Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.

This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
 

What type of patients were treated in the GENUINE trial?

Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.

What were the main outcomes of the trial?

Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.

IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.

After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).

Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
 

What types of adverse events were found in the trial?

The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.

Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
 

What about serious adverse events?

Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.

Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?

In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.

Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
 

On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?

I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.

Are there any other implications of the GENUINE trial?

I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.

Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).

Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.

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

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.

This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
 

What type of patients were treated in the GENUINE trial?

Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.

What were the main outcomes of the trial?

Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.

IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.

After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).

Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
 

What types of adverse events were found in the trial?

The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.

Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
 

What about serious adverse events?

Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.

Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?

In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.

Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
 

On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?

I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.

Are there any other implications of the GENUINE trial?

I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.

Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).

Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.

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

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.

This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
 

What type of patients were treated in the GENUINE trial?

Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.

What were the main outcomes of the trial?

Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.

IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.

After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).

Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
 

What types of adverse events were found in the trial?

The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.

Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
 

What about serious adverse events?

Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.

Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?

In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.

Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
 

On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?

I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.

Are there any other implications of the GENUINE trial?

I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.

Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).

Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.

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

There are three general classes of antifungal agents (number of agents): azole antifungals (9), echinocandins (3), and polyenes (5). The azole antifungals contain an azole ring and inhibit a wide range of fungi. Echinocandins target the fungal cell wall and the polyenes increase the fungal membrane permeability and lead to cell death.

Pregnancy

Azole antifungals inhibit the growth of fungi. Their trade names and molecular weights:

• Clotrimazole (Mycelex), an over-the-counter product, is available as a topical cream. Several studies have found no association between the drug and birth defects.
• Fluconazole (Diflucan) is a teratogen when doses of ≥400 mg/day are used during the first trimester. Smaller doses do not appear to cause embryo/fetal harm.
• Isavuconazonium (Cresemba) if used in pregnancy, exposure of the embryo/fetus would probably be low based on the >99% plasma protein binding, but the plasma half-life is 130 hours. Moreover, the drug is a potent animal teratogen and is best avoided in pregnancy.
• Itraconazole (Onmel, Sporanox, Tolsura), has a low risk, if any, of structural defects, according to what reported human experience suggests.
• Ketoconazole (Xolegel, Extina, Nizoral; 531) does not appear to adversely effect embryos and fetuses, but the human data are very limited. As with any drug, avoiding organogenesis is the best recommendation.
• Miconazole (Oravig) is usually used topically. Small amounts are absorbed from the vagina. The available evidence suggests that the drug does not increase the risk of congenital malformations.
• Posaconazole (Noxafil) does not have reported use in human pregnancy. The animal reproduction data suggest risk. Based on its molecular weight (about 701), the drug will most likely cross the placenta to the embryo/fetus. Thus, the best course is to avoid the drug during pregnancy, especially in the first trimester.
• Voriconazole (Vfend) has one human report of the drug use in pregnancy. The drug was started at about 19 weeks and continued until the woman gave birth at 35 weeks to a healthy male baby. At 6 months of age, the baby remained normal.

Echinocandin antifungals target the fungal cell wall by inhibiting its synthesis. Their trade names and molecular weights:

• Anidulafungin (Eraxis; 1,140) has no published human data. It is indicated for the treatment of candidemia and other forms of Candida infections. The animal data suggest low risk.
• Caspofungin (Cancidas; 1,213) has no published human data. It is indicated for presumed fungal infections in febrile, neutropenic patients. The animal data are suggestive of human risk, especially if exposure occurs in the first trimester. If possible, maternal treatment should be avoided in the first trimester.
• Micafungin (Mycamine; 1,292) has no published human data. It is indicated for the treatment of patients with esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. The animal data in one species suggest high risk. If possible, maternal treatment should be avoided in the first trimester.

Polyene antifungals cause depolarization of the fungal cell membrane to increase the membrane permeability, which leads to cell death. Their trade names and molecular weights:

• Amphotericin b (Amphocin; Fungizone; 924) There are three other amphotericin agents: amphotericin b cholesteryl sulfate (Amphotec); amphotericin b lipid complex (Abelcet); amphotericin b liposomal (AmBisome). No reports linking amphotericin b with congenital defects have been found. The drug does cross the human placenta. Although there was a higher rate of spontaneous abortions in rabbits given amphotericin b, there was no fetal harm in rats and rabbits when given amphotericin b lipid complex.
• Nystatin (Bio-Statin; Mycostatin; Nilstat; 926). The drug does not appear to cause embryo-fetal harm. Based on published data, the drug can be used at any time in pregnancy.

Breastfeeding

Small amounts of all the above drugs are probably excreted into breast milk if they are used close to breastfeeding. Most can probably be used during breastfeeding, but there are no data for any of these agents. The safest decision is to not use these drugs when breastfeeding.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

There are three general classes of antifungal agents (number of agents): azole antifungals (9), echinocandins (3), and polyenes (5). The azole antifungals contain an azole ring and inhibit a wide range of fungi. Echinocandins target the fungal cell wall and the polyenes increase the fungal membrane permeability and lead to cell death.

