Among women with a planned delivery in a New York City health system during the first half of April, the rate of asymptomatic SARS-CoV-2 infection was 16%, according to a study published in Obstetrics & Gynecology. Among the patients’ designated support persons, the asymptomatic carrier rate was 10%.

“If universal testing of pregnant patients in a high prevalence area is not performed, health care workers will be inadvertently exposed to COVID-19, unless universal precautions with personal protective equipment are taken,” wrote the researchers affiliated with the department of obstetrics, gynecology, and reproductive medicine at Icahn School of Medicine at Mount Sinai, New York.

Angela Bianco, MD, and colleagues conducted an observational study of women who were scheduled for a planned delivery within the Mount Sinai Health System between April 4 and April 15, 2020. Patients and their designated support person completed a telephone screen and underwent COVID-19 testing the day before a scheduled delivery. If support persons screened positive during the telephone interview about COVID-19 symptoms, they could not attend the birth, and patients could contact a different support person to be screened and tested. “All patients and their support persons were informed of their SARS-CoV-2 test results before admission,” the investigators wrote. “Those who tested positive were counseled regarding symptomatology that should prompt medical attention.”

In all, researchers screened 158 patients with a planned delivery, and 155 agreed to undergo COVID-19 testing. Of the 155 women tested, 24 (16%) tested positive for SARS CoV-2 infection. Among 146 support persons who had a negative interview screen and underwent SARS-CoV-2 testing, 14 (10%) tested positive for SARS-CoV-2 infection.

Test results were substantially concordant among patient and support person pairs. “Among patients who tested positive for COVID-19 infection and had a support person present, 11 of 19 (58%) support persons also tested positive for COVID-19 infection,” the authors reported. “Among patients who tested negative for COVID-19 infection and had a support person present, only 3 of 127 (2.4%) support persons tested positive for COVID-19 infection.”

Telephone screening did not identify any of the COVID-19–positive cases. Of the 24 patients with SARS-CoV-2 infection, none of their newborns tested positive at birth.

“Universal testing ... provides a mechanism for more accurate counseling of patients regarding issues such as newborn skin-to-skin contact and breastfeeding,” noted Dr. Bianco and colleagues. At their institution, parents with COVID-19 are instructed to wear a mask and practice proper hand hygiene when caring for their newborns.

Kristina Adams Waldorf, MD, said in an interview that the study by Bianco et al. underscores the high rate of asymptomatic or mildly symptomatic COVID-19 infections detected with universal screening in a hospital at the U.S. epicenter of the pandemic. “Each state and hospital will need to evaluate their own data to determine the value of universal screening for their patient population. In rural parts of America that have yet to see cases, universal screening may not make sense, but these areas are likely to be few and far between. The rest of America will need to quickly get on board with universal screening to protect their labor and delivery staff.”

Testing the partner was a strength of the study. “It is reassuring that when a pregnant woman tested negative for SARS-CoV-2, the rate was very, very low (2.4%) that her partner would test positive. However, it was disconcerting that telephone screening for common symptoms associated with COVID-19 was not very helpful in identifying cases,” said Dr. Waldorf, a professor of obstetrics and gynecology at the University of Washington, Seattle. She was not involved in the study by Bianco et al.

One study author receives payment from the American Board of Obstetrics and Gynecology for serving as a board examiner, receives payment from UpToDate, and serves as an expert witness in malpractice and products liability cases. The other authors did not report any potential conflicts of interest. Dr. Waldorf said she had no relevant financial disclosures.

jremaly@mdedge.com

SOURCE: Bianco A et al. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003985.

Among women with a planned delivery in a New York City health system during the first half of April, the rate of asymptomatic SARS-CoV-2 infection was 16%, according to a study published in Obstetrics & Gynecology. Among the patients’ designated support persons, the asymptomatic carrier rate was 10%.

“If universal testing of pregnant patients in a high prevalence area is not performed, health care workers will be inadvertently exposed to COVID-19, unless universal precautions with personal protective equipment are taken,” wrote the researchers affiliated with the department of obstetrics, gynecology, and reproductive medicine at Icahn School of Medicine at Mount Sinai, New York.

Angela Bianco, MD, and colleagues conducted an observational study of women who were scheduled for a planned delivery within the Mount Sinai Health System between April 4 and April 15, 2020. Patients and their designated support person completed a telephone screen and underwent COVID-19 testing the day before a scheduled delivery. If support persons screened positive during the telephone interview about COVID-19 symptoms, they could not attend the birth, and patients could contact a different support person to be screened and tested. “All patients and their support persons were informed of their SARS-CoV-2 test results before admission,” the investigators wrote. “Those who tested positive were counseled regarding symptomatology that should prompt medical attention.”

In all, researchers screened 158 patients with a planned delivery, and 155 agreed to undergo COVID-19 testing. Of the 155 women tested, 24 (16%) tested positive for SARS CoV-2 infection. Among 146 support persons who had a negative interview screen and underwent SARS-CoV-2 testing, 14 (10%) tested positive for SARS-CoV-2 infection.

Test results were substantially concordant among patient and support person pairs. “Among patients who tested positive for COVID-19 infection and had a support person present, 11 of 19 (58%) support persons also tested positive for COVID-19 infection,” the authors reported. “Among patients who tested negative for COVID-19 infection and had a support person present, only 3 of 127 (2.4%) support persons tested positive for COVID-19 infection.”

Telephone screening did not identify any of the COVID-19–positive cases. Of the 24 patients with SARS-CoV-2 infection, none of their newborns tested positive at birth.

“Universal testing ... provides a mechanism for more accurate counseling of patients regarding issues such as newborn skin-to-skin contact and breastfeeding,” noted Dr. Bianco and colleagues. At their institution, parents with COVID-19 are instructed to wear a mask and practice proper hand hygiene when caring for their newborns.

Kristina Adams Waldorf, MD, said in an interview that the study by Bianco et al. underscores the high rate of asymptomatic or mildly symptomatic COVID-19 infections detected with universal screening in a hospital at the U.S. epicenter of the pandemic. “Each state and hospital will need to evaluate their own data to determine the value of universal screening for their patient population. In rural parts of America that have yet to see cases, universal screening may not make sense, but these areas are likely to be few and far between. The rest of America will need to quickly get on board with universal screening to protect their labor and delivery staff.”

Testing the partner was a strength of the study. “It is reassuring that when a pregnant woman tested negative for SARS-CoV-2, the rate was very, very low (2.4%) that her partner would test positive. However, it was disconcerting that telephone screening for common symptoms associated with COVID-19 was not very helpful in identifying cases,” said Dr. Waldorf, a professor of obstetrics and gynecology at the University of Washington, Seattle. She was not involved in the study by Bianco et al.

One study author receives payment from the American Board of Obstetrics and Gynecology for serving as a board examiner, receives payment from UpToDate, and serves as an expert witness in malpractice and products liability cases. The other authors did not report any potential conflicts of interest. Dr. Waldorf said she had no relevant financial disclosures.

jremaly@mdedge.com

SOURCE: Bianco A et al. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003985.

Among women with a planned delivery in a New York City health system during the first half of April, the rate of asymptomatic SARS-CoV-2 infection was 16%, according to a study published in Obstetrics & Gynecology. Among the patients’ designated support persons, the asymptomatic carrier rate was 10%.

“If universal testing of pregnant patients in a high prevalence area is not performed, health care workers will be inadvertently exposed to COVID-19, unless universal precautions with personal protective equipment are taken,” wrote the researchers affiliated with the department of obstetrics, gynecology, and reproductive medicine at Icahn School of Medicine at Mount Sinai, New York.

Angela Bianco, MD, and colleagues conducted an observational study of women who were scheduled for a planned delivery within the Mount Sinai Health System between April 4 and April 15, 2020. Patients and their designated support person completed a telephone screen and underwent COVID-19 testing the day before a scheduled delivery. If support persons screened positive during the telephone interview about COVID-19 symptoms, they could not attend the birth, and patients could contact a different support person to be screened and tested. “All patients and their support persons were informed of their SARS-CoV-2 test results before admission,” the investigators wrote. “Those who tested positive were counseled regarding symptomatology that should prompt medical attention.”

In all, researchers screened 158 patients with a planned delivery, and 155 agreed to undergo COVID-19 testing. Of the 155 women tested, 24 (16%) tested positive for SARS CoV-2 infection. Among 146 support persons who had a negative interview screen and underwent SARS-CoV-2 testing, 14 (10%) tested positive for SARS-CoV-2 infection.

Test results were substantially concordant among patient and support person pairs. “Among patients who tested positive for COVID-19 infection and had a support person present, 11 of 19 (58%) support persons also tested positive for COVID-19 infection,” the authors reported. “Among patients who tested negative for COVID-19 infection and had a support person present, only 3 of 127 (2.4%) support persons tested positive for COVID-19 infection.”

Telephone screening did not identify any of the COVID-19–positive cases. Of the 24 patients with SARS-CoV-2 infection, none of their newborns tested positive at birth.

“Universal testing ... provides a mechanism for more accurate counseling of patients regarding issues such as newborn skin-to-skin contact and breastfeeding,” noted Dr. Bianco and colleagues. At their institution, parents with COVID-19 are instructed to wear a mask and practice proper hand hygiene when caring for their newborns.

Kristina Adams Waldorf, MD, said in an interview that the study by Bianco et al. underscores the high rate of asymptomatic or mildly symptomatic COVID-19 infections detected with universal screening in a hospital at the U.S. epicenter of the pandemic. “Each state and hospital will need to evaluate their own data to determine the value of universal screening for their patient population. In rural parts of America that have yet to see cases, universal screening may not make sense, but these areas are likely to be few and far between. The rest of America will need to quickly get on board with universal screening to protect their labor and delivery staff.”

Testing the partner was a strength of the study. “It is reassuring that when a pregnant woman tested negative for SARS-CoV-2, the rate was very, very low (2.4%) that her partner would test positive. However, it was disconcerting that telephone screening for common symptoms associated with COVID-19 was not very helpful in identifying cases,” said Dr. Waldorf, a professor of obstetrics and gynecology at the University of Washington, Seattle. She was not involved in the study by Bianco et al.

One study author receives payment from the American Board of Obstetrics and Gynecology for serving as a board examiner, receives payment from UpToDate, and serves as an expert witness in malpractice and products liability cases. The other authors did not report any potential conflicts of interest. Dr. Waldorf said she had no relevant financial disclosures.

jremaly@mdedge.com

SOURCE: Bianco A et al. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003985.

Labor & delivery units may need to consider regional prevalence of COVID-19 when deciding whether to test asymptomatic pregnant women for SARS-CoV-2 infection at the time of admission, research published online in Obstetrics & Gynecology suggests.

In Los Angeles, researchers stopped universal testing after none of the first 80 asymptomatic women had positive results. Researchers in Chicago, on the other hand, found a positive rate of approximately 1.6% among 614 asymptomatic patients and continue to test all patients.

“Decisions regarding universal testing need to be made in the context of regional prevalence of COVID-19 infection, with recognition that a ‘one-size-fits-all’ approach is unlikely to be justifiable,” Torri D. Metz, MD,of University of Utah Health in Salt Lake City said in an editorial accompanying research letters that described the experience in Los Angeles and Chicago. “In the setting of low population prevalence of COVID-19 infection or in locations with limited testing availability, deferring universal testing may represent the better part of valor when weighing risks, benefits, economic burden, and unintended consequences of testing for SARS-CoV-2 infection. In high-prevalence regions, universal testing may be a valuable addition to obstetric care that will prevent infections in health care workers and neonates.”

Testing all patients also may provide valuable population-level surveillance, added Dr. Metz, who is an associate professor of obstetrics and gynecology, a maternal-fetal medicine subspecialist, and vice-chair of research in obstetrics and gynecology.

One week of data

After New York hospitals reported an approximately 13% prevalence of SARS-CoV-2 infection among asymptomatic laboring women, Cedars-Sinai Medical Center in Los Angeles changed its policy from testing only women with COVID-19 symptoms to testing all women beginning April 4, 2020. “Data from New York made us very concerned about the possibility of asymptomatic infections among our own pregnant patients,” Mariam Naqvi, MD, a maternal-fetal medicine specialist at Cedars-Sinai Medical Center, said in a news release. “This would have implications for them, their babies, their households, and for the health of our staff caring for them.”

In 1 week, 82 pregnant women admitted to the obstetric unit were tested for SARS-CoV-2 infection. Of two women who reported COVID-19 symptoms, one tested positive for SARS-CoV-2. “Of the remaining 80 asymptomatic women, none tested positive for SARS-CoV-2 infection, and all remained symptom free throughout their hospitalizations,” Dr. Naqvi and colleagues reported. “One asymptomatic patient had an inadequate nasopharyngeal specimen and declined repeat testing.”

Precautions taken during universal testing meant that all members of the treatment team used valuable personal protective equipment. In some cases, mothers and newborns were separated until test results were available.

“We discontinued universal testing after a 7-day period, because we could not justify continued testing of asymptomatic women in the absence of positive test results for SARS-CoV-2 infection,” they noted. “Though universal testing did not yield enough positive results on our obstetric unit to warrant continued testing at this time, our approach may change if local rates of infection increase.”

20 days of testing

In a prospective case series of pregnant women admitted to Northwestern Memorial Hospital in Chicago from April 8 to April 27, 2020, universal testing did detect asymptomatic infections. Women with scheduled admissions were tested 12-36 hours before admission in a drive-through testing center, and women with unscheduled admissions received a test that has a 2- to 3-hour turnaround time. In addition, patients were screened for symptoms such as fever, shortness of breath, cough, sore throat, body aches, chills, new-onset vomiting, diarrhea, loss of taste or smell, and red or painful eyes.

“Asymptomatic women with pending tests were managed on the routine labor floor, but health care workers used personal protective equipment that included a respirator during the second stage of labor and delivery until the test result became available,” wrote Emily S. Miller, MD, MPH, of Northwestern University, Chicago, and colleagues.

During the first 20 days of universal testing, 635 pregnant women were admitted, and 23 (3.6%) tested positive for SARS-CoV-2 infection. Of 21 women with COVID-19 symptoms, 13 (62%) tested positive for SARS-CoV-2 infection. Of 614 women who were asymptomatic, 10 (1.6%) tested positive for SARS-CoV-2. “Our data corroborate the observation that pregnant women with SARS-CoV-2 infection on admission do not seem to be reliably identified using symptom screening alone,” the researchers wrote.
 

Unintended consequences

Despite a lack of effective treatments for mild to moderate COVID-19, “knowledge of the disease state allows ... health care workers to wear appropriate personal protective equipment to avoid exposure,” Dr. Metz wrote. It also allows “women to be counseled about ways to decrease transmission to neonates” and enables close monitoring of patients with infection.

At the same time, universal testing may have unintended consequences for infected patients, such as stigmatization, separation from the newborn, and delays in care related to health care providers spending more time donning personal protective equipment or changes in medical decision-making regarding cesarean delivery, she emphasized.

“Obstetricians should remain aware of disease prevalence in their communities and consider universal screening of asymptomatic women on an ongoing basis as new ‘hot spots’ for COVID-19 infection are identified,” Dr. Metz concluded.

One of Dr. Naqvi’s coauthors disclosed receiving funds from Contemporary OB/GYN, Keneka, and the American College of Obstetricians and Gynecologists and serving as a board examiner for the American Board of Obstetrics and Gynecology; her coauthors did not report any relevant financial disclosures. Dr. Metz disclosed that money was paid to her institution from Pfizer and GestVision for work related to an RSV vaccination trial and a preeclampsia test, respectively. Dr. Miller and colleagues did not report any potential conflicts of interest.

jremaly@mdedge.com

SOURCES: Naqvi M et al. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003987; Miller ES et al. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003983; Metz TD. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003972.


 

Labor & delivery units may need to consider regional prevalence of COVID-19 when deciding whether to test asymptomatic pregnant women for SARS-CoV-2 infection at the time of admission, research published online in Obstetrics & Gynecology suggests.

In Los Angeles, researchers stopped universal testing after none of the first 80 asymptomatic women had positive results. Researchers in Chicago, on the other hand, found a positive rate of approximately 1.6% among 614 asymptomatic patients and continue to test all patients.

“Decisions regarding universal testing need to be made in the context of regional prevalence of COVID-19 infection, with recognition that a ‘one-size-fits-all’ approach is unlikely to be justifiable,” Torri D. Metz, MD,of University of Utah Health in Salt Lake City said in an editorial accompanying research letters that described the experience in Los Angeles and Chicago. “In the setting of low population prevalence of COVID-19 infection or in locations with limited testing availability, deferring universal testing may represent the better part of valor when weighing risks, benefits, economic burden, and unintended consequences of testing for SARS-CoV-2 infection. In high-prevalence regions, universal testing may be a valuable addition to obstetric care that will prevent infections in health care workers and neonates.”

Testing all patients also may provide valuable population-level surveillance, added Dr. Metz, who is an associate professor of obstetrics and gynecology, a maternal-fetal medicine subspecialist, and vice-chair of research in obstetrics and gynecology.

One week of data

After New York hospitals reported an approximately 13% prevalence of SARS-CoV-2 infection among asymptomatic laboring women, Cedars-Sinai Medical Center in Los Angeles changed its policy from testing only women with COVID-19 symptoms to testing all women beginning April 4, 2020. “Data from New York made us very concerned about the possibility of asymptomatic infections among our own pregnant patients,” Mariam Naqvi, MD, a maternal-fetal medicine specialist at Cedars-Sinai Medical Center, said in a news release. “This would have implications for them, their babies, their households, and for the health of our staff caring for them.”

In 1 week, 82 pregnant women admitted to the obstetric unit were tested for SARS-CoV-2 infection. Of two women who reported COVID-19 symptoms, one tested positive for SARS-CoV-2. “Of the remaining 80 asymptomatic women, none tested positive for SARS-CoV-2 infection, and all remained symptom free throughout their hospitalizations,” Dr. Naqvi and colleagues reported. “One asymptomatic patient had an inadequate nasopharyngeal specimen and declined repeat testing.”

