditions, and veteran populations.⁹ Quarterly facility report cards, with longitudinal data and cross-facility comparisons, enable facilities to identify targets for QI and track improvement progress. One metric reports on the proportion of enrolled veterans with SMI who have primary care engagement, defined as having an assigned primary care practitioner (PCP) and a primary care visit in the prior 12 months.

In support of a QI initiative at the VA Greater Los Angeles Healthcare System (VAGLAHS), we sought to describe promising practices being utilized by VA facilities with higher levels of primary care engagement among their veterans with SMI populations.

Methods

We conducted semistructured telephone interviews with a purposeful sample of key informants at VA facilities with high levels of engagement in primary care among veterans with SMI. All project components were conducted by an interdisciplinary team, which included a medical anthropologist (JM), a mental health physician (PR), an internal medicine physician (KC), and other health services researchers (JB, AG). Because the primary objective of the project was QI, this project was designated as nonresearch by the VAGLAHS Institutional Review Board.

The VA Facility Complexity Model classifies facilities into 5 tiers: 1a (most complex), 1b, 1c, 2, and 3 (least complex), based on patient care volume, patient risk, complexity of clinical programs, and size of research and teaching programs. We sampled informants at VA facilities with complexity ratings of 1a or 1b with better than median scores for primary care engagement of veterans with SMI based on report cards from January 2019 to March 2019. To increase the likelihood of identifying lessons that can generalize to the VAGLAHS with its large population of veterans experiencing homelessness, we selected facilities serving populations consisting of more than 1000 veterans experiencing homelessness.

At each selected facility, we first aimed to interview mental health leaders responsible for quality measurement and improvement identified from a national VA database. We then used snowball sampling to identify other informants at these VA facilities who were knowledgeable about relevant processes. Potential interviewees were contacted via email.

Interviews

The interview guide was developed by the interdisciplinary team and based on published literature about strategies for engaging patients with SMI in care. Interview guide questions focused on local practice arrangements, panel management, population health practices, and quality measurement and improvement efforts for engaging veterans with SMI in primary care (Appendix). Interviews were conducted by telephone, from May 2019 through July 2019, by experienced qualitative interviewers (JM, JB). Interviewees were assured confidentiality of their responses.

Interview audio recordings were used to generate detailed notes (AG). Structured summaries were prepared from these notes, using a template based on the interview guide. We organized these summaries into matrices for analysis, grouping summarized points by interview domains to facilitate comparison across interviews.^10-11 Our team reviewed and discussed the matrices, and iteratively identified and defined themes to identify the common engagement approaches and the nature of the connections between mental health and primary care. To ensure rigor, findings were checked by the senior qualitative lead (JM).

Results

The median SMI engagement score—defined as the proportion of veterans with SMI who have had a primary care visit in the prior 12 months and who have an assigned PCP—was 75.6% across 1a and 1b VA facilities. We identified 16 VA facilities that had a median or higher score and more than 1000 enrolled veterans experiencing homelessness. From these16 facilities, we emailed 31 potential interviewees, 14 of whom were identified from a VA database and 17 referred by other interviewees. In total, we interviewed 18 key informants across 11 (69%) facilities, including chiefs of psychology and mental health services, PCPs with mental health expertise, QI specialists, a psychosocial rehabilitation leader, and a local recovery coordinator, who helps veterans with SMI access recovery-oriented services. Characteristics of the facilities and interviewees are shown in Table 1. Interviews lasted a mean 35 (range, 26-50) minutes.

Engagement Approaches

The strategies used to engage veterans with SMI were heterogenous, with no single strategy common across all facilities. However, we identified 2 categories of engagement approaches: targeted outreach and routine practices.