Pregnancy

Azole antifungals inhibit the growth of fungi. Their trade names and molecular weights:

• Clotrimazole (Mycelex), an over-the-counter product, is available as a topical cream. Several studies have found no association between the drug and birth defects.
• Fluconazole (Diflucan) is a teratogen when doses of ≥400 mg/day are used during the first trimester. Smaller doses do not appear to cause embryo/fetal harm.
• Isavuconazonium (Cresemba) if used in pregnancy, exposure of the embryo/fetus would probably be low based on the >99% plasma protein binding, but the plasma half-life is 130 hours. Moreover, the drug is a potent animal teratogen and is best avoided in pregnancy.
• Itraconazole (Onmel, Sporanox, Tolsura), has a low risk, if any, of structural defects, according to what reported human experience suggests.
• Ketoconazole (Xolegel, Extina, Nizoral; 531) does not appear to adversely effect embryos and fetuses, but the human data are very limited. As with any drug, avoiding organogenesis is the best recommendation.
• Miconazole (Oravig) is usually used topically. Small amounts are absorbed from the vagina. The available evidence suggests that the drug does not increase the risk of congenital malformations.
• Posaconazole (Noxafil) does not have reported use in human pregnancy. The animal reproduction data suggest risk. Based on its molecular weight (about 701), the drug will most likely cross the placenta to the embryo/fetus. Thus, the best course is to avoid the drug during pregnancy, especially in the first trimester.
• Voriconazole (Vfend) has one human report of the drug use in pregnancy. The drug was started at about 19 weeks and continued until the woman gave birth at 35 weeks to a healthy male baby. At 6 months of age, the baby remained normal.

Echinocandin antifungals target the fungal cell wall by inhibiting its synthesis. Their trade names and molecular weights:

• Anidulafungin (Eraxis; 1,140) has no published human data. It is indicated for the treatment of candidemia and other forms of Candida infections. The animal data suggest low risk.
• Caspofungin (Cancidas; 1,213) has no published human data. It is indicated for presumed fungal infections in febrile, neutropenic patients. The animal data are suggestive of human risk, especially if exposure occurs in the first trimester. If possible, maternal treatment should be avoided in the first trimester.
• Micafungin (Mycamine; 1,292) has no published human data. It is indicated for the treatment of patients with esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. The animal data in one species suggest high risk. If possible, maternal treatment should be avoided in the first trimester.

Polyene antifungals cause depolarization of the fungal cell membrane to increase the membrane permeability, which leads to cell death. Their trade names and molecular weights:

• Amphotericin b (Amphocin; Fungizone; 924) There are three other amphotericin agents: amphotericin b cholesteryl sulfate (Amphotec); amphotericin b lipid complex (Abelcet); amphotericin b liposomal (AmBisome). No reports linking amphotericin b with congenital defects have been found. The drug does cross the human placenta. Although there was a higher rate of spontaneous abortions in rabbits given amphotericin b, there was no fetal harm in rats and rabbits when given amphotericin b lipid complex.
• Nystatin (Bio-Statin; Mycostatin; Nilstat; 926). The drug does not appear to cause embryo-fetal harm. Based on published data, the drug can be used at any time in pregnancy.

Breastfeeding

Small amounts of all the above drugs are probably excreted into breast milk if they are used close to breastfeeding. Most can probably be used during breastfeeding, but there are no data for any of these agents. The safest decision is to not use these drugs when breastfeeding.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

There are three general classes of antifungal agents (number of agents): azole antifungals (9), echinocandins (3), and polyenes (5). The azole antifungals contain an azole ring and inhibit a wide range of fungi. Echinocandins target the fungal cell wall and the polyenes increase the fungal membrane permeability and lead to cell death.

Pregnancy

Azole antifungals inhibit the growth of fungi. Their trade names and molecular weights:

• Clotrimazole (Mycelex), an over-the-counter product, is available as a topical cream. Several studies have found no association between the drug and birth defects.
• Fluconazole (Diflucan) is a teratogen when doses of ≥400 mg/day are used during the first trimester. Smaller doses do not appear to cause embryo/fetal harm.
• Isavuconazonium (Cresemba) if used in pregnancy, exposure of the embryo/fetus would probably be low based on the >99% plasma protein binding, but the plasma half-life is 130 hours. Moreover, the drug is a potent animal teratogen and is best avoided in pregnancy.
• Itraconazole (Onmel, Sporanox, Tolsura), has a low risk, if any, of structural defects, according to what reported human experience suggests.
• Ketoconazole (Xolegel, Extina, Nizoral; 531) does not appear to adversely effect embryos and fetuses, but the human data are very limited. As with any drug, avoiding organogenesis is the best recommendation.
• Miconazole (Oravig) is usually used topically. Small amounts are absorbed from the vagina. The available evidence suggests that the drug does not increase the risk of congenital malformations.
• Posaconazole (Noxafil) does not have reported use in human pregnancy. The animal reproduction data suggest risk. Based on its molecular weight (about 701), the drug will most likely cross the placenta to the embryo/fetus. Thus, the best course is to avoid the drug during pregnancy, especially in the first trimester.
• Voriconazole (Vfend) has one human report of the drug use in pregnancy. The drug was started at about 19 weeks and continued until the woman gave birth at 35 weeks to a healthy male baby. At 6 months of age, the baby remained normal.

Echinocandin antifungals target the fungal cell wall by inhibiting its synthesis. Their trade names and molecular weights:

• Anidulafungin (Eraxis; 1,140) has no published human data. It is indicated for the treatment of candidemia and other forms of Candida infections. The animal data suggest low risk.
• Caspofungin (Cancidas; 1,213) has no published human data. It is indicated for presumed fungal infections in febrile, neutropenic patients. The animal data are suggestive of human risk, especially if exposure occurs in the first trimester. If possible, maternal treatment should be avoided in the first trimester.
• Micafungin (Mycamine; 1,292) has no published human data. It is indicated for the treatment of patients with esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. The animal data in one species suggest high risk. If possible, maternal treatment should be avoided in the first trimester.