Precautions taken during universal testing meant that all members of the treatment team used valuable personal protective equipment. In some cases, mothers and newborns were separated until test results were available.

“We discontinued universal testing after a 7-day period, because we could not justify continued testing of asymptomatic women in the absence of positive test results for SARS-CoV-2 infection,” they noted. “Though universal testing did not yield enough positive results on our obstetric unit to warrant continued testing at this time, our approach may change if local rates of infection increase.”

20 days of testing

In a prospective case series of pregnant women admitted to Northwestern Memorial Hospital in Chicago from April 8 to April 27, 2020, universal testing did detect asymptomatic infections. Women with scheduled admissions were tested 12-36 hours before admission in a drive-through testing center, and women with unscheduled admissions received a test that has a 2- to 3-hour turnaround time. In addition, patients were screened for symptoms such as fever, shortness of breath, cough, sore throat, body aches, chills, new-onset vomiting, diarrhea, loss of taste or smell, and red or painful eyes.

“Asymptomatic women with pending tests were managed on the routine labor floor, but health care workers used personal protective equipment that included a respirator during the second stage of labor and delivery until the test result became available,” wrote Emily S. Miller, MD, MPH, of Northwestern University, Chicago, and colleagues.

During the first 20 days of universal testing, 635 pregnant women were admitted, and 23 (3.6%) tested positive for SARS-CoV-2 infection. Of 21 women with COVID-19 symptoms, 13 (62%) tested positive for SARS-CoV-2 infection. Of 614 women who were asymptomatic, 10 (1.6%) tested positive for SARS-CoV-2. “Our data corroborate the observation that pregnant women with SARS-CoV-2 infection on admission do not seem to be reliably identified using symptom screening alone,” the researchers wrote.
 

Unintended consequences

Despite a lack of effective treatments for mild to moderate COVID-19, “knowledge of the disease state allows ... health care workers to wear appropriate personal protective equipment to avoid exposure,” Dr. Metz wrote. It also allows “women to be counseled about ways to decrease transmission to neonates” and enables close monitoring of patients with infection.

At the same time, universal testing may have unintended consequences for infected patients, such as stigmatization, separation from the newborn, and delays in care related to health care providers spending more time donning personal protective equipment or changes in medical decision-making regarding cesarean delivery, she emphasized.

“Obstetricians should remain aware of disease prevalence in their communities and consider universal screening of asymptomatic women on an ongoing basis as new ‘hot spots’ for COVID-19 infection are identified,” Dr. Metz concluded.

One of Dr. Naqvi’s coauthors disclosed receiving funds from Contemporary OB/GYN, Keneka, and the American College of Obstetricians and Gynecologists and serving as a board examiner for the American Board of Obstetrics and Gynecology; her coauthors did not report any relevant financial disclosures. Dr. Metz disclosed that money was paid to her institution from Pfizer and GestVision for work related to an RSV vaccination trial and a preeclampsia test, respectively. Dr. Miller and colleagues did not report any potential conflicts of interest.

jremaly@mdedge.com

SOURCES: Naqvi M et al. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003987; Miller ES et al. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003983; Metz TD. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003972.


 

Labor & delivery units may need to consider regional prevalence of COVID-19 when deciding whether to test asymptomatic pregnant women for SARS-CoV-2 infection at the time of admission, research published online in Obstetrics & Gynecology suggests.

In Los Angeles, researchers stopped universal testing after none of the first 80 asymptomatic women had positive results. Researchers in Chicago, on the other hand, found a positive rate of approximately 1.6% among 614 asymptomatic patients and continue to test all patients.

“Decisions regarding universal testing need to be made in the context of regional prevalence of COVID-19 infection, with recognition that a ‘one-size-fits-all’ approach is unlikely to be justifiable,” Torri D. Metz, MD,of University of Utah Health in Salt Lake City said in an editorial accompanying research letters that described the experience in Los Angeles and Chicago. “In the setting of low population prevalence of COVID-19 infection or in locations with limited testing availability, deferring universal testing may represent the better part of valor when weighing risks, benefits, economic burden, and unintended consequences of testing for SARS-CoV-2 infection. In high-prevalence regions, universal testing may be a valuable addition to obstetric care that will prevent infections in health care workers and neonates.”

Testing all patients also may provide valuable population-level surveillance, added Dr. Metz, who is an associate professor of obstetrics and gynecology, a maternal-fetal medicine subspecialist, and vice-chair of research in obstetrics and gynecology.

One week of data

After New York hospitals reported an approximately 13% prevalence of SARS-CoV-2 infection among asymptomatic laboring women, Cedars-Sinai Medical Center in Los Angeles changed its policy from testing only women with COVID-19 symptoms to testing all women beginning April 4, 2020. “Data from New York made us very concerned about the possibility of asymptomatic infections among our own pregnant patients,” Mariam Naqvi, MD, a maternal-fetal medicine specialist at Cedars-Sinai Medical Center, said in a news release. “This would have implications for them, their babies, their households, and for the health of our staff caring for them.”

In 1 week, 82 pregnant women admitted to the obstetric unit were tested for SARS-CoV-2 infection. Of two women who reported COVID-19 symptoms, one tested positive for SARS-CoV-2. “Of the remaining 80 asymptomatic women, none tested positive for SARS-CoV-2 infection, and all remained symptom free throughout their hospitalizations,” Dr. Naqvi and colleagues reported. “One asymptomatic patient had an inadequate nasopharyngeal specimen and declined repeat testing.”

Precautions taken during universal testing meant that all members of the treatment team used valuable personal protective equipment. In some cases, mothers and newborns were separated until test results were available.

“We discontinued universal testing after a 7-day period, because we could not justify continued testing of asymptomatic women in the absence of positive test results for SARS-CoV-2 infection,” they noted. “Though universal testing did not yield enough positive results on our obstetric unit to warrant continued testing at this time, our approach may change if local rates of infection increase.”

20 days of testing

In a prospective case series of pregnant women admitted to Northwestern Memorial Hospital in Chicago from April 8 to April 27, 2020, universal testing did detect asymptomatic infections. Women with scheduled admissions were tested 12-36 hours before admission in a drive-through testing center, and women with unscheduled admissions received a test that has a 2- to 3-hour turnaround time. In addition, patients were screened for symptoms such as fever, shortness of breath, cough, sore throat, body aches, chills, new-onset vomiting, diarrhea, loss of taste or smell, and red or painful eyes.

“Asymptomatic women with pending tests were managed on the routine labor floor, but health care workers used personal protective equipment that included a respirator during the second stage of labor and delivery until the test result became available,” wrote Emily S. Miller, MD, MPH, of Northwestern University, Chicago, and colleagues.

During the first 20 days of universal testing, 635 pregnant women were admitted, and 23 (3.6%) tested positive for SARS-CoV-2 infection. Of 21 women with COVID-19 symptoms, 13 (62%) tested positive for SARS-CoV-2 infection. Of 614 women who were asymptomatic, 10 (1.6%) tested positive for SARS-CoV-2. “Our data corroborate the observation that pregnant women with SARS-CoV-2 infection on admission do not seem to be reliably identified using symptom screening alone,” the researchers wrote.
 

Unintended consequences

Despite a lack of effective treatments for mild to moderate COVID-19, “knowledge of the disease state allows ... health care workers to wear appropriate personal protective equipment to avoid exposure,” Dr. Metz wrote. It also allows “women to be counseled about ways to decrease transmission to neonates” and enables close monitoring of patients with infection.

At the same time, universal testing may have unintended consequences for infected patients, such as stigmatization, separation from the newborn, and delays in care related to health care providers spending more time donning personal protective equipment or changes in medical decision-making regarding cesarean delivery, she emphasized.

“Obstetricians should remain aware of disease prevalence in their communities and consider universal screening of asymptomatic women on an ongoing basis as new ‘hot spots’ for COVID-19 infection are identified,” Dr. Metz concluded.

One of Dr. Naqvi’s coauthors disclosed receiving funds from Contemporary OB/GYN, Keneka, and the American College of Obstetricians and Gynecologists and serving as a board examiner for the American Board of Obstetrics and Gynecology; her coauthors did not report any relevant financial disclosures. Dr. Metz disclosed that money was paid to her institution from Pfizer and GestVision for work related to an RSV vaccination trial and a preeclampsia test, respectively. Dr. Miller and colleagues did not report any potential conflicts of interest.

jremaly@mdedge.com

SOURCES: Naqvi M et al. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003987; Miller ES et al. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003983; Metz TD. Obstet Gynecol. 2020 May 19. doi: 10.1097/AOG.0000000000003972.


 

Unacceptable pain more often remains among patients with early, methotrexate-refractory (RA who move on to triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine than biologic combination therapy with the tumor necrosis factor inhibitor infliximab (Remicade) plus methotrexate, according to findings from 21 months of follow-up in a post hoc analysis of data from the randomized, controlled Swedish Farmacotherapy (SWEFOT) trial.

Although RA patients who took biologic combination therapy had 32% lower risk for unacceptable pain (rated at >40 mm on a 0- to 100-mm visual analog scale) at 21 months, they still had no difference from patients taking triple therapy in the rate of pain described as refractory, or unacceptable despite inflammation control (C-reactive protein <10 mg/L).

While these results lend “some support to a better effect on long-term pain for the biological treatment, compared with triple therapy ... our findings are also in line with insufficient effects of current treatment strategies to prevent development of inflammation-independent pain components, warranting early alternative treatment approaches in affected patients,” Tor Olofsson, MD, PhD, of Lund (Sweden) University, and colleagues wrote in Arthritis Care & Research.

The pain outcomes analyzed in this post hoc study were all secondary outcomes of the original open-label SWEFOT trial, which during 2002-2005 enrolled 258 RA patients with less than a year of symptoms who did not reach low disease activity (28-joint Disease Activity Score ≤3.2) after 3 months of methotrexate and randomized them to an addition of either infliximab (3 mg/kg rounded up to nearest 100-mg increment) or sulfasalazine 1,000 mg twice daily plus hydroxychloroquine 400 mg once daily.

Overall, 90 of 128 patients in the infliximab group and 74 of 130 in the triple-therapy group continued the protocol until the 21-month follow-up. Patients in the infliximab group had a significantly lower area under the curve for visual analog scale for pain, most of which was accounted for during months 9-21. The percentage of patients in the infliximab group with unacceptable pain also dropped significantly from 57% at randomization to 32% at 21 months, while no difference was seen for triple therapy patients, of whom 45% had unacceptable pain at 21 months.

While patients in the infliximab group had a significantly lower risk of unacceptable pain without inflammatory control at 21 months, neither treatment arm showed a within-group difference in refractory pain from randomization to the 21-month follow-up.

Nearly one-third of patients overall still reported unacceptable pain 21 months after addition of either infliximab or sulfasalazine plus hydroxychloroquine. And at that time point, refractory pain constituted 82% of all unacceptable pain. “Notably, this pattern – with a domination of refractory pain – was evident already 3 months after starting combination therapy,” Dr. Olofsson and colleagues wrote.

The original SWEFOT study was supported in part by a grant from the Swedish Rheumatism Association, and in part by an annual unrestricted grant from Schering-Plough Sweden (now Merck Sharp & Dohme). The post hoc analysis was supported by Lund University and the Kockska Foundation, the Swedish Research Council, and the Stockholm County Council. Two authors disclosed financial relationships with multiple pharmaceutical companies.

jevans@mdedge.com

SOURCE: Olofsson T et al. Arthritis Care Res. 2020 May 20. doi: 10.1002/acr.24264.

Unacceptable pain more often remains among patients with early, methotrexate-refractory (RA who move on to triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine than biologic combination therapy with the tumor necrosis factor inhibitor infliximab (Remicade) plus methotrexate, according to findings from 21 months of follow-up in a post hoc analysis of data from the randomized, controlled Swedish Farmacotherapy (SWEFOT) trial.

Although RA patients who took biologic combination therapy had 32% lower risk for unacceptable pain (rated at >40 mm on a 0- to 100-mm visual analog scale) at 21 months, they still had no difference from patients taking triple therapy in the rate of pain described as refractory, or unacceptable despite inflammation control (C-reactive protein <10 mg/L).

While these results lend “some support to a better effect on long-term pain for the biological treatment, compared with triple therapy ... our findings are also in line with insufficient effects of current treatment strategies to prevent development of inflammation-independent pain components, warranting early alternative treatment approaches in affected patients,” Tor Olofsson, MD, PhD, of Lund (Sweden) University, and colleagues wrote in Arthritis Care & Research.

The pain outcomes analyzed in this post hoc study were all secondary outcomes of the original open-label SWEFOT trial, which during 2002-2005 enrolled 258 RA patients with less than a year of symptoms who did not reach low disease activity (28-joint Disease Activity Score ≤3.2) after 3 months of methotrexate and randomized them to an addition of either infliximab (3 mg/kg rounded up to nearest 100-mg increment) or sulfasalazine 1,000 mg twice daily plus hydroxychloroquine 400 mg once daily.

Overall, 90 of 128 patients in the infliximab group and 74 of 130 in the triple-therapy group continued the protocol until the 21-month follow-up. Patients in the infliximab group had a significantly lower area under the curve for visual analog scale for pain, most of which was accounted for during months 9-21. The percentage of patients in the infliximab group with unacceptable pain also dropped significantly from 57% at randomization to 32% at 21 months, while no difference was seen for triple therapy patients, of whom 45% had unacceptable pain at 21 months.

While patients in the infliximab group had a significantly lower risk of unacceptable pain without inflammatory control at 21 months, neither treatment arm showed a within-group difference in refractory pain from randomization to the 21-month follow-up.

Nearly one-third of patients overall still reported unacceptable pain 21 months after addition of either infliximab or sulfasalazine plus hydroxychloroquine. And at that time point, refractory pain constituted 82% of all unacceptable pain. “Notably, this pattern – with a domination of refractory pain – was evident already 3 months after starting combination therapy,” Dr. Olofsson and colleagues wrote.

The original SWEFOT study was supported in part by a grant from the Swedish Rheumatism Association, and in part by an annual unrestricted grant from Schering-Plough Sweden (now Merck Sharp & Dohme). The post hoc analysis was supported by Lund University and the Kockska Foundation, the Swedish Research Council, and the Stockholm County Council. Two authors disclosed financial relationships with multiple pharmaceutical companies.

jevans@mdedge.com

SOURCE: Olofsson T et al. Arthritis Care Res. 2020 May 20. doi: 10.1002/acr.24264.

Unacceptable pain more often remains among patients with early, methotrexate-refractory (RA who move on to triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine than biologic combination therapy with the tumor necrosis factor inhibitor infliximab (Remicade) plus methotrexate, according to findings from 21 months of follow-up in a post hoc analysis of data from the randomized, controlled Swedish Farmacotherapy (SWEFOT) trial.

Although RA patients who took biologic combination therapy had 32% lower risk for unacceptable pain (rated at >40 mm on a 0- to 100-mm visual analog scale) at 21 months, they still had no difference from patients taking triple therapy in the rate of pain described as refractory, or unacceptable despite inflammation control (C-reactive protein <10 mg/L).

While these results lend “some support to a better effect on long-term pain for the biological treatment, compared with triple therapy ... our findings are also in line with insufficient effects of current treatment strategies to prevent development of inflammation-independent pain components, warranting early alternative treatment approaches in affected patients,” Tor Olofsson, MD, PhD, of Lund (Sweden) University, and colleagues wrote in Arthritis Care & Research.

The pain outcomes analyzed in this post hoc study were all secondary outcomes of the original open-label SWEFOT trial, which during 2002-2005 enrolled 258 RA patients with less than a year of symptoms who did not reach low disease activity (28-joint Disease Activity Score ≤3.2) after 3 months of methotrexate and randomized them to an addition of either infliximab (3 mg/kg rounded up to nearest 100-mg increment) or sulfasalazine 1,000 mg twice daily plus hydroxychloroquine 400 mg once daily.

Overall, 90 of 128 patients in the infliximab group and 74 of 130 in the triple-therapy group continued the protocol until the 21-month follow-up. Patients in the infliximab group had a significantly lower area under the curve for visual analog scale for pain, most of which was accounted for during months 9-21. The percentage of patients in the infliximab group with unacceptable pain also dropped significantly from 57% at randomization to 32% at 21 months, while no difference was seen for triple therapy patients, of whom 45% had unacceptable pain at 21 months.

While patients in the infliximab group had a significantly lower risk of unacceptable pain without inflammatory control at 21 months, neither treatment arm showed a within-group difference in refractory pain from randomization to the 21-month follow-up.

Nearly one-third of patients overall still reported unacceptable pain 21 months after addition of either infliximab or sulfasalazine plus hydroxychloroquine. And at that time point, refractory pain constituted 82% of all unacceptable pain. “Notably, this pattern – with a domination of refractory pain – was evident already 3 months after starting combination therapy,” Dr. Olofsson and colleagues wrote.

The original SWEFOT study was supported in part by a grant from the Swedish Rheumatism Association, and in part by an annual unrestricted grant from Schering-Plough Sweden (now Merck Sharp & Dohme). The post hoc analysis was supported by Lund University and the Kockska Foundation, the Swedish Research Council, and the Stockholm County Council. Two authors disclosed financial relationships with multiple pharmaceutical companies.

jevans@mdedge.com

SOURCE: Olofsson T et al. Arthritis Care Res. 2020 May 20. doi: 10.1002/acr.24264.

A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.

The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.

REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.

The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.

“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.

This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.

“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.

“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.

Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).

Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).

The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”

Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.

REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.

“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.

“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.

Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”

Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”

Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.

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

A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.

The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.

REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.

The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.

“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.

This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.

“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.

“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.

Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).

Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).

The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”

Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.

REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.

“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.

“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.

Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”

Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”

Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.

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

A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.

The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.

REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.

The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.