Targeted outreach strategies included deliberate, systematic approaches to reach veterans with SMI outside of regularly scheduled visits. These strategies were designed to be proactive, often prioritizing veterans at risk of disengaging from care. Designated VA care team members identified and reached out to veterans well before 12 months had passed since their prior visit (the VA definition of disengagement from care); visits included any care at VA, including, but not exclusively, primary care. Table 2 describes the key components of targeted outreach strategies: (1) identifying veterans’ last visit; (2) prioritizing which veterans to outreach to; and (3) assigning responsibility and reaching out. A key defining feature of targeted outreach is that veterans were identified and prioritized for outreach independent from any visits with mental health or other VA services.

At some facilities, mental health support staff were able to directly schedule primary care appointments, which was identified as an important enabling factor in promoting mental health patient engagement in primary care. Some interviewees seemed to take for granted the idea that mental health practitioners would help engage patients in primary care—suggesting that these practices had perhaps become a cultural norm within their facility. However, some interviewees identified clear strategies for making these practices a consistent part of care—for example, by designing a protocol for initial mental health assessments to include a routine check for primary care engagement.

Mental Health/Primary Care Connections

Interviewees characterized the nature of the connections between mental health and primary care at their facilities. Nearly all interviewees described that their medical centers had extensive ties, formal and informal, between mental health and primary care.

Formal ties may include the reverse integration care model, in which primary care services are embedded in mental health settings. Interviewees at sites with programs based on this model noted that these programs enabled warm hand-offs from mental health to primary care and suggested that it can foster integration between primary care and mental health care for patients with SMI. However, the size, scope, and structure of these programs varied, sometimes serving a small proportion of a facility’s population of SMI patients. Other examples of formal ties included written agreements, establishing frequent, regular meetings between mental health and primary care leadership and front-line staff, and giving mental health clerks the ability to directly schedule primary care appointments.

Discussion

VA facilities with high levels of primary care engagement among veterans with SMI used extensive engagement strategies, including a diverse array of targeted outreach and routine practices. In both approaches, intentional organizational structural and process decisions, as well as formal and informal ties between mental health and primary care, established and supported them. In addition, organizational cultural factors were especially relevant to routine practice strategies.

To enable targeted outreach, a bevy of organizational resources, both local and national were required. Large accountable care organizations and integrated delivery systems, like the VA, are often better able to create dashboards and other informational resources for population health management compared with smaller, less integrated health care systems. Though these resources are difficult to create in fragmented systems, comparable tools have been explored by multiple state health departments.¹² Our findings suggest that these data tools, though resource intensive to develop, may enable facilities to be more methodical and reliable in conducting outreach to vulnerable patients.

In contrast to targeted outreach, routine practices depend less on population health management resources and more on cultural norms. Such norms are notoriously difficult to change, but intentional structural decisions like embedding primary care engagement in mental health protocols may signal that primary care engagement is an important and legitimate consideration for mental health care.¹³

We identified extensive and heterogenous connections between mental health and primary care in our sample of VA facilities with high engagement of patients with SMI in primary care. A growing body of literature on relational coordination studies the factors that contribute to organizational siloing and mechanisms for breaking down those silos so work can be coordinated across boundaries (eg, the organizational boundary between mental health and primary care).¹⁴ Coordinating care across these boundaries, through good relational coordination practices has been shown to improve outcomes in health care and other sectors. Notably, VA facilities in our sample had several of the defining characteristics of good relational coordination: relationships between mental health and primary care that include shared goals, shared knowledge, and mutual respect, all reinforced by frequent communication structured around problem solving.¹⁵ The relational coordination literature also offers a way to identify evidence-based interventions for facilitating relational coordination in places where it is lacking, for example, with information systems, boundary-spanning individuals, facility design, and formal conflict resolution.¹⁵ Future work might explore how relational coordination can be further used to optimize mental health and primary care connections to keep veterans with SMI engaged in care.

Our approach of interviewing informants in higher-performing facilities draws heavily on the idea of positive deviance, which holds that information on what works in health care is available from organizations that already are demonstrating “consistently exceptional performance.”¹⁶ This approach works best when high performance and organizational characteristics are observable for a large number of facilities, and when high-performing facilities are willing to share their strategies. These features allow investigators to identify promising practices and hypotheses that can then be empirically tested and compared. Such testing, including assessing for unintended consequences, is needed for the approaches we identified. Research is also needed to assess for factors that would promote the implementation of effective strategies.