Polyene antifungals cause depolarization of the fungal cell membrane to increase the membrane permeability, which leads to cell death. Their trade names and molecular weights:

• Amphotericin b (Amphocin; Fungizone; 924) There are three other amphotericin agents: amphotericin b cholesteryl sulfate (Amphotec); amphotericin b lipid complex (Abelcet); amphotericin b liposomal (AmBisome). No reports linking amphotericin b with congenital defects have been found. The drug does cross the human placenta. Although there was a higher rate of spontaneous abortions in rabbits given amphotericin b, there was no fetal harm in rats and rabbits when given amphotericin b lipid complex.
• Nystatin (Bio-Statin; Mycostatin; Nilstat; 926). The drug does not appear to cause embryo-fetal harm. Based on published data, the drug can be used at any time in pregnancy.

Breastfeeding

Small amounts of all the above drugs are probably excreted into breast milk if they are used close to breastfeeding. Most can probably be used during breastfeeding, but there are no data for any of these agents. The safest decision is to not use these drugs when breastfeeding.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

During the first 3 months of the COVID-19 pandemic last year, about one-third of people with rheumatoid arthritis in the United States made changes in their RA medications, and, before the American College of Rheumatology tweaked its guidelines midway through that period, they were about twice as likely to make medication changes on their own than before the pandemic, according to an analysis of data in FORWARD, the National Databank for Rheumatic Diseases.

The study, published in Arthritis Care & Research, also found that about 10% of RA patients on hydroxychloroquine lost access to the drug at a time it was drawing interest as a treatment for COVID-19. Another finding was that a high percentage of patients on non–tumor necrosis factor biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors canceled or postponed appointments.

“Our results show that persons with RA who had medication changes in the first 3 months of the COVID-19 pandemic in the U.S. were more likely to have worse disease activity and higher exposure to prior DMARDs, but no statistical difference was found in terms of comorbidities,” first author Kaleb Michaud, PhD, and coauthors wrote. Dr. Michaud is with the National Databank for Rheumatic Diseases, Wichita, Kan., and the University of Nebraska Medical Center, Omaha.

The study evaluated responses from 734 adults who participated in FORWARD, an observational, multidisease registry. They answered online surveys about COVID-19 in May 2020 and had provided data on their medication use before the pandemic. A total of 30% (n = 221) reported medication changes in that period.
 

Details on medication changes

Medication changers were more likely to use glucocorticoids (GCs) (32.6% vs. 18.1%) and less likely to use nonhydroxychloroquine conventional DMARDs (49.3% vs. 62%) pre-COVID. Changers also reported higher rates of economic hardship during the pandemic (22.6% vs. 14.6%).

In the midst of the study period, the ACR issued a clinical guideline for treatment of rheumatic and musculoskeletal diseases (RMDs), emphasizing the need to maintain DMARD therapy, control disease activity, and reduce prednisone/GC use. The guideline advised continuing hydroxychloroquine and interleukin-6 inhibitor biologics in people with suspected or confirmed COVID-19.

Dr. Michaud and coauthors acknowledged the ongoing lack of knowledge about real-world treatment patterns for RA during the pandemic. They set out with this study to fill those knowledge gaps.

They noted that patients on bDMARDs (17.6%) and JAK inhibitors (17.1%) were more than twice as likely to discontinue medications than were those on conventional DMARDs (8.2%).

Switching to telehealth was the most common pandemic-related behavior change among patients in all DMARD groups, with rates ranging from 31% to 47.1%, followed by canceling or postponing appointments, with rates ranging from 27.9% to 36.4% depending on the DMARD group.

The study also found that RA patients widely adopted the behavior changes that the Centers for Disease Control and Prevention recommended during the pandemic, although the rates of restricting social contacts were significantly lower than the 90% reported in an early Italian study.

Dr. Michaud and coauthors also provided some explanation of why people on GCs and DMARDs were more likely than others to change medication patterns. “This may reflect efforts to reduce the perceived risk of infections due to GCs as well as the likely less-controlled disease activity associated with GC use,” they wrote. While the ACR’s early pandemic guidance followed the 2015 guidelines – that patients should continue on GCs at the “lowest possible dose” and not stop them “abruptly” – most U.S. rheumatologists reported cutting back on GC use during the pandemic.

The researchers acknowledged that evidence linking GC use with hospitalization for COVID-19, which emerged after they had surveyed study participants, was consistent their findings, but that the overall risk of COVID-19 in RA patients still isn’t known.

Pfizer funded the analysis, and a coauthor is an employee of Pfizer.

During the first 3 months of the COVID-19 pandemic last year, about one-third of people with rheumatoid arthritis in the United States made changes in their RA medications, and, before the American College of Rheumatology tweaked its guidelines midway through that period, they were about twice as likely to make medication changes on their own than before the pandemic, according to an analysis of data in FORWARD, the National Databank for Rheumatic Diseases.

The study, published in Arthritis Care & Research, also found that about 10% of RA patients on hydroxychloroquine lost access to the drug at a time it was drawing interest as a treatment for COVID-19. Another finding was that a high percentage of patients on non–tumor necrosis factor biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors canceled or postponed appointments.