“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.

This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.

“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.

“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.

Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).

Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).

The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”

Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.

REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.

“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.

“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.

Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”

Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”

Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.

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

If one word describes Eladio (“Lad”) Braganza, age 77, it’s “tenacious.” For 28 days, he clung to life on a ventilator in a Seattle ICU. Now – after a 46-day hospitalization for SARS-CoV-2 infection – he’s making progress in inpatient rehab, determined to regain function.

“We were not sure if he was going to make it through his first night in the hospital, and for a while after that. We were really prepared that he would not survive his ventilator time,” his daughter, Maria Braganza, said in an interview just 5 days after her father had been transferred to inpatient rehab.

In many ways, Mr. Braganza’s experience is typical of seriously ill COVID-19 patients. Many go from walking and talking to being on a ventilator within 10 hours or less. Mr. Braganza was admitted to the hospital on March 21 and was intubated that day. To keep him on the ventilator, he was heavily sedated and unconscious at times. In the ICU, he experienced bouts of low blood pressure, a pattern of shock that occurs in COVID-19 patients and that does not always respond to fluids.

Doctors have quickly learned to treat these patients aggressively. Many patients in the ICU with COVID-19 develop an inflamed, atypical form of acute respiratory distress syndrome (ARDS), in which the lung’s compliance, or stiffness, does not match the severity of hypoxia. These patients require high levels of oxygen and high ventilator settings. Many develop pneumothorax, or collapsed lungs, because of the high pressures needed to deliver oxygen and the prolonged time on ventilation.

“The vast majority of COVID patients in the ICU have lung disease that is quite severe, much more severe than I have seen in my 20 years of doing this,” said critical care specialist Anna Nolan, MD, of the department of medicine at New York University.

After about 2 weeks, some of these patients can come off the ventilator, or they may undergo a tracheostomy, a hole in the neck through which a tube is placed to deliver oxygen. By this time, many have developed ICU-acquired weakness and muscle wasting. Some may be so debilitated that they cannot walk. Even the respiratory muscles that help them breathe may have weakened as a result of the ventilator doing the work for them.

These patients “get sick very fast, and it takes a long time for them to heal. What’s not really well appreciated is how much rehab and how much recovery time these patients are going to need,” said David Chong, MD. He is medical director of the ICU at New York–Presbyterian Hospital/Columbia University Medical Center, and he has been on the front lines during the COVID-19 surge in New York City.

The road to recovery

Regardless of the cause, many people who have a prolonged stint in the ICU face an even longer convalescence. Still-unanswered questions concern whether recovery time will be longer for those with COVID-19, compared with other illnesses, and whether some of the damage may be permanent. A number of small studies in Hong Kong and China, as well as studies of severe acute respiratory syndrome patients’ recoveries, have promoted speculation about possible long-lasting damage to lungs and other organs from COVID-19.

Yet some of these reports have left out important details about ARDS in COVID-19 patients who also may be most at risk for long-lasting damage. To clear up some of the confusion, the Pulmonary Fibrosis Foundation said on April 6 that some but not all of COVID-19 patients who develop ARDS may go on to develop lung fibrosis – scarring of the lungs – which may be permanent.

“Post-ARDS fibrosis typically is not progressive, but nonetheless can be severe and limiting. The recovery period for post-ARDS fibrosis is approximately 1 year and the residual deficits persist, but generally do not progress,” the foundation noted.

Emerging research on lung damage in COVID-19

Because the pandemic is only a few months in, it’s unclear as yet what the long-term consequences of severe COVID-19 may be. But emerging data are enabling researchers to venture an educated guess about what may happen in the months and years ahead.

The key to understanding the data is knowing that ARDS is a syndrome – the end product of a variety of diseases or insults to the lung. Under the microscope, lung damage from ARDS associated with COVID-19 is indistinguishable from lung damage resulting from other causes, such as vaping, sepsis, or shock caused by a motor vehicle accident, said Sanjay Mukhopadhyay, MD, director of pulmonary pathology at Cleveland Clinic.

Dr. Mukhopadhyay, who specializes in lung pathology, performed one of the first complete autopsies of a COVID-19 patient in the United States. In most autopsy series published to date, he said, the most common lung finding in patients who have died from COVID-19 is diffuse alveolar damage (DAD), a pattern of lung injury seen in ARDS from many other causes.

In DAD, the walls of the alveoli – thinly lined air sacs that facilitate gas exchange in the lung – develop a pink, hyaline membrane composed of damaged cells and plasma proteins that leak from capillaries in the wall of the alveolus. This hyaline membrane gets plastered against the wall of the alveolus and interferes with diffusion of oxygen into the body.

“We know what happens in ARDS from other causes. If you follow people who have been on a ventilator long term, some of their respiratory function goes back to normal,” Dr. Mukhopadhyay said. “But there are other people in whom some degree of respiratory impairment lingers. In these patients, we think the DAD progresses to an organizing stage.”

Organizing pneumonia refers to a family of diseases in which fibroblasts (cells involved in wound healing) arrive and form scar tissue that forms hyaline membranes and fibrin balls (tough proteins) that fill up the alveoli, making gas exchange very difficult.

Also called BOOP (bronchiolitis obliterans organizing pneumonia), this condition is sensitive to steroids. Early aggressive steroid treatment can prevent long-term lung damage. Without steroids, damage can become permanent. A variant of this condition is termed acute fibrinous and organizing pneumonia (AFOP), which is also sensitive to steroids. A report from France demonstrates AFOP in some patients who have died from COVID-19.

The trick is identifying who is developing BOOP and who is not, and beyond that, who might be most amenable to treatment. Use of steroids for patients with certain other problems, such as a bacterial infection on top of COVID-19, could be harmful. David H. Chong, MD, and colleagues at Columbia University Irving Medical Center, New York, are investigating this to determine which COVID-19 patients may benefit from early steroid therapy.

“It’s not clear if there is a predominant histologic type or if we are catching people at different phases of their disease, and therefore we’re seeing different lung pathology,” Dr. Chong said.

He thinks that many patients with severe COVID-19 probably will not develop this pattern of lung scarring. “We’re speculating that lung damage from severe COVID-19 is probably going to behave more like lung damage from regular ARDS, which is often reversible. We think the vast majority of these patients probably have DAD that is similar to most patients with ARDS from other etiologies,” Dr. Chong said.

That would be consistent with information from China. In an April interview with Chinese domestic media, Zhong Nanshan, MD, a pulmonologist at the head of China’s COVID-19 task force, stated that he expects that the lungs in most patients with COVID-19 will gradually recover. He was responding to a widely publicized small study that found evidence of residual lung abnormalities at hospital discharge in most patients (94%, 66/70) who suffered from COVID-19 pneumonia in Wuhan, China, from January to February 2020.

Tough research conditions

Experts say that follow-up in this Chinese study and others to date has not been nearly long enough to allow predictions about lasting lung damage in COVID-19.

They also highlight the tough conditions in which researchers are working. Few autopsies have been performed so far – autopsies take time, extra precautions must be taken to avoid spread of COVID-19, and many patients and families do not consent to an autopsy. Furthermore, autopsy data from patients who died of COVID-19 may not extrapolate to survivors.

“I would not hang my hat on any of the limited data I have seen on autopsies,” said Lina Miyakawa, MD, a critical care and pulmonary medicine specialist at Mount Sinai Hospital in New York City.

“Even though we have answers about how the lungs are damaged at the end stage, this does not elucidate any answers about the earlier lung damage from this disease,” she continued. “It would be informative to have pathological data from the early or transitional phase, to see if that may translate into a treatment modality for COVID-19 patients.”

The problem is that these patients often experience a large amount of sloughing of airway cells, along with mucous plugging (collections of mucous that can block airflow and collapse alveoli). Bronchoscopy, which is used to view the inside of the lungs and sometimes to retrieve biopsy specimens for microscopic evaluation, is too risky for many COVID-19 patients.

In addition, few CT data exist for severely ill COVID-19 patients, who can be so unstable that to transport them to undergo a CT scan can be dangerous, not to mention the concern regarding infection control.

Even if sufficient data did exist, findings from chest x-rays, CTs, pathology studies, and lung function tests do not always match up. A patient who has lung abnormalities on CT may not necessarily have clinically impaired lung function or abnormal pathologic findings, according to Ali Gholamrezanezhad, MD, an emergency radiologist who is with the department of clinical radiology at the University of Southern California, Los Angeles.

Together with colleagues at USC, Dr. Gholamrezanezhad has started a long-term study of patients who were hospitalized with COVID-19. The researchers will follow patients for at least 1 year and will use chest x-ray, chest CT, and exercise testing to evaluate lung recovery over time.

“In the acute phase, we have acute inflammation called ground glass opacities, which usually happen bilaterally in COVID-19. That is totally reversible damage that can return to normal with no scarring,” Dr. Gholamrezanezhad said.

On the basis of data from survivors of other severe pneumonias, such as Middle East respiratory syndrome, SARS-CoV-1 infection, and H1N1 influenza, Gholamrezanezhad thinks that most survivors of COVID-19 will be able to return to work and normal life, although some may show residual lung dysfunction. Age, underlying medical conditions, smoking, length of hospital stay, severity of illness, and quality of treatment may all play a role in how well these people recover.

The lung has a remarkable capacity to recover, he added. Critical illness can destroy type one pneumocytes — the cells that line the alveoli in the lung — but over time, these cells grow back and reline the lungs. When they do, they can also help repair the lungs.

On top of that, the lung has a large functional reserve, and when one section becomes damaged, the rest of the lung can compensate.

However, for some people, total maximum exercise capacity may be affected, he commented.

Mukhopadhyay said: “My feeling is you will get reversal to normal in some patients and you will get long-term fibrosis from ARDS in some survivors. The question is, how many will have complete resolution and how many will have fibrosis? To know the answer, we will need a lot more data than we have now.”

Convalescence of COVID-19 Patients

Like many who become seriously ill with COVID-19, Braganza had underlying medical problems. Before becoming ill, he had had a heart attack and stroke. He walked with a walker and had some age-related memory problems.

Five days after transfer to inpatient rehab, Braganza was walking up and down the hallway using a walker. He was still shaking off the effects of being heavily sedated for so long, and he experienced periods of confusion. When he first came off the ventilator, he mixed up days and nights. Sometimes he did not remember being so sick. A former software engineer, Braganza usually had no problem using technology, but he has had to relearn how to use his phone and connect his iPad to Wi-Fi.

“He is still struggling quite a bit with remembering how to do basic things,” Maria Braganza said. “He has times of being really depressed because he feels like he’s not making progress.”

Doctors are taking note and starting to think about what lies ahead for ICU survivors of COVID-19. They worry about the potential for disease recurrence as well as readmission for other problems, such as other infections and hip fractures.

“As COVID-19 survivors begin to recover, there will be a large burden of chronic critical illness. We expect a significant need for rehabilitation in most ICU survivors of COVID-19,” said Steve Lubinsky, MD, medical director of respiratory care at New York University Langone Tisch Hospital.

Thinking about her father, Maria Braganza brings an extra dimension to these concerns. She thinks about depression, loneliness, and social isolation among older survivors of COVID-19. These problems existed long before the pandemic, but COVID-19 has magnified them.

The rehab staff estimates that Mr. Braganza will spend 10-14 days in their program, but discharge home creates a conundrum. Before becoming ill, Mr. Braganza lived in an independent senior living facility. Now, because of social distancing, he will no longer be able to hang out and have meals with his friends.

“Dad’s already feeling really lonely in the hospital. If we stay on a semipermanent lockdown, will he be able to see the people he loves?” Maria Braganza said. “Even though somebody is older, they have a lot to give and a lot of experience. They just need a little extra to be able to have that life.”

Dr. Nolan, Dr. Chong, Dr. Mukhopadhyay, Dr. Miyakawa, Dr. Gholamrezanezhad, and Dr. Lubinsky report no relevant financial relationships.

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

If one word describes Eladio (“Lad”) Braganza, age 77, it’s “tenacious.” For 28 days, he clung to life on a ventilator in a Seattle ICU. Now – after a 46-day hospitalization for SARS-CoV-2 infection – he’s making progress in inpatient rehab, determined to regain function.

“We were not sure if he was going to make it through his first night in the hospital, and for a while after that. We were really prepared that he would not survive his ventilator time,” his daughter, Maria Braganza, said in an interview just 5 days after her father had been transferred to inpatient rehab.

In many ways, Mr. Braganza’s experience is typical of seriously ill COVID-19 patients. Many go from walking and talking to being on a ventilator within 10 hours or less. Mr. Braganza was admitted to the hospital on March 21 and was intubated that day. To keep him on the ventilator, he was heavily sedated and unconscious at times. In the ICU, he experienced bouts of low blood pressure, a pattern of shock that occurs in COVID-19 patients and that does not always respond to fluids.

Doctors have quickly learned to treat these patients aggressively. Many patients in the ICU with COVID-19 develop an inflamed, atypical form of acute respiratory distress syndrome (ARDS), in which the lung’s compliance, or stiffness, does not match the severity of hypoxia. These patients require high levels of oxygen and high ventilator settings. Many develop pneumothorax, or collapsed lungs, because of the high pressures needed to deliver oxygen and the prolonged time on ventilation.

“The vast majority of COVID patients in the ICU have lung disease that is quite severe, much more severe than I have seen in my 20 years of doing this,” said critical care specialist Anna Nolan, MD, of the department of medicine at New York University.

After about 2 weeks, some of these patients can come off the ventilator, or they may undergo a tracheostomy, a hole in the neck through which a tube is placed to deliver oxygen. By this time, many have developed ICU-acquired weakness and muscle wasting. Some may be so debilitated that they cannot walk. Even the respiratory muscles that help them breathe may have weakened as a result of the ventilator doing the work for them.

These patients “get sick very fast, and it takes a long time for them to heal. What’s not really well appreciated is how much rehab and how much recovery time these patients are going to need,” said David Chong, MD. He is medical director of the ICU at New York–Presbyterian Hospital/Columbia University Medical Center, and he has been on the front lines during the COVID-19 surge in New York City.

The road to recovery

Regardless of the cause, many people who have a prolonged stint in the ICU face an even longer convalescence. Still-unanswered questions concern whether recovery time will be longer for those with COVID-19, compared with other illnesses, and whether some of the damage may be permanent. A number of small studies in Hong Kong and China, as well as studies of severe acute respiratory syndrome patients’ recoveries, have promoted speculation about possible long-lasting damage to lungs and other organs from COVID-19.

Yet some of these reports have left out important details about ARDS in COVID-19 patients who also may be most at risk for long-lasting damage. To clear up some of the confusion, the Pulmonary Fibrosis Foundation said on April 6 that some but not all of COVID-19 patients who develop ARDS may go on to develop lung fibrosis – scarring of the lungs – which may be permanent.

“Post-ARDS fibrosis typically is not progressive, but nonetheless can be severe and limiting. The recovery period for post-ARDS fibrosis is approximately 1 year and the residual deficits persist, but generally do not progress,” the foundation noted.

Emerging research on lung damage in COVID-19

Because the pandemic is only a few months in, it’s unclear as yet what the long-term consequences of severe COVID-19 may be. But emerging data are enabling researchers to venture an educated guess about what may happen in the months and years ahead.

The key to understanding the data is knowing that ARDS is a syndrome – the end product of a variety of diseases or insults to the lung. Under the microscope, lung damage from ARDS associated with COVID-19 is indistinguishable from lung damage resulting from other causes, such as vaping, sepsis, or shock caused by a motor vehicle accident, said Sanjay Mukhopadhyay, MD, director of pulmonary pathology at Cleveland Clinic.

Dr. Mukhopadhyay, who specializes in lung pathology, performed one of the first complete autopsies of a COVID-19 patient in the United States. In most autopsy series published to date, he said, the most common lung finding in patients who have died from COVID-19 is diffuse alveolar damage (DAD), a pattern of lung injury seen in ARDS from many other causes.

In DAD, the walls of the alveoli – thinly lined air sacs that facilitate gas exchange in the lung – develop a pink, hyaline membrane composed of damaged cells and plasma proteins that leak from capillaries in the wall of the alveolus. This hyaline membrane gets plastered against the wall of the alveolus and interferes with diffusion of oxygen into the body.

“We know what happens in ARDS from other causes. If you follow people who have been on a ventilator long term, some of their respiratory function goes back to normal,” Dr. Mukhopadhyay said. “But there are other people in whom some degree of respiratory impairment lingers. In these patients, we think the DAD progresses to an organizing stage.”

Organizing pneumonia refers to a family of diseases in which fibroblasts (cells involved in wound healing) arrive and form scar tissue that forms hyaline membranes and fibrin balls (tough proteins) that fill up the alveoli, making gas exchange very difficult.

Also called BOOP (bronchiolitis obliterans organizing pneumonia), this condition is sensitive to steroids. Early aggressive steroid treatment can prevent long-term lung damage. Without steroids, damage can become permanent. A variant of this condition is termed acute fibrinous and organizing pneumonia (AFOP), which is also sensitive to steroids. A report from France demonstrates AFOP in some patients who have died from COVID-19.

The trick is identifying who is developing BOOP and who is not, and beyond that, who might be most amenable to treatment. Use of steroids for patients with certain other problems, such as a bacterial infection on top of COVID-19, could be harmful. David H. Chong, MD, and colleagues at Columbia University Irving Medical Center, New York, are investigating this to determine which COVID-19 patients may benefit from early steroid therapy.

“It’s not clear if there is a predominant histologic type or if we are catching people at different phases of their disease, and therefore we’re seeing different lung pathology,” Dr. Chong said.

He thinks that many patients with severe COVID-19 probably will not develop this pattern of lung scarring. “We’re speculating that lung damage from severe COVID-19 is probably going to behave more like lung damage from regular ARDS, which is often reversible. We think the vast majority of these patients probably have DAD that is similar to most patients with ARDS from other etiologies,” Dr. Chong said.