Limitations

As a QI project seeking to identify promising practices, our interviews were limited to 18 key informants across 11 VA facilities with high engagement of care among veterans with SMI. No inferences can be made that these practices are directly related to this high level of engagement, nor the differential impact of different practices. Future work is needed to assess for these relationships. We also did not interview veterans to understand their perspectives on these strategies, which is an additional important topic for future work. In addition, these interviews were performed before the start of the COVID-19 pandemic. Further work is needed to understand how these strategies may have been modified in response to changes in practice. The shift to care from in-person to virtual services may have impacted both clinical interactions with veterans, as well as between clinicians.

Conclusions

Interviews with key informants demonstrate that while engaging and retaining veterans with SMI in primary care is vital, it also requires intentional and potentially resource-intensive practices, including targeted outreach and routine engagement strategies embedded into mental health visits. These promising practices can provide valuable insights for both VA and community health care systems providing care to patients with SMI.

Acknowledgments

We thank Gracielle J. Tan, MD for administrative assistance in preparing this manuscript.

People with serious mental illness (SMI) are at substantial risk for premature mortality, dying on average 10 to 20 years earlier than others.¹ The reasons for this disparity are complex; however, the high prevalence of chronic disease and physical comorbidities in the SMI population have been identified as prominent factors.² Engagement and reengagement in care, including primary care for medical comorbidities, can mitigate these mortality risks.^2-4 Among veterans with SMI lost to follow-up care for more than 12 months, those not successfully reengaged in care were more likely to die compared with those reengaged in care.^2,3

Given this evidence, health care systems, including the US Department of Veterans Affairs (VA), have looked to better engage these patients in care. These efforts have included mental health population health management, colocation of mental health with primary care, designation of primary care teams specializing in SMI, and integration of mental health and primary care services for patients experiencing homelessness.^5-8

As part of a national approach to encourage locally driven quality improvement (QI), the VA compiles performance metrics for each facility, across a gamut of care settings, conditions, and veteran populations.⁹ Quarterly facility report cards, with longitudinal data and cross-facility comparisons, enable facilities to identify targets for QI and track improvement progress. One metric reports on the proportion of enrolled veterans with SMI who have primary care engagement, defined as having an assigned primary care practitioner (PCP) and a primary care visit in the prior 12 months.

In support of a QI initiative at the VA Greater Los Angeles Healthcare System (VAGLAHS), we sought to describe promising practices being utilized by VA facilities with higher levels of primary care engagement among their veterans with SMI populations.

Methods

We conducted semistructured telephone interviews with a purposeful sample of key informants at VA facilities with high levels of engagement in primary care among veterans with SMI. All project components were conducted by an interdisciplinary team, which included a medical anthropologist (JM), a mental health physician (PR), an internal medicine physician (KC), and other health services researchers (JB, AG). Because the primary objective of the project was QI, this project was designated as nonresearch by the VAGLAHS Institutional Review Board.

The VA Facility Complexity Model classifies facilities into 5 tiers: 1a (most complex), 1b, 1c, 2, and 3 (least complex), based on patient care volume, patient risk, complexity of clinical programs, and size of research and teaching programs. We sampled informants at VA facilities with complexity ratings of 1a or 1b with better than median scores for primary care engagement of veterans with SMI based on report cards from January 2019 to March 2019. To increase the likelihood of identifying lessons that can generalize to the VAGLAHS with its large population of veterans experiencing homelessness, we selected facilities serving populations consisting of more than 1000 veterans experiencing homelessness.

At each selected facility, we first aimed to interview mental health leaders responsible for quality measurement and improvement identified from a national VA database. We then used snowball sampling to identify other informants at these VA facilities who were knowledgeable about relevant processes. Potential interviewees were contacted via email.