“Our results show that persons with RA who had medication changes in the first 3 months of the COVID-19 pandemic in the U.S. were more likely to have worse disease activity and higher exposure to prior DMARDs, but no statistical difference was found in terms of comorbidities,” first author Kaleb Michaud, PhD, and coauthors wrote. Dr. Michaud is with the National Databank for Rheumatic Diseases, Wichita, Kan., and the University of Nebraska Medical Center, Omaha.

The study evaluated responses from 734 adults who participated in FORWARD, an observational, multidisease registry. They answered online surveys about COVID-19 in May 2020 and had provided data on their medication use before the pandemic. A total of 30% (n = 221) reported medication changes in that period.
 

Details on medication changes

Medication changers were more likely to use glucocorticoids (GCs) (32.6% vs. 18.1%) and less likely to use nonhydroxychloroquine conventional DMARDs (49.3% vs. 62%) pre-COVID. Changers also reported higher rates of economic hardship during the pandemic (22.6% vs. 14.6%).

In the midst of the study period, the ACR issued a clinical guideline for treatment of rheumatic and musculoskeletal diseases (RMDs), emphasizing the need to maintain DMARD therapy, control disease activity, and reduce prednisone/GC use. The guideline advised continuing hydroxychloroquine and interleukin-6 inhibitor biologics in people with suspected or confirmed COVID-19.

Dr. Michaud and coauthors acknowledged the ongoing lack of knowledge about real-world treatment patterns for RA during the pandemic. They set out with this study to fill those knowledge gaps.

They noted that patients on bDMARDs (17.6%) and JAK inhibitors (17.1%) were more than twice as likely to discontinue medications than were those on conventional DMARDs (8.2%).

Switching to telehealth was the most common pandemic-related behavior change among patients in all DMARD groups, with rates ranging from 31% to 47.1%, followed by canceling or postponing appointments, with rates ranging from 27.9% to 36.4% depending on the DMARD group.

The study also found that RA patients widely adopted the behavior changes that the Centers for Disease Control and Prevention recommended during the pandemic, although the rates of restricting social contacts were significantly lower than the 90% reported in an early Italian study.

Dr. Michaud and coauthors also provided some explanation of why people on GCs and DMARDs were more likely than others to change medication patterns. “This may reflect efforts to reduce the perceived risk of infections due to GCs as well as the likely less-controlled disease activity associated with GC use,” they wrote. While the ACR’s early pandemic guidance followed the 2015 guidelines – that patients should continue on GCs at the “lowest possible dose” and not stop them “abruptly” – most U.S. rheumatologists reported cutting back on GC use during the pandemic.

The researchers acknowledged that evidence linking GC use with hospitalization for COVID-19, which emerged after they had surveyed study participants, was consistent their findings, but that the overall risk of COVID-19 in RA patients still isn’t known.

Pfizer funded the analysis, and a coauthor is an employee of Pfizer.

During the first 3 months of the COVID-19 pandemic last year, about one-third of people with rheumatoid arthritis in the United States made changes in their RA medications, and, before the American College of Rheumatology tweaked its guidelines midway through that period, they were about twice as likely to make medication changes on their own than before the pandemic, according to an analysis of data in FORWARD, the National Databank for Rheumatic Diseases.

The study, published in Arthritis Care & Research, also found that about 10% of RA patients on hydroxychloroquine lost access to the drug at a time it was drawing interest as a treatment for COVID-19. Another finding was that a high percentage of patients on non–tumor necrosis factor biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors canceled or postponed appointments.

“Our results show that persons with RA who had medication changes in the first 3 months of the COVID-19 pandemic in the U.S. were more likely to have worse disease activity and higher exposure to prior DMARDs, but no statistical difference was found in terms of comorbidities,” first author Kaleb Michaud, PhD, and coauthors wrote. Dr. Michaud is with the National Databank for Rheumatic Diseases, Wichita, Kan., and the University of Nebraska Medical Center, Omaha.

The study evaluated responses from 734 adults who participated in FORWARD, an observational, multidisease registry. They answered online surveys about COVID-19 in May 2020 and had provided data on their medication use before the pandemic. A total of 30% (n = 221) reported medication changes in that period.
 

Details on medication changes

Medication changers were more likely to use glucocorticoids (GCs) (32.6% vs. 18.1%) and less likely to use nonhydroxychloroquine conventional DMARDs (49.3% vs. 62%) pre-COVID. Changers also reported higher rates of economic hardship during the pandemic (22.6% vs. 14.6%).

In the midst of the study period, the ACR issued a clinical guideline for treatment of rheumatic and musculoskeletal diseases (RMDs), emphasizing the need to maintain DMARD therapy, control disease activity, and reduce prednisone/GC use. The guideline advised continuing hydroxychloroquine and interleukin-6 inhibitor biologics in people with suspected or confirmed COVID-19.

Dr. Michaud and coauthors acknowledged the ongoing lack of knowledge about real-world treatment patterns for RA during the pandemic. They set out with this study to fill those knowledge gaps.

They noted that patients on bDMARDs (17.6%) and JAK inhibitors (17.1%) were more than twice as likely to discontinue medications than were those on conventional DMARDs (8.2%).

Switching to telehealth was the most common pandemic-related behavior change among patients in all DMARD groups, with rates ranging from 31% to 47.1%, followed by canceling or postponing appointments, with rates ranging from 27.9% to 36.4% depending on the DMARD group.

The study also found that RA patients widely adopted the behavior changes that the Centers for Disease Control and Prevention recommended during the pandemic, although the rates of restricting social contacts were significantly lower than the 90% reported in an early Italian study.