That would be consistent with information from China. In an April interview with Chinese domestic media, Zhong Nanshan, MD, a pulmonologist at the head of China’s COVID-19 task force, stated that he expects that the lungs in most patients with COVID-19 will gradually recover. He was responding to a widely publicized small study that found evidence of residual lung abnormalities at hospital discharge in most patients (94%, 66/70) who suffered from COVID-19 pneumonia in Wuhan, China, from January to February 2020.

Tough research conditions

Experts say that follow-up in this Chinese study and others to date has not been nearly long enough to allow predictions about lasting lung damage in COVID-19.

They also highlight the tough conditions in which researchers are working. Few autopsies have been performed so far – autopsies take time, extra precautions must be taken to avoid spread of COVID-19, and many patients and families do not consent to an autopsy. Furthermore, autopsy data from patients who died of COVID-19 may not extrapolate to survivors.

“I would not hang my hat on any of the limited data I have seen on autopsies,” said Lina Miyakawa, MD, a critical care and pulmonary medicine specialist at Mount Sinai Hospital in New York City.

“Even though we have answers about how the lungs are damaged at the end stage, this does not elucidate any answers about the earlier lung damage from this disease,” she continued. “It would be informative to have pathological data from the early or transitional phase, to see if that may translate into a treatment modality for COVID-19 patients.”

The problem is that these patients often experience a large amount of sloughing of airway cells, along with mucous plugging (collections of mucous that can block airflow and collapse alveoli). Bronchoscopy, which is used to view the inside of the lungs and sometimes to retrieve biopsy specimens for microscopic evaluation, is too risky for many COVID-19 patients.

In addition, few CT data exist for severely ill COVID-19 patients, who can be so unstable that to transport them to undergo a CT scan can be dangerous, not to mention the concern regarding infection control.

Even if sufficient data did exist, findings from chest x-rays, CTs, pathology studies, and lung function tests do not always match up. A patient who has lung abnormalities on CT may not necessarily have clinically impaired lung function or abnormal pathologic findings, according to Ali Gholamrezanezhad, MD, an emergency radiologist who is with the department of clinical radiology at the University of Southern California, Los Angeles.

Together with colleagues at USC, Dr. Gholamrezanezhad has started a long-term study of patients who were hospitalized with COVID-19. The researchers will follow patients for at least 1 year and will use chest x-ray, chest CT, and exercise testing to evaluate lung recovery over time.

“In the acute phase, we have acute inflammation called ground glass opacities, which usually happen bilaterally in COVID-19. That is totally reversible damage that can return to normal with no scarring,” Dr. Gholamrezanezhad said.

On the basis of data from survivors of other severe pneumonias, such as Middle East respiratory syndrome, SARS-CoV-1 infection, and H1N1 influenza, Gholamrezanezhad thinks that most survivors of COVID-19 will be able to return to work and normal life, although some may show residual lung dysfunction. Age, underlying medical conditions, smoking, length of hospital stay, severity of illness, and quality of treatment may all play a role in how well these people recover.

The lung has a remarkable capacity to recover, he added. Critical illness can destroy type one pneumocytes — the cells that line the alveoli in the lung — but over time, these cells grow back and reline the lungs. When they do, they can also help repair the lungs.

On top of that, the lung has a large functional reserve, and when one section becomes damaged, the rest of the lung can compensate.

However, for some people, total maximum exercise capacity may be affected, he commented.

Mukhopadhyay said: “My feeling is you will get reversal to normal in some patients and you will get long-term fibrosis from ARDS in some survivors. The question is, how many will have complete resolution and how many will have fibrosis? To know the answer, we will need a lot more data than we have now.”

Convalescence of COVID-19 Patients

Like many who become seriously ill with COVID-19, Braganza had underlying medical problems. Before becoming ill, he had had a heart attack and stroke. He walked with a walker and had some age-related memory problems.

Five days after transfer to inpatient rehab, Braganza was walking up and down the hallway using a walker. He was still shaking off the effects of being heavily sedated for so long, and he experienced periods of confusion. When he first came off the ventilator, he mixed up days and nights. Sometimes he did not remember being so sick. A former software engineer, Braganza usually had no problem using technology, but he has had to relearn how to use his phone and connect his iPad to Wi-Fi.

“He is still struggling quite a bit with remembering how to do basic things,” Maria Braganza said. “He has times of being really depressed because he feels like he’s not making progress.”

Doctors are taking note and starting to think about what lies ahead for ICU survivors of COVID-19. They worry about the potential for disease recurrence as well as readmission for other problems, such as other infections and hip fractures.

“As COVID-19 survivors begin to recover, there will be a large burden of chronic critical illness. We expect a significant need for rehabilitation in most ICU survivors of COVID-19,” said Steve Lubinsky, MD, medical director of respiratory care at New York University Langone Tisch Hospital.

Thinking about her father, Maria Braganza brings an extra dimension to these concerns. She thinks about depression, loneliness, and social isolation among older survivors of COVID-19. These problems existed long before the pandemic, but COVID-19 has magnified them.

The rehab staff estimates that Mr. Braganza will spend 10-14 days in their program, but discharge home creates a conundrum. Before becoming ill, Mr. Braganza lived in an independent senior living facility. Now, because of social distancing, he will no longer be able to hang out and have meals with his friends.

“Dad’s already feeling really lonely in the hospital. If we stay on a semipermanent lockdown, will he be able to see the people he loves?” Maria Braganza said. “Even though somebody is older, they have a lot to give and a lot of experience. They just need a little extra to be able to have that life.”

Dr. Nolan, Dr. Chong, Dr. Mukhopadhyay, Dr. Miyakawa, Dr. Gholamrezanezhad, and Dr. Lubinsky report no relevant financial relationships.

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

If one word describes Eladio (“Lad”) Braganza, age 77, it’s “tenacious.” For 28 days, he clung to life on a ventilator in a Seattle ICU. Now – after a 46-day hospitalization for SARS-CoV-2 infection – he’s making progress in inpatient rehab, determined to regain function.

“We were not sure if he was going to make it through his first night in the hospital, and for a while after that. We were really prepared that he would not survive his ventilator time,” his daughter, Maria Braganza, said in an interview just 5 days after her father had been transferred to inpatient rehab.

In many ways, Mr. Braganza’s experience is typical of seriously ill COVID-19 patients. Many go from walking and talking to being on a ventilator within 10 hours or less. Mr. Braganza was admitted to the hospital on March 21 and was intubated that day. To keep him on the ventilator, he was heavily sedated and unconscious at times. In the ICU, he experienced bouts of low blood pressure, a pattern of shock that occurs in COVID-19 patients and that does not always respond to fluids.

Doctors have quickly learned to treat these patients aggressively. Many patients in the ICU with COVID-19 develop an inflamed, atypical form of acute respiratory distress syndrome (ARDS), in which the lung’s compliance, or stiffness, does not match the severity of hypoxia. These patients require high levels of oxygen and high ventilator settings. Many develop pneumothorax, or collapsed lungs, because of the high pressures needed to deliver oxygen and the prolonged time on ventilation.

“The vast majority of COVID patients in the ICU have lung disease that is quite severe, much more severe than I have seen in my 20 years of doing this,” said critical care specialist Anna Nolan, MD, of the department of medicine at New York University.

After about 2 weeks, some of these patients can come off the ventilator, or they may undergo a tracheostomy, a hole in the neck through which a tube is placed to deliver oxygen. By this time, many have developed ICU-acquired weakness and muscle wasting. Some may be so debilitated that they cannot walk. Even the respiratory muscles that help them breathe may have weakened as a result of the ventilator doing the work for them.

These patients “get sick very fast, and it takes a long time for them to heal. What’s not really well appreciated is how much rehab and how much recovery time these patients are going to need,” said David Chong, MD. He is medical director of the ICU at New York–Presbyterian Hospital/Columbia University Medical Center, and he has been on the front lines during the COVID-19 surge in New York City.

The road to recovery

Regardless of the cause, many people who have a prolonged stint in the ICU face an even longer convalescence. Still-unanswered questions concern whether recovery time will be longer for those with COVID-19, compared with other illnesses, and whether some of the damage may be permanent. A number of small studies in Hong Kong and China, as well as studies of severe acute respiratory syndrome patients’ recoveries, have promoted speculation about possible long-lasting damage to lungs and other organs from COVID-19.

Yet some of these reports have left out important details about ARDS in COVID-19 patients who also may be most at risk for long-lasting damage. To clear up some of the confusion, the Pulmonary Fibrosis Foundation said on April 6 that some but not all of COVID-19 patients who develop ARDS may go on to develop lung fibrosis – scarring of the lungs – which may be permanent.

“Post-ARDS fibrosis typically is not progressive, but nonetheless can be severe and limiting. The recovery period for post-ARDS fibrosis is approximately 1 year and the residual deficits persist, but generally do not progress,” the foundation noted.

Emerging research on lung damage in COVID-19

Because the pandemic is only a few months in, it’s unclear as yet what the long-term consequences of severe COVID-19 may be. But emerging data are enabling researchers to venture an educated guess about what may happen in the months and years ahead.

The key to understanding the data is knowing that ARDS is a syndrome – the end product of a variety of diseases or insults to the lung. Under the microscope, lung damage from ARDS associated with COVID-19 is indistinguishable from lung damage resulting from other causes, such as vaping, sepsis, or shock caused by a motor vehicle accident, said Sanjay Mukhopadhyay, MD, director of pulmonary pathology at Cleveland Clinic.

Dr. Mukhopadhyay, who specializes in lung pathology, performed one of the first complete autopsies of a COVID-19 patient in the United States. In most autopsy series published to date, he said, the most common lung finding in patients who have died from COVID-19 is diffuse alveolar damage (DAD), a pattern of lung injury seen in ARDS from many other causes.

In DAD, the walls of the alveoli – thinly lined air sacs that facilitate gas exchange in the lung – develop a pink, hyaline membrane composed of damaged cells and plasma proteins that leak from capillaries in the wall of the alveolus. This hyaline membrane gets plastered against the wall of the alveolus and interferes with diffusion of oxygen into the body.

“We know what happens in ARDS from other causes. If you follow people who have been on a ventilator long term, some of their respiratory function goes back to normal,” Dr. Mukhopadhyay said. “But there are other people in whom some degree of respiratory impairment lingers. In these patients, we think the DAD progresses to an organizing stage.”

Organizing pneumonia refers to a family of diseases in which fibroblasts (cells involved in wound healing) arrive and form scar tissue that forms hyaline membranes and fibrin balls (tough proteins) that fill up the alveoli, making gas exchange very difficult.

Also called BOOP (bronchiolitis obliterans organizing pneumonia), this condition is sensitive to steroids. Early aggressive steroid treatment can prevent long-term lung damage. Without steroids, damage can become permanent. A variant of this condition is termed acute fibrinous and organizing pneumonia (AFOP), which is also sensitive to steroids. A report from France demonstrates AFOP in some patients who have died from COVID-19.

The trick is identifying who is developing BOOP and who is not, and beyond that, who might be most amenable to treatment. Use of steroids for patients with certain other problems, such as a bacterial infection on top of COVID-19, could be harmful. David H. Chong, MD, and colleagues at Columbia University Irving Medical Center, New York, are investigating this to determine which COVID-19 patients may benefit from early steroid therapy.

“It’s not clear if there is a predominant histologic type or if we are catching people at different phases of their disease, and therefore we’re seeing different lung pathology,” Dr. Chong said.

He thinks that many patients with severe COVID-19 probably will not develop this pattern of lung scarring. “We’re speculating that lung damage from severe COVID-19 is probably going to behave more like lung damage from regular ARDS, which is often reversible. We think the vast majority of these patients probably have DAD that is similar to most patients with ARDS from other etiologies,” Dr. Chong said.

That would be consistent with information from China. In an April interview with Chinese domestic media, Zhong Nanshan, MD, a pulmonologist at the head of China’s COVID-19 task force, stated that he expects that the lungs in most patients with COVID-19 will gradually recover. He was responding to a widely publicized small study that found evidence of residual lung abnormalities at hospital discharge in most patients (94%, 66/70) who suffered from COVID-19 pneumonia in Wuhan, China, from January to February 2020.

Tough research conditions

Experts say that follow-up in this Chinese study and others to date has not been nearly long enough to allow predictions about lasting lung damage in COVID-19.

They also highlight the tough conditions in which researchers are working. Few autopsies have been performed so far – autopsies take time, extra precautions must be taken to avoid spread of COVID-19, and many patients and families do not consent to an autopsy. Furthermore, autopsy data from patients who died of COVID-19 may not extrapolate to survivors.

“I would not hang my hat on any of the limited data I have seen on autopsies,” said Lina Miyakawa, MD, a critical care and pulmonary medicine specialist at Mount Sinai Hospital in New York City.

“Even though we have answers about how the lungs are damaged at the end stage, this does not elucidate any answers about the earlier lung damage from this disease,” she continued. “It would be informative to have pathological data from the early or transitional phase, to see if that may translate into a treatment modality for COVID-19 patients.”

The problem is that these patients often experience a large amount of sloughing of airway cells, along with mucous plugging (collections of mucous that can block airflow and collapse alveoli). Bronchoscopy, which is used to view the inside of the lungs and sometimes to retrieve biopsy specimens for microscopic evaluation, is too risky for many COVID-19 patients.

In addition, few CT data exist for severely ill COVID-19 patients, who can be so unstable that to transport them to undergo a CT scan can be dangerous, not to mention the concern regarding infection control.

Even if sufficient data did exist, findings from chest x-rays, CTs, pathology studies, and lung function tests do not always match up. A patient who has lung abnormalities on CT may not necessarily have clinically impaired lung function or abnormal pathologic findings, according to Ali Gholamrezanezhad, MD, an emergency radiologist who is with the department of clinical radiology at the University of Southern California, Los Angeles.

Together with colleagues at USC, Dr. Gholamrezanezhad has started a long-term study of patients who were hospitalized with COVID-19. The researchers will follow patients for at least 1 year and will use chest x-ray, chest CT, and exercise testing to evaluate lung recovery over time.

“In the acute phase, we have acute inflammation called ground glass opacities, which usually happen bilaterally in COVID-19. That is totally reversible damage that can return to normal with no scarring,” Dr. Gholamrezanezhad said.

On the basis of data from survivors of other severe pneumonias, such as Middle East respiratory syndrome, SARS-CoV-1 infection, and H1N1 influenza, Gholamrezanezhad thinks that most survivors of COVID-19 will be able to return to work and normal life, although some may show residual lung dysfunction. Age, underlying medical conditions, smoking, length of hospital stay, severity of illness, and quality of treatment may all play a role in how well these people recover.

The lung has a remarkable capacity to recover, he added. Critical illness can destroy type one pneumocytes — the cells that line the alveoli in the lung — but over time, these cells grow back and reline the lungs. When they do, they can also help repair the lungs.

On top of that, the lung has a large functional reserve, and when one section becomes damaged, the rest of the lung can compensate.

However, for some people, total maximum exercise capacity may be affected, he commented.

Mukhopadhyay said: “My feeling is you will get reversal to normal in some patients and you will get long-term fibrosis from ARDS in some survivors. The question is, how many will have complete resolution and how many will have fibrosis? To know the answer, we will need a lot more data than we have now.”

Convalescence of COVID-19 Patients

Like many who become seriously ill with COVID-19, Braganza had underlying medical problems. Before becoming ill, he had had a heart attack and stroke. He walked with a walker and had some age-related memory problems.

Five days after transfer to inpatient rehab, Braganza was walking up and down the hallway using a walker. He was still shaking off the effects of being heavily sedated for so long, and he experienced periods of confusion. When he first came off the ventilator, he mixed up days and nights. Sometimes he did not remember being so sick. A former software engineer, Braganza usually had no problem using technology, but he has had to relearn how to use his phone and connect his iPad to Wi-Fi.

“He is still struggling quite a bit with remembering how to do basic things,” Maria Braganza said. “He has times of being really depressed because he feels like he’s not making progress.”

Doctors are taking note and starting to think about what lies ahead for ICU survivors of COVID-19. They worry about the potential for disease recurrence as well as readmission for other problems, such as other infections and hip fractures.

“As COVID-19 survivors begin to recover, there will be a large burden of chronic critical illness. We expect a significant need for rehabilitation in most ICU survivors of COVID-19,” said Steve Lubinsky, MD, medical director of respiratory care at New York University Langone Tisch Hospital.

Thinking about her father, Maria Braganza brings an extra dimension to these concerns. She thinks about depression, loneliness, and social isolation among older survivors of COVID-19. These problems existed long before the pandemic, but COVID-19 has magnified them.

The rehab staff estimates that Mr. Braganza will spend 10-14 days in their program, but discharge home creates a conundrum. Before becoming ill, Mr. Braganza lived in an independent senior living facility. Now, because of social distancing, he will no longer be able to hang out and have meals with his friends.

“Dad’s already feeling really lonely in the hospital. If we stay on a semipermanent lockdown, will he be able to see the people he loves?” Maria Braganza said. “Even though somebody is older, they have a lot to give and a lot of experience. They just need a little extra to be able to have that life.”

Dr. Nolan, Dr. Chong, Dr. Mukhopadhyay, Dr. Miyakawa, Dr. Gholamrezanezhad, and Dr. Lubinsky report no relevant financial relationships.

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

The American Diabetes Association has dedicated a whole section of its journal, Diabetes Care, to the topic of “Diabetes and COVID-19,” publishing a range of articles with new data to help guide physicians in caring for patients.

“Certain groups are more vulnerable to COVID-19, notably older people and those with underlying medical conditions. Because diabetes is one of the conditions associated with high risk, the diabetes community urgently needs to know more about COVID-19 and its effects on people with diabetes,” an introductory commentary noted.

Entitled “COVID-19 in people with diabetes: Urgently needed lessons from early reports,” the commentary is penned by the journal’s editor-in-chief, Matthew Riddle, MD, of Oregon Health & Science University, Portland, and colleagues.