Dr. Michaud and coauthors also provided some explanation of why people on GCs and DMARDs were more likely than others to change medication patterns. “This may reflect efforts to reduce the perceived risk of infections due to GCs as well as the likely less-controlled disease activity associated with GC use,” they wrote. While the ACR’s early pandemic guidance followed the 2015 guidelines – that patients should continue on GCs at the “lowest possible dose” and not stop them “abruptly” – most U.S. rheumatologists reported cutting back on GC use during the pandemic.

The researchers acknowledged that evidence linking GC use with hospitalization for COVID-19, which emerged after they had surveyed study participants, was consistent their findings, but that the overall risk of COVID-19 in RA patients still isn’t known.

Pfizer funded the analysis, and a coauthor is an employee of Pfizer.

Although most patients with chronic inflammatory diseases mounted immune responses after two doses of mRNA-based COVID-19 vaccines, glucocorticoids and B-cell–depleting therapies markedly reduced the response, according to a recently published preprint of a new study.

Mongkolchon Akesin/Getty Images

The study, published on MedRxiv and not yet peer reviewed, involved a prospective look at 133 patients with chronic inflammatory disease (CID) and 53 patients with healthy immune systems at Washington University, St. Louis, and the University of California, San Francisco. It is regarded as the largest and most detailed study yet in how vaccines perform in people with immune-mediated inflammatory disease. The patients were enrolled between December 2020 and March 2021, and the most common diseases were inflammatory bowel disease (32%), rheumatoid arthritis (29%), spondyloarthritis (15%), and systemic lupus erythematosus (11%).
 

A ‘modest’ reduction in antibody response

Senior author Alfred Kim, MD, PhD, of the department of medicine at Washington University, said the overall results so far are encouraging.

“Most patients with an autoimmune disease that are on immunosuppression can mount antibody responses,” he said. “We’re seeing the majority of our subjects respond.”

The immune-healthy controls and most of the patients with CID had a robust immune response against the spike protein, although the CID group had a mean reduction in antibody titers that was three times lower than the controls (P = .0092). The CID group similarly had a 2.7-fold reduction in preventing neutralization, or halting the virus’ ability to infect (P < .0001), researchers reported.

This reduction in response is “modest,” he said.

“Is the level of reduction going to be detrimental for protection? Time will tell,” he said, adding that researchers anticipate that it won’t have a critical effect on protection because responses tended to be within the range of the immunocompetent controls, who themselves had wildly varied antibody titers across a 20-fold range. “ ‘Optimal’ isn’t necessarily the same as ‘sufficient.’ ”
 

Type of medication has big impact on antibody titers

But there was a wide variety of effects on the immune response depending on the medication. Glucorticoids resulted in a response that was 10 times lower than the immune-healthy controls, as well as fewer circulating plasmablasts after vaccination. Researchers found that 98% of controls were seropositive for antibody, compared with 92% of those with CID who were not taking prednisone, and 65% of CID patients on prednisone (P = .0006 and .0115, respectively). Prevention of neutralization of the virus was similarly reduced in those groups, compared with the controls. Dr. Kim noted this was a small sample size, with about 15 patients. These effects were seen regardless of the dose.

“We would’ve anticipated this would have been dose dependent, so this was a little bit surprising,” Dr. Kim said.

B-cell–depleting therapies, such as rituximab (Rituxan) and ocrelizumab (Ocrevus), reduced antibody titers by 36 times, compared with controls (P < .0001), with a similar reduction in preventing infection (P = .0066), the researchers found. The reduction in antibody titers was the most pronounced among those who had received B-cell–depleting therapies within the previous 6 months. Dr. Kim noted this was a small sample size, with about 10 patients.

CID study subjects taking an antimetabolite, including methotrexate, had an average of a two- to threefold reduction in antibody titers and in neutralization (P = .0006). This reduction was greatest with methotrexate, researchers found (P = .0027).

JAK inhibitors also significantly reduced antibody titers (P = .0066), but the reduction in neutralization of the virus was not significant. In addition, researchers found a reduction in antibody titers, the prevention of viral infection, and circulating plasmablasts among those on tumor necrosis factor (TNF) inhibitors, compared with controls, but these were insignificant statistically except for virus neutralization.

Dr. Kim said he hopes the glucocorticoid data spur physicians to try harder to wean patients off the drugs, when possible, in keeping with recommendations already in place.

“The general culture in rheumatology has been very lax about the need to reduce glucocorticoids,” he said. “This reinvigorates that call.” Questions about possible drug holidays from glucocorticoids remain, regarding how long a holiday would be needed, he said. He noted that many patients on glucocorticoids nonetheless mounted responses.

Those on B-cell–depleting therapies present a “much more difficult” question, he said. Some patients possibly could wait a bit longer than their normal, every-6-month schedule, but it’s an individual decision, he said. Since a booster of influenza vaccine has been found to enhance the response even within the 6-month window among ocrelizumab patients, a booster of COVID-19 vaccine might also help, although this remains to be studied.

The study group has already increased its sample size and is looking at adverse reactions and long-term immune responses, Dr. Kim said.

Encouraging, rather than discouraging, results

Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic in Ohio, said the findings shouldn’t discourage clinicians from encouraging vaccination.

“There’s still a preponderance of people who will develop a robust antibody vaccine response,” he said.

He cautioned that the findings look only at antibodies to the spike protein and at plasmablasts. The reduction in these titers is “of concern,” he said, but “we don’t really know with certainty what are the effects of these drugs, and these data are on the overall biologic protective effect of the vaccine. There’s much more to a vaccine response than anti–spike protein and plasmablasts,” including cell-mediated immune response.

For an individual patient, the findings “mean a lot,” he said.

“I think that people who are on significant prednisone and B-cell–depleting agents, I think you have to share with them that there’s a reasonable chance that you’re not going to be making a response similar to healthy people,” he said. “Thus, even with your vaccine, we’re not going to cut you loose to do things that are violating social distancing and group settings. … Should you be hugging your grandchildren if you’re a rituximab vaccine recipient? I think I would wait until we have a little bit more data.”

Kevin Winthrop, MD, MPH, professor of ophthalmology at Oregon Health & Science University, Portland, where he studies vaccinations in the immunocompromised, said that glucocorticoids tend to have little effect on vaccinations generally at low doses.

When effects are seen they can be difficult to interpret, he said.

“It’s hard to extricate that from the effect of the underlying disease,” he said. The drug can be a proxy for worse disease control.

Although it’s a small study, it’s reassuring that overall the responses were similar to healthy controls.

For B-cell–depleting therapies, his usual guidance is to not give vaccine until a patient is at least 3 months out from their last dose, and not to restart until at least 2 weeks after vaccination.

“It’s not surprising that some of these DMARDs [disease-modifying antirheumatic drugs] do negatively affect vaccine response, particularly B-cell–depletion therapy. We need to do some studies to find a way to overcome that, or optimize delivery of the vaccine.”

Dr. Kim reported participating in consulting, advisory board, or speaker’s bureau for Alexion, Aurinia, Annexon Biosciences, Exagen Diagnostics, and GlaxoSmithKline, and receiving funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. Dr. Winthrop reported receiving consulting fees from Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, GlaxoSmithKline, Roche, Gilead, Bristol-Myers Squibb, Regeneron, Sanofi, AstraZeneca, Novartis, and research grants from Bristol-Myers Squibb and Pfizer. Dr. Calabrese reported no relevant disclosures.

Although most patients with chronic inflammatory diseases mounted immune responses after two doses of mRNA-based COVID-19 vaccines, glucocorticoids and B-cell–depleting therapies markedly reduced the response, according to a recently published preprint of a new study.

Mongkolchon Akesin/Getty Images

The study, published on MedRxiv and not yet peer reviewed, involved a prospective look at 133 patients with chronic inflammatory disease (CID) and 53 patients with healthy immune systems at Washington University, St. Louis, and the University of California, San Francisco. It is regarded as the largest and most detailed study yet in how vaccines perform in people with immune-mediated inflammatory disease. The patients were enrolled between December 2020 and March 2021, and the most common diseases were inflammatory bowel disease (32%), rheumatoid arthritis (29%), spondyloarthritis (15%), and systemic lupus erythematosus (11%).
 

A ‘modest’ reduction in antibody response

Senior author Alfred Kim, MD, PhD, of the department of medicine at Washington University, said the overall results so far are encouraging.

“Most patients with an autoimmune disease that are on immunosuppression can mount antibody responses,” he said. “We’re seeing the majority of our subjects respond.”

The immune-healthy controls and most of the patients with CID had a robust immune response against the spike protein, although the CID group had a mean reduction in antibody titers that was three times lower than the controls (P = .0092). The CID group similarly had a 2.7-fold reduction in preventing neutralization, or halting the virus’ ability to infect (P < .0001), researchers reported.

This reduction in response is “modest,” he said.

“Is the level of reduction going to be detrimental for protection? Time will tell,” he said, adding that researchers anticipate that it won’t have a critical effect on protection because responses tended to be within the range of the immunocompetent controls, who themselves had wildly varied antibody titers across a 20-fold range. “ ‘Optimal’ isn’t necessarily the same as ‘sufficient.’ ”
 

Type of medication has big impact on antibody titers

But there was a wide variety of effects on the immune response depending on the medication. Glucorticoids resulted in a response that was 10 times lower than the immune-healthy controls, as well as fewer circulating plasmablasts after vaccination. Researchers found that 98% of controls were seropositive for antibody, compared with 92% of those with CID who were not taking prednisone, and 65% of CID patients on prednisone (P = .0006 and .0115, respectively). Prevention of neutralization of the virus was similarly reduced in those groups, compared with the controls. Dr. Kim noted this was a small sample size, with about 15 patients. These effects were seen regardless of the dose.

“We would’ve anticipated this would have been dose dependent, so this was a little bit surprising,” Dr. Kim said.

B-cell–depleting therapies, such as rituximab (Rituxan) and ocrelizumab (Ocrevus), reduced antibody titers by 36 times, compared with controls (P < .0001), with a similar reduction in preventing infection (P = .0066), the researchers found. The reduction in antibody titers was the most pronounced among those who had received B-cell–depleting therapies within the previous 6 months. Dr. Kim noted this was a small sample size, with about 10 patients.

CID study subjects taking an antimetabolite, including methotrexate, had an average of a two- to threefold reduction in antibody titers and in neutralization (P = .0006). This reduction was greatest with methotrexate, researchers found (P = .0027).

JAK inhibitors also significantly reduced antibody titers (P = .0066), but the reduction in neutralization of the virus was not significant. In addition, researchers found a reduction in antibody titers, the prevention of viral infection, and circulating plasmablasts among those on tumor necrosis factor (TNF) inhibitors, compared with controls, but these were insignificant statistically except for virus neutralization.

Dr. Kim said he hopes the glucocorticoid data spur physicians to try harder to wean patients off the drugs, when possible, in keeping with recommendations already in place.