Also writing in the same issue, William T. Cefalu, MD, and colleagues from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) noted it is known that the SARS-CoV-2 virus enters cells via the angiotensin-converting enzyme 2 (ACE-2) receptor. The ACE-2 receptor is known to be in the lungs and upper respiratory tract, “but we also know that it is expressed in other tissues such as heart, small and large intestines, and pancreas,” they wrote, and also “in the kidney.”

Hence, there are emerging reports of acute kidney injury resulting from COVID-19, as well as the impact on many other endocrine/metabolic and gastrointestinal outcomes.

“Pilot clinical studies (observational and interventional) are needed that will support the understanding or treatment of COVID-19–related diseases within the mission of the NIDDK,” they stated.
 

Although rapidly collected, data “offer important clues”

Some of the new ground covered in the journal articles includes an analysis of COVID-19 outcomes by type of glucose-lowering medication; remote glucose monitoring in hospitalized patients with COVID-19; a suggested approach to cardiovascular risk management in the COVID-19 era, as already reported by Medscape Medical News; and the diagnosis and management of gestational diabetes during the pandemic.

Other articles provide new data for previously reported phenomena, including obesity as a risk factor for worse COVID-19 outcomes and the role of inpatient glycemic control on COVID-19 outcomes.

“The data reported in these articles were rapidly collected and analyzed, in most cases under urgent and stressful conditions,” Dr. Riddle and colleagues cautioned. “Thus, some of the analyses are understandably limited due to missing data, incomplete follow-up, and inability to identify infected but asymptomatic patients.”

Even so, they wrote, some points are clear. “The consistency of findings in these rapidly published reports is reassuring in terms of scientific validity, but the story unfolding is worrisome.”

Specifically, while diabetes does not appear to increase the likelihood of SARS-CoV-2 infection, progression to severe illness is more likely in people with diabetes and COVID-19: They are two to three times as likely to require intensive care, and to die, compared with those infected but without diabetes.

“Neither the mechanisms underlying the increased risk nor the best interventions to limit it have yet been defined, but the studies in this collection of articles offer important clues,” Dr. Riddle and colleagues wrote.
 

Existing insulin use linked to COVID-19 death risk

One of the articles is a retrospective study of 904 hospitalized COVID-19 patients by Yuchen Chen, MD, of the Huazhong University of Science and Technology, Wuhan, China, and colleagues.

Among the 136 patients with diabetes, risk factors for mortality included older age (adjusted odds ratio, 1.09 per year increase; P = .001) elevated C-reactive protein (aOR, 1.12; P = .043), and insulin use (aOR, 3.58; P = .009).

“Attention needs to be paid to patients with diabetes and COVID-19 who use insulin,” the Chinese authors wrote. “Whether this was due to effects of insulin itself or to characteristics of the patients for whom it was prescribed is not clear,” Dr. Riddle and colleagues noted.

Dr. Chen and colleagues also found no difference in clinical outcomes between those diabetes patients with COVID-19 who were taking an ACE inhibitor or angiotensin II type I receptor blocker, compared with those who did not, which supports existing recommendations to continue use of this type of medication.
 

Remote glucose monitoring a novel tool for COVID-19 isolation

Another publication, by Gilat Shehav-Zaltzman of Sheba Medical Center, Tel Hashomer, Israel, and colleagues, describes the use of remote continuous glucose monitoring (CGM) in two hospitalized COVID-19 patients who were in isolation – one with type 1 diabetes and the other with type 2 diabetes – treated with basal-bolus insulin.

Using Medtronic CGM systems, the hospital staff was able to view patients’ real-time data uploaded to the Web from computer terminals in virus-free areas outside the patients’ rooms. The hospital’s endocrinology team had trained the intensive care staff on how to replace the sensors weekly and calibrate them twice daily.

“Converting a personal CGM system originally designed for diabetes self-management to team-based, real-time remote glucose monitoring offers a novel tool for inpatient diabetes control in COVID-19 isolation facilities,” the authors wrote.

“Such a solution in addition to ongoing remotely monitored clinical parameters (such as pulse rate, electrocardiogram, and oxygen saturation) adds to quality of diabetes care while minimizing risk of staff exposure and burden,” they observed.

Dr. Riddle and colleagues concurred: “Newer methods of remotely monitoring glucose patterns could be uniquely helpful.”

Key question: Does glycemic management make a difference?

With regard to the important issue of in-hospital control of glucose, Celestino Sardu, MD, PhD, of the University of Campania Luigi Vanvitelli, Naples, Italy, and colleagues reported on 59 patients hospitalized with confirmed COVID-19 and moderately severe pneumonia.

They were categorized as normoglycemic (n = 34) or hyperglycemic (n = 25), as well as with or without diabetes, on the basis of a diagnosis preceding the current illness. Of the 25 patients with hyperglycemia, 15 patients were treated with insulin infusion and 10 patients were not.

In a risk-adjusted analysis, both patients with hyperglycemia and patients with diabetes had a higher risk of severe disease than did those without diabetes and with normoglycemia. Patients with hyperglycemia treated with insulin infusion had a lower risk of severe disease than did patients who didn’t receive an insulin infusion.

And although they noted limitations, the authors wrote, “Our data evidenced that optimal glucose control in the immediate postadmission period for almost 18 days was associated with a significant reduction of inflammatory cytokines and procoagulative status.”

Dr. Riddle and colleagues wrote that the findings of this unrandomized comparison were interpreted “as suggesting that insulin infusion may improve outcomes.”

“If the benefits of seeking excellent glycemic control by this means are confirmed, close monitoring of glucose levels will be essential.”
 

More on obesity and COVID-19, this time from China

Because it has become increasingly clear that obesity is a risk factor for severe COVID-19, new data from China – where this was less apparent initially – support observations in Europe and the United States.

An article by Qingxian Cai, PhD, of Southern University of Science and Technology, Shenzhen, Guangdong, China, and colleagues looks at this. They found that, among 383 hospitalized patients with COVID-19, the 41 patients with obesity (defined as a body mass index ≥ 28 kg/m²) were significantly more likely to progress to severe disease compared with the 203 patients classified as having normal weight (BMI, 18.5-23.9), with an odds ratio of 3.4.

A similar finding comes from Feng Gao, MD, PhD, of the First Affiliated Hospital of Wenzhou (China) Medical University and colleagues, who studied 75 patients hospitalized with confirmed COVID-19 and obesity (defined as a BMI > 25 in this Asian population) to 75 patients without obesity matched by age and sex. After adjustment for clinical characteristics including the presence of diabetes, those with obesity had a threefold greater risk of progression to severe or critical COVID-19 status, with a nearly linear relationship.
 

Emerging from the crisis: Protect the vulnerable, increase knowledge base

As the research community emerges from the crisis, “there should be renewed efforts for multidisciplinary research ... aimed at greatly increasing the knowledge base to understand how ... the current COVID-19 threat” affects “both healthy people and people with chronic diseases and conditions,” Dr. Cefalu and colleagues concluded in their commentary.

Dr. Riddle and coauthors agreed: “We will enter a longer interval in which we must continue to support the most vulnerable populations – especially older people, those with diabetes or obesity, and those who lack the resources to limit day-to-day exposure to infection. We hope a growing sense of community will help in this task.”

Dr. Riddle has reported receiving research grant support through Oregon Health & Science University from AstraZeneca, Eli Lilly, and Novo Nordisk, and honoraria for consulting from Adocia, AstraZeneca, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Sanofi, and Theracos. Dr. Cefalu has reported no relevant financial relationships.

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

The American Diabetes Association has dedicated a whole section of its journal, Diabetes Care, to the topic of “Diabetes and COVID-19,” publishing a range of articles with new data to help guide physicians in caring for patients.

“Certain groups are more vulnerable to COVID-19, notably older people and those with underlying medical conditions. Because diabetes is one of the conditions associated with high risk, the diabetes community urgently needs to know more about COVID-19 and its effects on people with diabetes,” an introductory commentary noted.

Entitled “COVID-19 in people with diabetes: Urgently needed lessons from early reports,” the commentary is penned by the journal’s editor-in-chief, Matthew Riddle, MD, of Oregon Health & Science University, Portland, and colleagues.

Also writing in the same issue, William T. Cefalu, MD, and colleagues from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) noted it is known that the SARS-CoV-2 virus enters cells via the angiotensin-converting enzyme 2 (ACE-2) receptor. The ACE-2 receptor is known to be in the lungs and upper respiratory tract, “but we also know that it is expressed in other tissues such as heart, small and large intestines, and pancreas,” they wrote, and also “in the kidney.”

Hence, there are emerging reports of acute kidney injury resulting from COVID-19, as well as the impact on many other endocrine/metabolic and gastrointestinal outcomes.

“Pilot clinical studies (observational and interventional) are needed that will support the understanding or treatment of COVID-19–related diseases within the mission of the NIDDK,” they stated.
 

Although rapidly collected, data “offer important clues”

Some of the new ground covered in the journal articles includes an analysis of COVID-19 outcomes by type of glucose-lowering medication; remote glucose monitoring in hospitalized patients with COVID-19; a suggested approach to cardiovascular risk management in the COVID-19 era, as already reported by Medscape Medical News; and the diagnosis and management of gestational diabetes during the pandemic.

Other articles provide new data for previously reported phenomena, including obesity as a risk factor for worse COVID-19 outcomes and the role of inpatient glycemic control on COVID-19 outcomes.

“The data reported in these articles were rapidly collected and analyzed, in most cases under urgent and stressful conditions,” Dr. Riddle and colleagues cautioned. “Thus, some of the analyses are understandably limited due to missing data, incomplete follow-up, and inability to identify infected but asymptomatic patients.”

Even so, they wrote, some points are clear. “The consistency of findings in these rapidly published reports is reassuring in terms of scientific validity, but the story unfolding is worrisome.”

Specifically, while diabetes does not appear to increase the likelihood of SARS-CoV-2 infection, progression to severe illness is more likely in people with diabetes and COVID-19: They are two to three times as likely to require intensive care, and to die, compared with those infected but without diabetes.

“Neither the mechanisms underlying the increased risk nor the best interventions to limit it have yet been defined, but the studies in this collection of articles offer important clues,” Dr. Riddle and colleagues wrote.
 

Existing insulin use linked to COVID-19 death risk

One of the articles is a retrospective study of 904 hospitalized COVID-19 patients by Yuchen Chen, MD, of the Huazhong University of Science and Technology, Wuhan, China, and colleagues.

Among the 136 patients with diabetes, risk factors for mortality included older age (adjusted odds ratio, 1.09 per year increase; P = .001) elevated C-reactive protein (aOR, 1.12; P = .043), and insulin use (aOR, 3.58; P = .009).

“Attention needs to be paid to patients with diabetes and COVID-19 who use insulin,” the Chinese authors wrote. “Whether this was due to effects of insulin itself or to characteristics of the patients for whom it was prescribed is not clear,” Dr. Riddle and colleagues noted.

Dr. Chen and colleagues also found no difference in clinical outcomes between those diabetes patients with COVID-19 who were taking an ACE inhibitor or angiotensin II type I receptor blocker, compared with those who did not, which supports existing recommendations to continue use of this type of medication.
 

Remote glucose monitoring a novel tool for COVID-19 isolation

Another publication, by Gilat Shehav-Zaltzman of Sheba Medical Center, Tel Hashomer, Israel, and colleagues, describes the use of remote continuous glucose monitoring (CGM) in two hospitalized COVID-19 patients who were in isolation – one with type 1 diabetes and the other with type 2 diabetes – treated with basal-bolus insulin.

Using Medtronic CGM systems, the hospital staff was able to view patients’ real-time data uploaded to the Web from computer terminals in virus-free areas outside the patients’ rooms. The hospital’s endocrinology team had trained the intensive care staff on how to replace the sensors weekly and calibrate them twice daily.

“Converting a personal CGM system originally designed for diabetes self-management to team-based, real-time remote glucose monitoring offers a novel tool for inpatient diabetes control in COVID-19 isolation facilities,” the authors wrote.

“Such a solution in addition to ongoing remotely monitored clinical parameters (such as pulse rate, electrocardiogram, and oxygen saturation) adds to quality of diabetes care while minimizing risk of staff exposure and burden,” they observed.

Dr. Riddle and colleagues concurred: “Newer methods of remotely monitoring glucose patterns could be uniquely helpful.”

Key question: Does glycemic management make a difference?

With regard to the important issue of in-hospital control of glucose, Celestino Sardu, MD, PhD, of the University of Campania Luigi Vanvitelli, Naples, Italy, and colleagues reported on 59 patients hospitalized with confirmed COVID-19 and moderately severe pneumonia.

They were categorized as normoglycemic (n = 34) or hyperglycemic (n = 25), as well as with or without diabetes, on the basis of a diagnosis preceding the current illness. Of the 25 patients with hyperglycemia, 15 patients were treated with insulin infusion and 10 patients were not.

In a risk-adjusted analysis, both patients with hyperglycemia and patients with diabetes had a higher risk of severe disease than did those without diabetes and with normoglycemia. Patients with hyperglycemia treated with insulin infusion had a lower risk of severe disease than did patients who didn’t receive an insulin infusion.

And although they noted limitations, the authors wrote, “Our data evidenced that optimal glucose control in the immediate postadmission period for almost 18 days was associated with a significant reduction of inflammatory cytokines and procoagulative status.”

Dr. Riddle and colleagues wrote that the findings of this unrandomized comparison were interpreted “as suggesting that insulin infusion may improve outcomes.”

“If the benefits of seeking excellent glycemic control by this means are confirmed, close monitoring of glucose levels will be essential.”
 

More on obesity and COVID-19, this time from China

Because it has become increasingly clear that obesity is a risk factor for severe COVID-19, new data from China – where this was less apparent initially – support observations in Europe and the United States.

An article by Qingxian Cai, PhD, of Southern University of Science and Technology, Shenzhen, Guangdong, China, and colleagues looks at this. They found that, among 383 hospitalized patients with COVID-19, the 41 patients with obesity (defined as a body mass index ≥ 28 kg/m²) were significantly more likely to progress to severe disease compared with the 203 patients classified as having normal weight (BMI, 18.5-23.9), with an odds ratio of 3.4.

A similar finding comes from Feng Gao, MD, PhD, of the First Affiliated Hospital of Wenzhou (China) Medical University and colleagues, who studied 75 patients hospitalized with confirmed COVID-19 and obesity (defined as a BMI > 25 in this Asian population) to 75 patients without obesity matched by age and sex. After adjustment for clinical characteristics including the presence of diabetes, those with obesity had a threefold greater risk of progression to severe or critical COVID-19 status, with a nearly linear relationship.
 

Emerging from the crisis: Protect the vulnerable, increase knowledge base

As the research community emerges from the crisis, “there should be renewed efforts for multidisciplinary research ... aimed at greatly increasing the knowledge base to understand how ... the current COVID-19 threat” affects “both healthy people and people with chronic diseases and conditions,” Dr. Cefalu and colleagues concluded in their commentary.

Dr. Riddle and coauthors agreed: “We will enter a longer interval in which we must continue to support the most vulnerable populations – especially older people, those with diabetes or obesity, and those who lack the resources to limit day-to-day exposure to infection. We hope a growing sense of community will help in this task.”

Dr. Riddle has reported receiving research grant support through Oregon Health & Science University from AstraZeneca, Eli Lilly, and Novo Nordisk, and honoraria for consulting from Adocia, AstraZeneca, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Sanofi, and Theracos. Dr. Cefalu has reported no relevant financial relationships.

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

The American Diabetes Association has dedicated a whole section of its journal, Diabetes Care, to the topic of “Diabetes and COVID-19,” publishing a range of articles with new data to help guide physicians in caring for patients.

“Certain groups are more vulnerable to COVID-19, notably older people and those with underlying medical conditions. Because diabetes is one of the conditions associated with high risk, the diabetes community urgently needs to know more about COVID-19 and its effects on people with diabetes,” an introductory commentary noted.

Entitled “COVID-19 in people with diabetes: Urgently needed lessons from early reports,” the commentary is penned by the journal’s editor-in-chief, Matthew Riddle, MD, of Oregon Health & Science University, Portland, and colleagues.

Also writing in the same issue, William T. Cefalu, MD, and colleagues from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) noted it is known that the SARS-CoV-2 virus enters cells via the angiotensin-converting enzyme 2 (ACE-2) receptor. The ACE-2 receptor is known to be in the lungs and upper respiratory tract, “but we also know that it is expressed in other tissues such as heart, small and large intestines, and pancreas,” they wrote, and also “in the kidney.”

Hence, there are emerging reports of acute kidney injury resulting from COVID-19, as well as the impact on many other endocrine/metabolic and gastrointestinal outcomes.

“Pilot clinical studies (observational and interventional) are needed that will support the understanding or treatment of COVID-19–related diseases within the mission of the NIDDK,” they stated.
 

Although rapidly collected, data “offer important clues”

Some of the new ground covered in the journal articles includes an analysis of COVID-19 outcomes by type of glucose-lowering medication; remote glucose monitoring in hospitalized patients with COVID-19; a suggested approach to cardiovascular risk management in the COVID-19 era, as already reported by Medscape Medical News; and the diagnosis and management of gestational diabetes during the pandemic.

Other articles provide new data for previously reported phenomena, including obesity as a risk factor for worse COVID-19 outcomes and the role of inpatient glycemic control on COVID-19 outcomes.

“The data reported in these articles were rapidly collected and analyzed, in most cases under urgent and stressful conditions,” Dr. Riddle and colleagues cautioned. “Thus, some of the analyses are understandably limited due to missing data, incomplete follow-up, and inability to identify infected but asymptomatic patients.”

Even so, they wrote, some points are clear. “The consistency of findings in these rapidly published reports is reassuring in terms of scientific validity, but the story unfolding is worrisome.”

Specifically, while diabetes does not appear to increase the likelihood of SARS-CoV-2 infection, progression to severe illness is more likely in people with diabetes and COVID-19: They are two to three times as likely to require intensive care, and to die, compared with those infected but without diabetes.

“Neither the mechanisms underlying the increased risk nor the best interventions to limit it have yet been defined, but the studies in this collection of articles offer important clues,” Dr. Riddle and colleagues wrote.
 

Existing insulin use linked to COVID-19 death risk

One of the articles is a retrospective study of 904 hospitalized COVID-19 patients by Yuchen Chen, MD, of the Huazhong University of Science and Technology, Wuhan, China, and colleagues.

Among the 136 patients with diabetes, risk factors for mortality included older age (adjusted odds ratio, 1.09 per year increase; P = .001) elevated C-reactive protein (aOR, 1.12; P = .043), and insulin use (aOR, 3.58; P = .009).

“Attention needs to be paid to patients with diabetes and COVID-19 who use insulin,” the Chinese authors wrote. “Whether this was due to effects of insulin itself or to characteristics of the patients for whom it was prescribed is not clear,” Dr. Riddle and colleagues noted.

Dr. Chen and colleagues also found no difference in clinical outcomes between those diabetes patients with COVID-19 who were taking an ACE inhibitor or angiotensin II type I receptor blocker, compared with those who did not, which supports existing recommendations to continue use of this type of medication.
 

Remote glucose monitoring a novel tool for COVID-19 isolation

Another publication, by Gilat Shehav-Zaltzman of Sheba Medical Center, Tel Hashomer, Israel, and colleagues, describes the use of remote continuous glucose monitoring (CGM) in two hospitalized COVID-19 patients who were in isolation – one with type 1 diabetes and the other with type 2 diabetes – treated with basal-bolus insulin.

Using Medtronic CGM systems, the hospital staff was able to view patients’ real-time data uploaded to the Web from computer terminals in virus-free areas outside the patients’ rooms. The hospital’s endocrinology team had trained the intensive care staff on how to replace the sensors weekly and calibrate them twice daily.

“Converting a personal CGM system originally designed for diabetes self-management to team-based, real-time remote glucose monitoring offers a novel tool for inpatient diabetes control in COVID-19 isolation facilities,” the authors wrote.

“Such a solution in addition to ongoing remotely monitored clinical parameters (such as pulse rate, electrocardiogram, and oxygen saturation) adds to quality of diabetes care while minimizing risk of staff exposure and burden,” they observed.

Dr. Riddle and colleagues concurred: “Newer methods of remotely monitoring glucose patterns could be uniquely helpful.”

Key question: Does glycemic management make a difference?

With regard to the important issue of in-hospital control of glucose, Celestino Sardu, MD, PhD, of the University of Campania Luigi Vanvitelli, Naples, Italy, and colleagues reported on 59 patients hospitalized with confirmed COVID-19 and moderately severe pneumonia.

They were categorized as normoglycemic (n = 34) or hyperglycemic (n = 25), as well as with or without diabetes, on the basis of a diagnosis preceding the current illness. Of the 25 patients with hyperglycemia, 15 patients were treated with insulin infusion and 10 patients were not.

In a risk-adjusted analysis, both patients with hyperglycemia and patients with diabetes had a higher risk of severe disease than did those without diabetes and with normoglycemia. Patients with hyperglycemia treated with insulin infusion had a lower risk of severe disease than did patients who didn’t receive an insulin infusion.

And although they noted limitations, the authors wrote, “Our data evidenced that optimal glucose control in the immediate postadmission period for almost 18 days was associated with a significant reduction of inflammatory cytokines and procoagulative status.”

Dr. Riddle and colleagues wrote that the findings of this unrandomized comparison were interpreted “as suggesting that insulin infusion may improve outcomes.”

“If the benefits of seeking excellent glycemic control by this means are confirmed, close monitoring of glucose levels will be essential.”
 

More on obesity and COVID-19, this time from China

Because it has become increasingly clear that obesity is a risk factor for severe COVID-19, new data from China – where this was less apparent initially – support observations in Europe and the United States.

An article by Qingxian Cai, PhD, of Southern University of Science and Technology, Shenzhen, Guangdong, China, and colleagues looks at this. They found that, among 383 hospitalized patients with COVID-19, the 41 patients with obesity (defined as a body mass index ≥ 28 kg/m²) were significantly more likely to progress to severe disease compared with the 203 patients classified as having normal weight (BMI, 18.5-23.9), with an odds ratio of 3.4.

A similar finding comes from Feng Gao, MD, PhD, of the First Affiliated Hospital of Wenzhou (China) Medical University and colleagues, who studied 75 patients hospitalized with confirmed COVID-19 and obesity (defined as a BMI > 25 in this Asian population) to 75 patients without obesity matched by age and sex. After adjustment for clinical characteristics including the presence of diabetes, those with obesity had a threefold greater risk of progression to severe or critical COVID-19 status, with a nearly linear relationship.
 

Emerging from the crisis: Protect the vulnerable, increase knowledge base

As the research community emerges from the crisis, “there should be renewed efforts for multidisciplinary research ... aimed at greatly increasing the knowledge base to understand how ... the current COVID-19 threat” affects “both healthy people and people with chronic diseases and conditions,” Dr. Cefalu and colleagues concluded in their commentary.

Dr. Riddle and coauthors agreed: “We will enter a longer interval in which we must continue to support the most vulnerable populations – especially older people, those with diabetes or obesity, and those who lack the resources to limit day-to-day exposure to infection. We hope a growing sense of community will help in this task.”

Dr. Riddle has reported receiving research grant support through Oregon Health & Science University from AstraZeneca, Eli Lilly, and Novo Nordisk, and honoraria for consulting from Adocia, AstraZeneca, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Sanofi, and Theracos. Dr. Cefalu has reported no relevant financial relationships.

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

A diagnosis of guttate psoriasis was made based on the physical exam findings and the preceding group A beta-hemolytic streptococcal infection.

This condition affects approximately 2% of all patients with psoriasis; it is characterized by the acute onset of multiple erythematous and scaly papules and small plaques that look like droplets (“gutta”). It tends to affect children and young adults and typically occurs following an acute infection (eg, streptococcal pharyngitis). In this case, a rapid strep test was positive for group A Streptococcus, which supported the diagnosis.

The differential includes skin conditions such as pityriasis rosea, tinea corporis, and contact dermatitis.

The first-line treatment for streptococcal infection is amoxicillin (50 mg/kg/d [maximum: 1000 mg/d] orally for 10 d) or penicillin G benzathine (for children < 60 lb, 6 × 10⁵ units intramuscularly; children ≥ 60 lb, 1.2 × 10⁶ units intramuscularly). For the psoriasis lesions, treatment options include topical steroids, vitamin D derivatives, or combinations of both. In most cases, guttate psoriasis completely resolves. However, one-third of children with guttate psoriasis go on to develop plaque psoriasis later in life.

This patient was treated with penicillin G benzathine (1.2 × 106 units intramuscularly) and a calcipotriol/betamethasone combination gel. However, a less costly treatment is generic betamethasone (or triamcinolone) and/or generic calcipotriol (a vitamin D derivative). The streptococcal infection and skin lesions completely resolved. No adverse events were reported, and no relapse was observed after 3 months.

‌

This case was adapted from: Matos RS, Torres T. Rapid onset rash in child. J Fam Pract. 2018;67:E1-E2.

A diagnosis of guttate psoriasis was made based on the physical exam findings and the preceding group A beta-hemolytic streptococcal infection.

This condition affects approximately 2% of all patients with psoriasis; it is characterized by the acute onset of multiple erythematous and scaly papules and small plaques that look like droplets (“gutta”). It tends to affect children and young adults and typically occurs following an acute infection (eg, streptococcal pharyngitis). In this case, a rapid strep test was positive for group A Streptococcus, which supported the diagnosis.

The differential includes skin conditions such as pityriasis rosea, tinea corporis, and contact dermatitis.

The first-line treatment for streptococcal infection is amoxicillin (50 mg/kg/d [maximum: 1000 mg/d] orally for 10 d) or penicillin G benzathine (for children < 60 lb, 6 × 10⁵ units intramuscularly; children ≥ 60 lb, 1.2 × 10⁶ units intramuscularly). For the psoriasis lesions, treatment options include topical steroids, vitamin D derivatives, or combinations of both. In most cases, guttate psoriasis completely resolves. However, one-third of children with guttate psoriasis go on to develop plaque psoriasis later in life.

This patient was treated with penicillin G benzathine (1.2 × 106 units intramuscularly) and a calcipotriol/betamethasone combination gel. However, a less costly treatment is generic betamethasone (or triamcinolone) and/or generic calcipotriol (a vitamin D derivative). The streptococcal infection and skin lesions completely resolved. No adverse events were reported, and no relapse was observed after 3 months.

‌

This case was adapted from: Matos RS, Torres T. Rapid onset rash in child. J Fam Pract. 2018;67:E1-E2.

A diagnosis of guttate psoriasis was made based on the physical exam findings and the preceding group A beta-hemolytic streptococcal infection.

This condition affects approximately 2% of all patients with psoriasis; it is characterized by the acute onset of multiple erythematous and scaly papules and small plaques that look like droplets (“gutta”). It tends to affect children and young adults and typically occurs following an acute infection (eg, streptococcal pharyngitis). In this case, a rapid strep test was positive for group A Streptococcus, which supported the diagnosis.

The differential includes skin conditions such as pityriasis rosea, tinea corporis, and contact dermatitis.

The first-line treatment for streptococcal infection is amoxicillin (50 mg/kg/d [maximum: 1000 mg/d] orally for 10 d) or penicillin G benzathine (for children < 60 lb, 6 × 10⁵ units intramuscularly; children ≥ 60 lb, 1.2 × 10⁶ units intramuscularly). For the psoriasis lesions, treatment options include topical steroids, vitamin D derivatives, or combinations of both. In most cases, guttate psoriasis completely resolves. However, one-third of children with guttate psoriasis go on to develop plaque psoriasis later in life.

This patient was treated with penicillin G benzathine (1.2 × 106 units intramuscularly) and a calcipotriol/betamethasone combination gel. However, a less costly treatment is generic betamethasone (or triamcinolone) and/or generic calcipotriol (a vitamin D derivative). The streptococcal infection and skin lesions completely resolved. No adverse events were reported, and no relapse was observed after 3 months.

‌

This case was adapted from: Matos RS, Torres T. Rapid onset rash in child. J Fam Pract. 2018;67:E1-E2.

High-dose aducanumab, a human monoclonal antibody in development, significantly reduced clinical decline in people with early Alzheimer’s disease in one randomized, placebo-controlled phase 3 study but not in another identical study. Aducanumab was associated with favorable changes in activities of daily living and in Alzheimer’s disease biomarkers.

The EMERGE and ENGAGE studies compared low-dose and high-dose aducanumab and placebo over 78 weeks. The high-dose EMERGE cohort experienced a 22% improvement in the primary outcome – adjusted mean Clinical Dementia Rating Sum of Box (CDR-SB) scores – compared with baseline.

“We have with EMERGE, in the high-dose group, a positive result,” said lead author Samantha Budd Haeberlein, PhD, who presented this research online as part of the 2020 American Academy of Neurology Science Highlights.

In contrast, the low-dose EMERGE group, as well as the low-dose and high-dose cohorts in the ENGAGE study, experienced no statistically significant change in CDR-SB outcomes.

Clinical benefit was associated with the degree of exposure to aducanumab. For example, a protocol adjustment during the study increased the mean dose of aducanumab, a move associated with better outcomes.

“We believe that the difference between the results was largely due to patients’ greater exposure to the high dose of aducanumab,” Dr. Haerberlein, senior vice president and head of the neurodegeneration development unit at Biogen in Cambridge, Mass., said in an interview.

Although the studies shared an identical design, “because ENGAGE began enrolling first and recruitment remained ahead of EMERGE, more patients in EMERGE were impacted by the protocol amendments, which we believe resulted in a higher number of patients exposed to the highest dose in EMERGE versus ENGAGE,” Dr. Haerberlein added.

The EMERGE and ENGAGE studies were conducted at 348 sites in 20 countries. The research included a total of 3,285 participants with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

The mean age was 70 years, about 52% were women, and slightly more than half had a history of taking medication for Alzheimer’s disease. The mean Mini-Mental State Exam (MMSE) score was 26 at baseline.
 

Key findings

Dr. Haerberlein and colleagues reported that the 22% decrease in CDR-SB scores in the high-dose EMERGE participants was significant (P = .01). No significant difference emerged, however, in the ENGAGE study, where high-dose participants had a 2% decrease at 78 weeks in CDR-SB scores (P = .83).

The high-dose EMERGE regimen was also associated with an 18% improvement in MMSE scores (P < .05). In the ENGAGE study, the high-dose MMSE scores increased a nonsignificant 3% (P = .81).

The researchers reported no significant differences in the low-dose cohorts in both studies regarding CDR-SB or MMSE scores at week 78, compared with baseline.

They also assessed amyloid using PET scans. Levels remained essentially the same throughout both studies in the placebo participants. In contrast, there was a statistically significant, dose- and time-dependent reduction associated with both low- and high-dose aducanumab.

Aducanumab treatment was associated with significant benefits on measures of cognition and function such as memory, orientation, and language, Dr. Haeberlein said. “Patients also experienced benefits on activities of daily living including conducting personal finances; performing household chores such as cleaning, shopping, and doing laundry; and independently traveling out of the home.”

Furthermore, reductions in the CSF biomarker phospho-tau in the high-dose EMERGE and ENGAGE cohorts were statistically significant. In contrast, changes in total tau were not significant.

The proportion of patients who experienced an adverse event during EMERGE was similar across groups – 92% of the high-dose group, 88% of the low-dose group, and 87% of the placebo cohort. Similar rates were reported in the ENGAGE high-dose, 90%; low-dose, 90%; and placebo cohorts, 86%.

Adverse events reported in more than 10% of participants included headache, nasopharyngitis, and two forms of amyloid-related imaging abnormalities (ARIA), one of which related to edema (ARIA-E) and the other to hemosiderosis (ARIA-H).
 

Future plans

Going forward, the researchers are conducting a redosing study to offer aducanumab to all participants in the clinical trials. Also, Biogen is completing the filing of a Biologics License Application with the Food and Drug Administration and with regulatory agencies in other countries.

Early identification and treatment of Alzheimer’s disease remains a priority, Dr. Haeberlein said, because it offers an opportunity to begin health measures like exercise, mental activity, and social engagement; allows people more time to plan for the future; and gives families and loved ones’ time to prepare and support each other. From a research perspective, early identification of this population can maximize chances of participation in a clinical trial as well.
 

Unanswered questions

“Briefly, while both [studies] were looking at aducanumab’s effect on rate of decline across a variety of measures, one statistically showed a positive impact in a subset and the other did not,” Richard J. Caselli, MD, said when asked to comment on the EMERGE and ENGAGE findings. “The subset were the mildest affected patients on the highest dose for the longest time.”

The main difference between the two studies was that one was adequately powered for this subanalysis and the other was not. Even the underpowered subanalysis showed a beneficial trend, added Dr. Caselli, a neurologist at the Mayo Clinic in Phoenix, Arizona.

Dr. Caselli said these findings raise a number of unanswered questions. For example, is a subanalysis valid? Is the degree of improvement clinically meaningful or meaningful enough to justify the anticipated cost of the drug itself – “likely to be very expensive” plus the “cost and hassle” of monthly IV infusions? Is there enough provider and infusion center capacity going forward? What will the reimbursement from third party payers be like?

Biogen sponsored the EMERGE and ENGAGE studies. Dr. Haeberlein is a Biogen employee. Dr. Caselli had no relevant disclosures.

SOURCE: Haeberlein SB et al. AAN 2020, Abstract 46977.

High-dose aducanumab, a human monoclonal antibody in development, significantly reduced clinical decline in people with early Alzheimer’s disease in one randomized, placebo-controlled phase 3 study but not in another identical study. Aducanumab was associated with favorable changes in activities of daily living and in Alzheimer’s disease biomarkers.

The EMERGE and ENGAGE studies compared low-dose and high-dose aducanumab and placebo over 78 weeks. The high-dose EMERGE cohort experienced a 22% improvement in the primary outcome – adjusted mean Clinical Dementia Rating Sum of Box (CDR-SB) scores – compared with baseline.

“We have with EMERGE, in the high-dose group, a positive result,” said lead author Samantha Budd Haeberlein, PhD, who presented this research online as part of the 2020 American Academy of Neurology Science Highlights.

In contrast, the low-dose EMERGE group, as well as the low-dose and high-dose cohorts in the ENGAGE study, experienced no statistically significant change in CDR-SB outcomes.

Clinical benefit was associated with the degree of exposure to aducanumab. For example, a protocol adjustment during the study increased the mean dose of aducanumab, a move associated with better outcomes.

“We believe that the difference between the results was largely due to patients’ greater exposure to the high dose of aducanumab,” Dr. Haerberlein, senior vice president and head of the neurodegeneration development unit at Biogen in Cambridge, Mass., said in an interview.

Although the studies shared an identical design, “because ENGAGE began enrolling first and recruitment remained ahead of EMERGE, more patients in EMERGE were impacted by the protocol amendments, which we believe resulted in a higher number of patients exposed to the highest dose in EMERGE versus ENGAGE,” Dr. Haerberlein added.

The EMERGE and ENGAGE studies were conducted at 348 sites in 20 countries. The research included a total of 3,285 participants with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

The mean age was 70 years, about 52% were women, and slightly more than half had a history of taking medication for Alzheimer’s disease. The mean Mini-Mental State Exam (MMSE) score was 26 at baseline.
 

Key findings

Dr. Haerberlein and colleagues reported that the 22% decrease in CDR-SB scores in the high-dose EMERGE participants was significant (P = .01). No significant difference emerged, however, in the ENGAGE study, where high-dose participants had a 2% decrease at 78 weeks in CDR-SB scores (P = .83).