“The general culture in rheumatology has been very lax about the need to reduce glucocorticoids,” he said. “This reinvigorates that call.” Questions about possible drug holidays from glucocorticoids remain, regarding how long a holiday would be needed, he said. He noted that many patients on glucocorticoids nonetheless mounted responses.

Those on B-cell–depleting therapies present a “much more difficult” question, he said. Some patients possibly could wait a bit longer than their normal, every-6-month schedule, but it’s an individual decision, he said. Since a booster of influenza vaccine has been found to enhance the response even within the 6-month window among ocrelizumab patients, a booster of COVID-19 vaccine might also help, although this remains to be studied.

The study group has already increased its sample size and is looking at adverse reactions and long-term immune responses, Dr. Kim said.

Encouraging, rather than discouraging, results

Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic in Ohio, said the findings shouldn’t discourage clinicians from encouraging vaccination.

“There’s still a preponderance of people who will develop a robust antibody vaccine response,” he said.

He cautioned that the findings look only at antibodies to the spike protein and at plasmablasts. The reduction in these titers is “of concern,” he said, but “we don’t really know with certainty what are the effects of these drugs, and these data are on the overall biologic protective effect of the vaccine. There’s much more to a vaccine response than anti–spike protein and plasmablasts,” including cell-mediated immune response.

For an individual patient, the findings “mean a lot,” he said.

“I think that people who are on significant prednisone and B-cell–depleting agents, I think you have to share with them that there’s a reasonable chance that you’re not going to be making a response similar to healthy people,” he said. “Thus, even with your vaccine, we’re not going to cut you loose to do things that are violating social distancing and group settings. … Should you be hugging your grandchildren if you’re a rituximab vaccine recipient? I think I would wait until we have a little bit more data.”

Kevin Winthrop, MD, MPH, professor of ophthalmology at Oregon Health & Science University, Portland, where he studies vaccinations in the immunocompromised, said that glucocorticoids tend to have little effect on vaccinations generally at low doses.

When effects are seen they can be difficult to interpret, he said.

“It’s hard to extricate that from the effect of the underlying disease,” he said. The drug can be a proxy for worse disease control.

Although it’s a small study, it’s reassuring that overall the responses were similar to healthy controls.

For B-cell–depleting therapies, his usual guidance is to not give vaccine until a patient is at least 3 months out from their last dose, and not to restart until at least 2 weeks after vaccination.

“It’s not surprising that some of these DMARDs [disease-modifying antirheumatic drugs] do negatively affect vaccine response, particularly B-cell–depletion therapy. We need to do some studies to find a way to overcome that, or optimize delivery of the vaccine.”

Dr. Kim reported participating in consulting, advisory board, or speaker’s bureau for Alexion, Aurinia, Annexon Biosciences, Exagen Diagnostics, and GlaxoSmithKline, and receiving funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. Dr. Winthrop reported receiving consulting fees from Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, GlaxoSmithKline, Roche, Gilead, Bristol-Myers Squibb, Regeneron, Sanofi, AstraZeneca, Novartis, and research grants from Bristol-Myers Squibb and Pfizer. Dr. Calabrese reported no relevant disclosures.

Although most patients with chronic inflammatory diseases mounted immune responses after two doses of mRNA-based COVID-19 vaccines, glucocorticoids and B-cell–depleting therapies markedly reduced the response, according to a recently published preprint of a new study.

Mongkolchon Akesin/Getty Images

The study, published on MedRxiv and not yet peer reviewed, involved a prospective look at 133 patients with chronic inflammatory disease (CID) and 53 patients with healthy immune systems at Washington University, St. Louis, and the University of California, San Francisco. It is regarded as the largest and most detailed study yet in how vaccines perform in people with immune-mediated inflammatory disease. The patients were enrolled between December 2020 and March 2021, and the most common diseases were inflammatory bowel disease (32%), rheumatoid arthritis (29%), spondyloarthritis (15%), and systemic lupus erythematosus (11%).
 

A ‘modest’ reduction in antibody response

Senior author Alfred Kim, MD, PhD, of the department of medicine at Washington University, said the overall results so far are encouraging.

“Most patients with an autoimmune disease that are on immunosuppression can mount antibody responses,” he said. “We’re seeing the majority of our subjects respond.”

The immune-healthy controls and most of the patients with CID had a robust immune response against the spike protein, although the CID group had a mean reduction in antibody titers that was three times lower than the controls (P = .0092). The CID group similarly had a 2.7-fold reduction in preventing neutralization, or halting the virus’ ability to infect (P < .0001), researchers reported.

This reduction in response is “modest,” he said.

“Is the level of reduction going to be detrimental for protection? Time will tell,” he said, adding that researchers anticipate that it won’t have a critical effect on protection because responses tended to be within the range of the immunocompetent controls, who themselves had wildly varied antibody titers across a 20-fold range. “ ‘Optimal’ isn’t necessarily the same as ‘sufficient.’ ”
 

Type of medication has big impact on antibody titers

But there was a wide variety of effects on the immune response depending on the medication. Glucorticoids resulted in a response that was 10 times lower than the immune-healthy controls, as well as fewer circulating plasmablasts after vaccination. Researchers found that 98% of controls were seropositive for antibody, compared with 92% of those with CID who were not taking prednisone, and 65% of CID patients on prednisone (P = .0006 and .0115, respectively). Prevention of neutralization of the virus was similarly reduced in those groups, compared with the controls. Dr. Kim noted this was a small sample size, with about 15 patients. These effects were seen regardless of the dose.