The high-dose EMERGE regimen was also associated with an 18% improvement in MMSE scores (P < .05). In the ENGAGE study, the high-dose MMSE scores increased a nonsignificant 3% (P = .81).

The researchers reported no significant differences in the low-dose cohorts in both studies regarding CDR-SB or MMSE scores at week 78, compared with baseline.

They also assessed amyloid using PET scans. Levels remained essentially the same throughout both studies in the placebo participants. In contrast, there was a statistically significant, dose- and time-dependent reduction associated with both low- and high-dose aducanumab.

Aducanumab treatment was associated with significant benefits on measures of cognition and function such as memory, orientation, and language, Dr. Haeberlein said. “Patients also experienced benefits on activities of daily living including conducting personal finances; performing household chores such as cleaning, shopping, and doing laundry; and independently traveling out of the home.”

Furthermore, reductions in the CSF biomarker phospho-tau in the high-dose EMERGE and ENGAGE cohorts were statistically significant. In contrast, changes in total tau were not significant.

The proportion of patients who experienced an adverse event during EMERGE was similar across groups – 92% of the high-dose group, 88% of the low-dose group, and 87% of the placebo cohort. Similar rates were reported in the ENGAGE high-dose, 90%; low-dose, 90%; and placebo cohorts, 86%.

Adverse events reported in more than 10% of participants included headache, nasopharyngitis, and two forms of amyloid-related imaging abnormalities (ARIA), one of which related to edema (ARIA-E) and the other to hemosiderosis (ARIA-H).
 

Future plans

Going forward, the researchers are conducting a redosing study to offer aducanumab to all participants in the clinical trials. Also, Biogen is completing the filing of a Biologics License Application with the Food and Drug Administration and with regulatory agencies in other countries.

Early identification and treatment of Alzheimer’s disease remains a priority, Dr. Haeberlein said, because it offers an opportunity to begin health measures like exercise, mental activity, and social engagement; allows people more time to plan for the future; and gives families and loved ones’ time to prepare and support each other. From a research perspective, early identification of this population can maximize chances of participation in a clinical trial as well.
 

Unanswered questions

“Briefly, while both [studies] were looking at aducanumab’s effect on rate of decline across a variety of measures, one statistically showed a positive impact in a subset and the other did not,” Richard J. Caselli, MD, said when asked to comment on the EMERGE and ENGAGE findings. “The subset were the mildest affected patients on the highest dose for the longest time.”

The main difference between the two studies was that one was adequately powered for this subanalysis and the other was not. Even the underpowered subanalysis showed a beneficial trend, added Dr. Caselli, a neurologist at the Mayo Clinic in Phoenix, Arizona.

Dr. Caselli said these findings raise a number of unanswered questions. For example, is a subanalysis valid? Is the degree of improvement clinically meaningful or meaningful enough to justify the anticipated cost of the drug itself – “likely to be very expensive” plus the “cost and hassle” of monthly IV infusions? Is there enough provider and infusion center capacity going forward? What will the reimbursement from third party payers be like?

Biogen sponsored the EMERGE and ENGAGE studies. Dr. Haeberlein is a Biogen employee. Dr. Caselli had no relevant disclosures.

SOURCE: Haeberlein SB et al. AAN 2020, Abstract 46977.

High-dose aducanumab, a human monoclonal antibody in development, significantly reduced clinical decline in people with early Alzheimer’s disease in one randomized, placebo-controlled phase 3 study but not in another identical study. Aducanumab was associated with favorable changes in activities of daily living and in Alzheimer’s disease biomarkers.

The EMERGE and ENGAGE studies compared low-dose and high-dose aducanumab and placebo over 78 weeks. The high-dose EMERGE cohort experienced a 22% improvement in the primary outcome – adjusted mean Clinical Dementia Rating Sum of Box (CDR-SB) scores – compared with baseline.

“We have with EMERGE, in the high-dose group, a positive result,” said lead author Samantha Budd Haeberlein, PhD, who presented this research online as part of the 2020 American Academy of Neurology Science Highlights.

In contrast, the low-dose EMERGE group, as well as the low-dose and high-dose cohorts in the ENGAGE study, experienced no statistically significant change in CDR-SB outcomes.

Clinical benefit was associated with the degree of exposure to aducanumab. For example, a protocol adjustment during the study increased the mean dose of aducanumab, a move associated with better outcomes.

“We believe that the difference between the results was largely due to patients’ greater exposure to the high dose of aducanumab,” Dr. Haerberlein, senior vice president and head of the neurodegeneration development unit at Biogen in Cambridge, Mass., said in an interview.

Although the studies shared an identical design, “because ENGAGE began enrolling first and recruitment remained ahead of EMERGE, more patients in EMERGE were impacted by the protocol amendments, which we believe resulted in a higher number of patients exposed to the highest dose in EMERGE versus ENGAGE,” Dr. Haerberlein added.

The EMERGE and ENGAGE studies were conducted at 348 sites in 20 countries. The research included a total of 3,285 participants with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

The mean age was 70 years, about 52% were women, and slightly more than half had a history of taking medication for Alzheimer’s disease. The mean Mini-Mental State Exam (MMSE) score was 26 at baseline.
 

Key findings

Dr. Haerberlein and colleagues reported that the 22% decrease in CDR-SB scores in the high-dose EMERGE participants was significant (P = .01). No significant difference emerged, however, in the ENGAGE study, where high-dose participants had a 2% decrease at 78 weeks in CDR-SB scores (P = .83).

The high-dose EMERGE regimen was also associated with an 18% improvement in MMSE scores (P < .05). In the ENGAGE study, the high-dose MMSE scores increased a nonsignificant 3% (P = .81).

The researchers reported no significant differences in the low-dose cohorts in both studies regarding CDR-SB or MMSE scores at week 78, compared with baseline.

They also assessed amyloid using PET scans. Levels remained essentially the same throughout both studies in the placebo participants. In contrast, there was a statistically significant, dose- and time-dependent reduction associated with both low- and high-dose aducanumab.

Aducanumab treatment was associated with significant benefits on measures of cognition and function such as memory, orientation, and language, Dr. Haeberlein said. “Patients also experienced benefits on activities of daily living including conducting personal finances; performing household chores such as cleaning, shopping, and doing laundry; and independently traveling out of the home.”

Furthermore, reductions in the CSF biomarker phospho-tau in the high-dose EMERGE and ENGAGE cohorts were statistically significant. In contrast, changes in total tau were not significant.

The proportion of patients who experienced an adverse event during EMERGE was similar across groups – 92% of the high-dose group, 88% of the low-dose group, and 87% of the placebo cohort. Similar rates were reported in the ENGAGE high-dose, 90%; low-dose, 90%; and placebo cohorts, 86%.

Adverse events reported in more than 10% of participants included headache, nasopharyngitis, and two forms of amyloid-related imaging abnormalities (ARIA), one of which related to edema (ARIA-E) and the other to hemosiderosis (ARIA-H).
 

Future plans

Going forward, the researchers are conducting a redosing study to offer aducanumab to all participants in the clinical trials. Also, Biogen is completing the filing of a Biologics License Application with the Food and Drug Administration and with regulatory agencies in other countries.

Early identification and treatment of Alzheimer’s disease remains a priority, Dr. Haeberlein said, because it offers an opportunity to begin health measures like exercise, mental activity, and social engagement; allows people more time to plan for the future; and gives families and loved ones’ time to prepare and support each other. From a research perspective, early identification of this population can maximize chances of participation in a clinical trial as well.
 

Unanswered questions

“Briefly, while both [studies] were looking at aducanumab’s effect on rate of decline across a variety of measures, one statistically showed a positive impact in a subset and the other did not,” Richard J. Caselli, MD, said when asked to comment on the EMERGE and ENGAGE findings. “The subset were the mildest affected patients on the highest dose for the longest time.”

The main difference between the two studies was that one was adequately powered for this subanalysis and the other was not. Even the underpowered subanalysis showed a beneficial trend, added Dr. Caselli, a neurologist at the Mayo Clinic in Phoenix, Arizona.

Dr. Caselli said these findings raise a number of unanswered questions. For example, is a subanalysis valid? Is the degree of improvement clinically meaningful or meaningful enough to justify the anticipated cost of the drug itself – “likely to be very expensive” plus the “cost and hassle” of monthly IV infusions? Is there enough provider and infusion center capacity going forward? What will the reimbursement from third party payers be like?

Biogen sponsored the EMERGE and ENGAGE studies. Dr. Haeberlein is a Biogen employee. Dr. Caselli had no relevant disclosures.

SOURCE: Haeberlein SB et al. AAN 2020, Abstract 46977.

The Food and Drug Administration has approved the combination of nivolumab (Opdivo), ipilimumab (Yervoy), and two cycles of platinum-doublet chemotherapy as frontline treatment for patients with metastatic or recurrent non–small cell lung cancer (NSCLC) who have no EGFR or ALK genomic tumor aberrations.

The FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Singapore’s Health Sciences Authority on the review that led to this approval, as part of Project Orbis. The FDA approved the application 2 months ahead of schedule.

The combination chemotherapy was investigated in the CHECKMATE-9LA trial (NCT03215706), which enrolled patients with metastatic or recurrent NSCLC.

Patients were randomized to receive nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy (n = 361) or platinum-doublet chemotherapy for four cycles (n = 358).

There was a significant overall survival benefit in the nivolumab-ipilimumab arm, compared with the chemotherapy-only arm. The median overall survival was 14.1 months and 10.7 months, respectively (hazard ratio, 0.69; P = .0006).

The median progression-free survival was 6.8 months in the nivolumab-ipilimumab arm and 5 months in the chemotherapy-only arm (HR, 0.70; P = .0001). The overall response rate was 38% and 25%, respectively (P = .0003).

The most common adverse events in the nivolumab-ipilimumab arm, which occurred in at least 20% of patients, were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Serious adverse events occurred in 57% of patients in the nivolumab-ipilimumab arm. Fatal adverse events occurred in seven patients (2%) in that arm. Fatal events were hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

For more details, see the full prescribing information for nivolumab or ipilimumab. Nivolumab and ipilimumab are both products of Bristol-Myers Squibb.

The Food and Drug Administration has approved the combination of nivolumab (Opdivo), ipilimumab (Yervoy), and two cycles of platinum-doublet chemotherapy as frontline treatment for patients with metastatic or recurrent non–small cell lung cancer (NSCLC) who have no EGFR or ALK genomic tumor aberrations.

The FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Singapore’s Health Sciences Authority on the review that led to this approval, as part of Project Orbis. The FDA approved the application 2 months ahead of schedule.

The combination chemotherapy was investigated in the CHECKMATE-9LA trial (NCT03215706), which enrolled patients with metastatic or recurrent NSCLC.

Patients were randomized to receive nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy (n = 361) or platinum-doublet chemotherapy for four cycles (n = 358).

There was a significant overall survival benefit in the nivolumab-ipilimumab arm, compared with the chemotherapy-only arm. The median overall survival was 14.1 months and 10.7 months, respectively (hazard ratio, 0.69; P = .0006).

The median progression-free survival was 6.8 months in the nivolumab-ipilimumab arm and 5 months in the chemotherapy-only arm (HR, 0.70; P = .0001). The overall response rate was 38% and 25%, respectively (P = .0003).

The most common adverse events in the nivolumab-ipilimumab arm, which occurred in at least 20% of patients, were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Serious adverse events occurred in 57% of patients in the nivolumab-ipilimumab arm. Fatal adverse events occurred in seven patients (2%) in that arm. Fatal events were hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

For more details, see the full prescribing information for nivolumab or ipilimumab. Nivolumab and ipilimumab are both products of Bristol-Myers Squibb.

The Food and Drug Administration has approved the combination of nivolumab (Opdivo), ipilimumab (Yervoy), and two cycles of platinum-doublet chemotherapy as frontline treatment for patients with metastatic or recurrent non–small cell lung cancer (NSCLC) who have no EGFR or ALK genomic tumor aberrations.

The FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Singapore’s Health Sciences Authority on the review that led to this approval, as part of Project Orbis. The FDA approved the application 2 months ahead of schedule.

The combination chemotherapy was investigated in the CHECKMATE-9LA trial (NCT03215706), which enrolled patients with metastatic or recurrent NSCLC.

Patients were randomized to receive nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy (n = 361) or platinum-doublet chemotherapy for four cycles (n = 358).

There was a significant overall survival benefit in the nivolumab-ipilimumab arm, compared with the chemotherapy-only arm. The median overall survival was 14.1 months and 10.7 months, respectively (hazard ratio, 0.69; P = .0006).

The median progression-free survival was 6.8 months in the nivolumab-ipilimumab arm and 5 months in the chemotherapy-only arm (HR, 0.70; P = .0001). The overall response rate was 38% and 25%, respectively (P = .0003).

The most common adverse events in the nivolumab-ipilimumab arm, which occurred in at least 20% of patients, were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Serious adverse events occurred in 57% of patients in the nivolumab-ipilimumab arm. Fatal adverse events occurred in seven patients (2%) in that arm. Fatal events were hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

For more details, see the full prescribing information for nivolumab or ipilimumab. Nivolumab and ipilimumab are both products of Bristol-Myers Squibb.

Roughly 16%-22% of patients with hypertension appeared to have primary aldosteronism as the likely major cause of their elevated blood pressure, in an analysis of about 1,000 Americans, which is a much higher prevalence than previously appreciated and a finding that could potentially reorient both screening for aldosteronism and management for this subset of patients.

“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and coinvestigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” they wrote in the report.

The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.

“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”

The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which also included 289 normotensive subjects) regardless of whether or not they also had low levels of serum renin. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.

When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
 

A role for subtler forms of aldosteronism

Defining PA as at least 12 mcg secreted in a 24-hour urine collection “is relatively arbitrary, and our findings show that it bisects a continuous distribution. How we should redefine PA is also arbitrary, but step one is to recognize that many people have milder forms of PA” that could have an important effect on blood pressure, Dr. Vaidya said in an interview.

“This is the very first study to show that aldosterone may be contributing to the hypertensive process even though it is not severe enough to be diagnosed as PA according to current criteria,” said Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville and a coauthor on the new report. “More patients than we have ever known have an aldosterone component to their hypertension,” Dr. Carey said in an interview.

The new report on the prevalence of unrecognized PA in hypertensive patients “is a game changer,” wrote John W. Funder, MD, professor of medicine at Monash University in Clayton, Australia, in an editorial published along with the new report. In the editorial, he synthesized the new findings with results from prior reports to estimate that excess aldosteronism could play a clinically meaningful role in close to half of patients with hypertension, although Dr. Stowasser called this an “overestimate.” The new results also showed that “the single spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading. The authors cautioned readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere,” Dr. Funder wrote. “The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion. A single morning spot measurement of plasma aldosterone cannot take into account ultradian variation in aldosterone secretion.”
 

The importance of finding excess aldosterone

Identifying patients with hypertension and PA, as well as hypertensives with excess aldosterone production that may not meet the traditional definition of PA, is especially important because they are excellent candidates for two forms of targeted and very effective treatments that have a reliable and substantial impact on lowering blood pressure in these patients. One treatment is unilateral adrenal gland removal in patients who produce excess aldosterone because of benign adenomas in one adrenal gland, which accounts for “approximately 30%” of patients with PA. “Patients with suspected PA should have an opportunity to find out whether they have a unilateral variety and chance for surgical cure,” said Dr. Stowasser in an interview. “Patients with PA do far better in terms of blood pressure control, prevention of cardiovascular complications, and quality of life if they are treated specifically, either medically or particularly by surgery.”

The specific medical treatment he cited refers to one of the mineralocorticoid receptor antagonist (MRA) drugs, spironolactone and eplerenone (Inspra), because mineralocorticoid receptor blockade directly short-circuits the path by which aldosterone increases blood pressure. “We’re advocating earlier use of MRAs” for hypertensive patients identified with excess aldosterone production, said Dr. Carey. He noted that alternative, nonsteroidal MRAs, such as finerenone, have shown promise for efficacy levels similar to what spironolactone provides but without as many adverse effects because of greater receptor specificity. Finerenone and other nonsteroidal MRAs are all currently investigational. Spironolactone and eplerenone both cause hyperkalemia, although treatment with potassium binding agents can blunt the risk this poses. Spironolactone also causes bothersome adverse effects in men, including impotence and gynecomastia because of its action on androgen receptors, effects that diminished with eplerenone, but eplerenone is not as effective as spironolactone, Dr. Carey said.
 

Study details

The new study ran a post hoc analysis on data collected in five independent studies run at centers in four U.S. locations: Birmingham, Ala.; Boston; Charlottesville, Va.; and Salt Lake City. The studies included a total of 1,846 adults, mostly patients with hypertension of varying severity but also several hundred normotensive people. Data on 24-hour sodium excretion during an oral sodium suppression test were available for all participants, and the researchers excluded 831 people with an “inadequate” sodium balance of less than 190 mmol based on this metric, leaving a study population of 1,015. The researchers acknowledged the limitation that the study participants were not representative of the U.S. population.

The analysis included 289 normotensive people not on any blood pressure–lowering medications, and 239 fit the definition of having suppressed renin. The adjusted prevalence of aldosteronism at the level of at least 12 mcg excreted in a 24-hour urine specimen was 11% among all 289 normotensive subjects and 12% among the 239 with suppressed renin. When the definition of aldosteronism loosened to at least 10 mcg excreted during 24 hours the adjusted prevalence of excess aldosterone among normotensives increased to 19% among the entire group and 20% among those with suppressed renin. This finding may have identified a primordial phase of nascent hypertension that needs further study but may eventually provide a new scenario for intervention. “If a normotensive person has compliant arteries and healthy kidneys they can handle the excess salt and volume load of PA,” but when compensatory mechanisms start falling short through aging or other deteriorations, then blood pressure starts to rise, suggested Dr. Vaidya.
 

Whom to screen for aldosteronism and how

While several experts agreed these findings added to an existing and growing literature showing that PA is common and needs greater diagnostic attention, they differed on what this may mean for the specifics of screening and diagnosis, especially at the primary care level.

“Our results showed more explicitly that excess aldosterone exists on a broad severity spectrum and can’t be regarded as a categorical diagnosis that a patient either has or does not have. The hard part is figuring out where we should begin interventions,” said Dr. Vaidya.

In his editorial, Dr. Funder wrote that “much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed.”

One answer may be to apply a less stringent ARR threshold for further work-up. Dr. Stowasser’s program in Brisbane, as well as some other groups worldwide, use an ARR of at least 20 ng/dL as an indication of possible PA. “If you lower the cutoff to 20 [ng/dL], and ignore the plasma aldosterone level, then the ARR should pick up the great majority of patients with PA,” he said.

Another controversial aspect is whether aldosterone detection should be screened by 24-hour urine collection or by spot testing. In his editorial, Dr. Funder called spot testing “useless” and “misleading,” but Dr. Vaidya acknowledged that the 24-hour collection used in his current study is “not practical” for widespread use. Despite that, the Mayo Clinic in Rochester has focused on 24-hour urine collected “for more than 4 decades,” said Dr. Young, even though “a morning blood sample remains a simple screening test” that will catch “more than 95% of patients with PA” when combined with a plasma aldosterone threshold of 10 ng/dL. Dr. Stowasser noted that “patients don’t like” 24-hour collection, and not infrequently muck up collection” by forgetting to collect their entire 1-day output. Regardless of its shortcomings, 24-hour urine has the advantage of greater precision and accuracy than spot measurement, and using it on newly diagnosed hypertensive patients who also show renin suppression may be a viable approach, Dr. Carey suggested.

Regardless of exactly how guidelines for assessing aldosterone in hypertensive patients change, prospects seem ripe for some sort of revision and for greater participation and buy-in by primary care physicians than in the past. Dr. Carey, who also served as vice-chair of the American College of Cardiology and American Heart Association Task Force that wrote the most current U.S. guideline for managing hypertension, said it was too soon to revise that document, but the time had come to revise the Endocrine Society’s 2016 guideline for diagnosing and treating PA and to hash out the revision “in partnership” with one or more primary care societies. He also highlighted that publishing the current study in a high-profile primary care journal was an intentional effort to reach a large segment of the primary care community.

The new report “has the potential to change the current state of inertia” over wider PA diagnosis and targeted treatment “by being published in a widely read, major international journal,” commented Dr. Stowasser.

Dr. Vaidya has been a consultant to Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics. None of the other report coauthors had commercial disclosures, including Dr. Carey. Dr. Funder, Dr. Stowasser, and Dr. Young had no disclosures.

mzoler@mdedge.com

SOURCE: Brown JM et al. Ann Int Med. 2020 May 25. doi: 10.7326/M20-0065.
 

Roughly 16%-22% of patients with hypertension appeared to have primary aldosteronism as the likely major cause of their elevated blood pressure, in an analysis of about 1,000 Americans, which is a much higher prevalence than previously appreciated and a finding that could potentially reorient both screening for aldosteronism and management for this subset of patients.

“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and coinvestigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” they wrote in the report.

The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.

“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”

The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which also included 289 normotensive subjects) regardless of whether or not they also had low levels of serum renin. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.

When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
 

A role for subtler forms of aldosteronism

Defining PA as at least 12 mcg secreted in a 24-hour urine collection “is relatively arbitrary, and our findings show that it bisects a continuous distribution. How we should redefine PA is also arbitrary, but step one is to recognize that many people have milder forms of PA” that could have an important effect on blood pressure, Dr. Vaidya said in an interview.

“This is the very first study to show that aldosterone may be contributing to the hypertensive process even though it is not severe enough to be diagnosed as PA according to current criteria,” said Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville and a coauthor on the new report. “More patients than we have ever known have an aldosterone component to their hypertension,” Dr. Carey said in an interview.

The new report on the prevalence of unrecognized PA in hypertensive patients “is a game changer,” wrote John W. Funder, MD, professor of medicine at Monash University in Clayton, Australia, in an editorial published along with the new report. In the editorial, he synthesized the new findings with results from prior reports to estimate that excess aldosteronism could play a clinically meaningful role in close to half of patients with hypertension, although Dr. Stowasser called this an “overestimate.” The new results also showed that “the single spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading. The authors cautioned readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere,” Dr. Funder wrote. “The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion. A single morning spot measurement of plasma aldosterone cannot take into account ultradian variation in aldosterone secretion.”
 

The importance of finding excess aldosterone

Identifying patients with hypertension and PA, as well as hypertensives with excess aldosterone production that may not meet the traditional definition of PA, is especially important because they are excellent candidates for two forms of targeted and very effective treatments that have a reliable and substantial impact on lowering blood pressure in these patients. One treatment is unilateral adrenal gland removal in patients who produce excess aldosterone because of benign adenomas in one adrenal gland, which accounts for “approximately 30%” of patients with PA. “Patients with suspected PA should have an opportunity to find out whether they have a unilateral variety and chance for surgical cure,” said Dr. Stowasser in an interview. “Patients with PA do far better in terms of blood pressure control, prevention of cardiovascular complications, and quality of life if they are treated specifically, either medically or particularly by surgery.”

The specific medical treatment he cited refers to one of the mineralocorticoid receptor antagonist (MRA) drugs, spironolactone and eplerenone (Inspra), because mineralocorticoid receptor blockade directly short-circuits the path by which aldosterone increases blood pressure. “We’re advocating earlier use of MRAs” for hypertensive patients identified with excess aldosterone production, said Dr. Carey. He noted that alternative, nonsteroidal MRAs, such as finerenone, have shown promise for efficacy levels similar to what spironolactone provides but without as many adverse effects because of greater receptor specificity. Finerenone and other nonsteroidal MRAs are all currently investigational. Spironolactone and eplerenone both cause hyperkalemia, although treatment with potassium binding agents can blunt the risk this poses. Spironolactone also causes bothersome adverse effects in men, including impotence and gynecomastia because of its action on androgen receptors, effects that diminished with eplerenone, but eplerenone is not as effective as spironolactone, Dr. Carey said.
 

Study details

The new study ran a post hoc analysis on data collected in five independent studies run at centers in four U.S. locations: Birmingham, Ala.; Boston; Charlottesville, Va.; and Salt Lake City. The studies included a total of 1,846 adults, mostly patients with hypertension of varying severity but also several hundred normotensive people. Data on 24-hour sodium excretion during an oral sodium suppression test were available for all participants, and the researchers excluded 831 people with an “inadequate” sodium balance of less than 190 mmol based on this metric, leaving a study population of 1,015. The researchers acknowledged the limitation that the study participants were not representative of the U.S. population.

The analysis included 289 normotensive people not on any blood pressure–lowering medications, and 239 fit the definition of having suppressed renin. The adjusted prevalence of aldosteronism at the level of at least 12 mcg excreted in a 24-hour urine specimen was 11% among all 289 normotensive subjects and 12% among the 239 with suppressed renin. When the definition of aldosteronism loosened to at least 10 mcg excreted during 24 hours the adjusted prevalence of excess aldosterone among normotensives increased to 19% among the entire group and 20% among those with suppressed renin. This finding may have identified a primordial phase of nascent hypertension that needs further study but may eventually provide a new scenario for intervention. “If a normotensive person has compliant arteries and healthy kidneys they can handle the excess salt and volume load of PA,” but when compensatory mechanisms start falling short through aging or other deteriorations, then blood pressure starts to rise, suggested Dr. Vaidya.
 

Whom to screen for aldosteronism and how

While several experts agreed these findings added to an existing and growing literature showing that PA is common and needs greater diagnostic attention, they differed on what this may mean for the specifics of screening and diagnosis, especially at the primary care level.

“Our results showed more explicitly that excess aldosterone exists on a broad severity spectrum and can’t be regarded as a categorical diagnosis that a patient either has or does not have. The hard part is figuring out where we should begin interventions,” said Dr. Vaidya.

In his editorial, Dr. Funder wrote that “much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed.”

One answer may be to apply a less stringent ARR threshold for further work-up. Dr. Stowasser’s program in Brisbane, as well as some other groups worldwide, use an ARR of at least 20 ng/dL as an indication of possible PA. “If you lower the cutoff to 20 [ng/dL], and ignore the plasma aldosterone level, then the ARR should pick up the great majority of patients with PA,” he said.

Another controversial aspect is whether aldosterone detection should be screened by 24-hour urine collection or by spot testing. In his editorial, Dr. Funder called spot testing “useless” and “misleading,” but Dr. Vaidya acknowledged that the 24-hour collection used in his current study is “not practical” for widespread use. Despite that, the Mayo Clinic in Rochester has focused on 24-hour urine collected “for more than 4 decades,” said Dr. Young, even though “a morning blood sample remains a simple screening test” that will catch “more than 95% of patients with PA” when combined with a plasma aldosterone threshold of 10 ng/dL. Dr. Stowasser noted that “patients don’t like” 24-hour collection, and not infrequently muck up collection” by forgetting to collect their entire 1-day output. Regardless of its shortcomings, 24-hour urine has the advantage of greater precision and accuracy than spot measurement, and using it on newly diagnosed hypertensive patients who also show renin suppression may be a viable approach, Dr. Carey suggested.

Regardless of exactly how guidelines for assessing aldosterone in hypertensive patients change, prospects seem ripe for some sort of revision and for greater participation and buy-in by primary care physicians than in the past. Dr. Carey, who also served as vice-chair of the American College of Cardiology and American Heart Association Task Force that wrote the most current U.S. guideline for managing hypertension, said it was too soon to revise that document, but the time had come to revise the Endocrine Society’s 2016 guideline for diagnosing and treating PA and to hash out the revision “in partnership” with one or more primary care societies. He also highlighted that publishing the current study in a high-profile primary care journal was an intentional effort to reach a large segment of the primary care community.

The new report “has the potential to change the current state of inertia” over wider PA diagnosis and targeted treatment “by being published in a widely read, major international journal,” commented Dr. Stowasser.

Dr. Vaidya has been a consultant to Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics. None of the other report coauthors had commercial disclosures, including Dr. Carey. Dr. Funder, Dr. Stowasser, and Dr. Young had no disclosures.

mzoler@mdedge.com

SOURCE: Brown JM et al. Ann Int Med. 2020 May 25. doi: 10.7326/M20-0065.
 

Roughly 16%-22% of patients with hypertension appeared to have primary aldosteronism as the likely major cause of their elevated blood pressure, in an analysis of about 1,000 Americans, which is a much higher prevalence than previously appreciated and a finding that could potentially reorient both screening for aldosteronism and management for this subset of patients.

“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and coinvestigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” they wrote in the report.

The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.

“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”

The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which also included 289 normotensive subjects) regardless of whether or not they also had low levels of serum renin. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.

When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
 

A role for subtler forms of aldosteronism

Defining PA as at least 12 mcg secreted in a 24-hour urine collection “is relatively arbitrary, and our findings show that it bisects a continuous distribution. How we should redefine PA is also arbitrary, but step one is to recognize that many people have milder forms of PA” that could have an important effect on blood pressure, Dr. Vaidya said in an interview.

“This is the very first study to show that aldosterone may be contributing to the hypertensive process even though it is not severe enough to be diagnosed as PA according to current criteria,” said Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville and a coauthor on the new report. “More patients than we have ever known have an aldosterone component to their hypertension,” Dr. Carey said in an interview.

The new report on the prevalence of unrecognized PA in hypertensive patients “is a game changer,” wrote John W. Funder, MD, professor of medicine at Monash University in Clayton, Australia, in an editorial published along with the new report. In the editorial, he synthesized the new findings with results from prior reports to estimate that excess aldosteronism could play a clinically meaningful role in close to half of patients with hypertension, although Dr. Stowasser called this an “overestimate.” The new results also showed that “the single spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading. The authors cautioned readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere,” Dr. Funder wrote. “The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion. A single morning spot measurement of plasma aldosterone cannot take into account ultradian variation in aldosterone secretion.”
 

The importance of finding excess aldosterone

Identifying patients with hypertension and PA, as well as hypertensives with excess aldosterone production that may not meet the traditional definition of PA, is especially important because they are excellent candidates for two forms of targeted and very effective treatments that have a reliable and substantial impact on lowering blood pressure in these patients. One treatment is unilateral adrenal gland removal in patients who produce excess aldosterone because of benign adenomas in one adrenal gland, which accounts for “approximately 30%” of patients with PA. “Patients with suspected PA should have an opportunity to find out whether they have a unilateral variety and chance for surgical cure,” said Dr. Stowasser in an interview. “Patients with PA do far better in terms of blood pressure control, prevention of cardiovascular complications, and quality of life if they are treated specifically, either medically or particularly by surgery.”

The specific medical treatment he cited refers to one of the mineralocorticoid receptor antagonist (MRA) drugs, spironolactone and eplerenone (Inspra), because mineralocorticoid receptor blockade directly short-circuits the path by which aldosterone increases blood pressure. “We’re advocating earlier use of MRAs” for hypertensive patients identified with excess aldosterone production, said Dr. Carey. He noted that alternative, nonsteroidal MRAs, such as finerenone, have shown promise for efficacy levels similar to what spironolactone provides but without as many adverse effects because of greater receptor specificity. Finerenone and other nonsteroidal MRAs are all currently investigational. Spironolactone and eplerenone both cause hyperkalemia, although treatment with potassium binding agents can blunt the risk this poses. Spironolactone also causes bothersome adverse effects in men, including impotence and gynecomastia because of its action on androgen receptors, effects that diminished with eplerenone, but eplerenone is not as effective as spironolactone, Dr. Carey said.
 

Study details

The new study ran a post hoc analysis on data collected in five independent studies run at centers in four U.S. locations: Birmingham, Ala.; Boston; Charlottesville, Va.; and Salt Lake City. The studies included a total of 1,846 adults, mostly patients with hypertension of varying severity but also several hundred normotensive people. Data on 24-hour sodium excretion during an oral sodium suppression test were available for all participants, and the researchers excluded 831 people with an “inadequate” sodium balance of less than 190 mmol based on this metric, leaving a study population of 1,015. The researchers acknowledged the limitation that the study participants were not representative of the U.S. population.

The analysis included 289 normotensive people not on any blood pressure–lowering medications, and 239 fit the definition of having suppressed renin. The adjusted prevalence of aldosteronism at the level of at least 12 mcg excreted in a 24-hour urine specimen was 11% among all 289 normotensive subjects and 12% among the 239 with suppressed renin. When the definition of aldosteronism loosened to at least 10 mcg excreted during 24 hours the adjusted prevalence of excess aldosterone among normotensives increased to 19% among the entire group and 20% among those with suppressed renin. This finding may have identified a primordial phase of nascent hypertension that needs further study but may eventually provide a new scenario for intervention. “If a normotensive person has compliant arteries and healthy kidneys they can handle the excess salt and volume load of PA,” but when compensatory mechanisms start falling short through aging or other deteriorations, then blood pressure starts to rise, suggested Dr. Vaidya.
 

Whom to screen for aldosteronism and how

While several experts agreed these findings added to an existing and growing literature showing that PA is common and needs greater diagnostic attention, they differed on what this may mean for the specifics of screening and diagnosis, especially at the primary care level.

“Our results showed more explicitly that excess aldosterone exists on a broad severity spectrum and can’t be regarded as a categorical diagnosis that a patient either has or does not have. The hard part is figuring out where we should begin interventions,” said Dr. Vaidya.

In his editorial, Dr. Funder wrote that “much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed.”

One answer may be to apply a less stringent ARR threshold for further work-up. Dr. Stowasser’s program in Brisbane, as well as some other groups worldwide, use an ARR of at least 20 ng/dL as an indication of possible PA. “If you lower the cutoff to 20 [ng/dL], and ignore the plasma aldosterone level, then the ARR should pick up the great majority of patients with PA,” he said.

Another controversial aspect is whether aldosterone detection should be screened by 24-hour urine collection or by spot testing. In his editorial, Dr. Funder called spot testing “useless” and “misleading,” but Dr. Vaidya acknowledged that the 24-hour collection used in his current study is “not practical” for widespread use. Despite that, the Mayo Clinic in Rochester has focused on 24-hour urine collected “for more than 4 decades,” said Dr. Young, even though “a morning blood sample remains a simple screening test” that will catch “more than 95% of patients with PA” when combined with a plasma aldosterone threshold of 10 ng/dL. Dr. Stowasser noted that “patients don’t like” 24-hour collection, and not infrequently muck up collection” by forgetting to collect their entire 1-day output. Regardless of its shortcomings, 24-hour urine has the advantage of greater precision and accuracy than spot measurement, and using it on newly diagnosed hypertensive patients who also show renin suppression may be a viable approach, Dr. Carey suggested.

Regardless of exactly how guidelines for assessing aldosterone in hypertensive patients change, prospects seem ripe for some sort of revision and for greater participation and buy-in by primary care physicians than in the past. Dr. Carey, who also served as vice-chair of the American College of Cardiology and American Heart Association Task Force that wrote the most current U.S. guideline for managing hypertension, said it was too soon to revise that document, but the time had come to revise the Endocrine Society’s 2016 guideline for diagnosing and treating PA and to hash out the revision “in partnership” with one or more primary care societies. He also highlighted that publishing the current study in a high-profile primary care journal was an intentional effort to reach a large segment of the primary care community.

The new report “has the potential to change the current state of inertia” over wider PA diagnosis and targeted treatment “by being published in a widely read, major international journal,” commented Dr. Stowasser.

Dr. Vaidya has been a consultant to Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics. None of the other report coauthors had commercial disclosures, including Dr. Carey. Dr. Funder, Dr. Stowasser, and Dr. Young had no disclosures.

mzoler@mdedge.com

SOURCE: Brown JM et al. Ann Int Med. 2020 May 25. doi: 10.7326/M20-0065.