“We would’ve anticipated this would have been dose dependent, so this was a little bit surprising,” Dr. Kim said.

B-cell–depleting therapies, such as rituximab (Rituxan) and ocrelizumab (Ocrevus), reduced antibody titers by 36 times, compared with controls (P < .0001), with a similar reduction in preventing infection (P = .0066), the researchers found. The reduction in antibody titers was the most pronounced among those who had received B-cell–depleting therapies within the previous 6 months. Dr. Kim noted this was a small sample size, with about 10 patients.

CID study subjects taking an antimetabolite, including methotrexate, had an average of a two- to threefold reduction in antibody titers and in neutralization (P = .0006). This reduction was greatest with methotrexate, researchers found (P = .0027).

JAK inhibitors also significantly reduced antibody titers (P = .0066), but the reduction in neutralization of the virus was not significant. In addition, researchers found a reduction in antibody titers, the prevention of viral infection, and circulating plasmablasts among those on tumor necrosis factor (TNF) inhibitors, compared with controls, but these were insignificant statistically except for virus neutralization.

Dr. Kim said he hopes the glucocorticoid data spur physicians to try harder to wean patients off the drugs, when possible, in keeping with recommendations already in place.

“The general culture in rheumatology has been very lax about the need to reduce glucocorticoids,” he said. “This reinvigorates that call.” Questions about possible drug holidays from glucocorticoids remain, regarding how long a holiday would be needed, he said. He noted that many patients on glucocorticoids nonetheless mounted responses.

Those on B-cell–depleting therapies present a “much more difficult” question, he said. Some patients possibly could wait a bit longer than their normal, every-6-month schedule, but it’s an individual decision, he said. Since a booster of influenza vaccine has been found to enhance the response even within the 6-month window among ocrelizumab patients, a booster of COVID-19 vaccine might also help, although this remains to be studied.

The study group has already increased its sample size and is looking at adverse reactions and long-term immune responses, Dr. Kim said.

Encouraging, rather than discouraging, results

Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic in Ohio, said the findings shouldn’t discourage clinicians from encouraging vaccination.

“There’s still a preponderance of people who will develop a robust antibody vaccine response,” he said.

He cautioned that the findings look only at antibodies to the spike protein and at plasmablasts. The reduction in these titers is “of concern,” he said, but “we don’t really know with certainty what are the effects of these drugs, and these data are on the overall biologic protective effect of the vaccine. There’s much more to a vaccine response than anti–spike protein and plasmablasts,” including cell-mediated immune response.

For an individual patient, the findings “mean a lot,” he said.

“I think that people who are on significant prednisone and B-cell–depleting agents, I think you have to share with them that there’s a reasonable chance that you’re not going to be making a response similar to healthy people,” he said. “Thus, even with your vaccine, we’re not going to cut you loose to do things that are violating social distancing and group settings. … Should you be hugging your grandchildren if you’re a rituximab vaccine recipient? I think I would wait until we have a little bit more data.”

Kevin Winthrop, MD, MPH, professor of ophthalmology at Oregon Health & Science University, Portland, where he studies vaccinations in the immunocompromised, said that glucocorticoids tend to have little effect on vaccinations generally at low doses.

When effects are seen they can be difficult to interpret, he said.

“It’s hard to extricate that from the effect of the underlying disease,” he said. The drug can be a proxy for worse disease control.

Although it’s a small study, it’s reassuring that overall the responses were similar to healthy controls.

For B-cell–depleting therapies, his usual guidance is to not give vaccine until a patient is at least 3 months out from their last dose, and not to restart until at least 2 weeks after vaccination.

“It’s not surprising that some of these DMARDs [disease-modifying antirheumatic drugs] do negatively affect vaccine response, particularly B-cell–depletion therapy. We need to do some studies to find a way to overcome that, or optimize delivery of the vaccine.”

Dr. Kim reported participating in consulting, advisory board, or speaker’s bureau for Alexion, Aurinia, Annexon Biosciences, Exagen Diagnostics, and GlaxoSmithKline, and receiving funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. Dr. Winthrop reported receiving consulting fees from Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, GlaxoSmithKline, Roche, Gilead, Bristol-Myers Squibb, Regeneron, Sanofi, AstraZeneca, Novartis, and research grants from Bristol-Myers Squibb and Pfizer. Dr. Calabrese reported no relevant disclosures.

The Food and Drug Administration has approved a new estrogen for the first time in more than 50 years.

The novel combined oral contraceptive, marketed as Nextstellis, contains 3 mg drospirenone (DRSP) and 14.2 mg of estetrol (E4) in tablet form. Estetrol is an estrogen that is naturally produced during pregnancy, but will now be produced from a plant source; it has not previously been used in oral contraceptives.

Approval of the unique estetrol/drospirenone combination was based on data from a pair of phase 3 clinical trials including 3,725 women. Overall, Nextstellis was safe and effective while meeting its primary endpoint of pregnancy prevention, according to a company press release. Participants also reported favorable results on secondary endpoints including cycle control, bleeding profile, safety, and tolerability.

Although many women take short-acting contraceptives containing estrogen and progestin, concerns persist about side effects, said Mitchell Creinin, MD, of the University of California, in the press release. In addition to providing effective contraception, the drug showed minimal impact on specific markers of concern, including triglycerides, cholesterol, and glucose, as well as weight and endocrine markers, Dr. Creinin said.

Nextstellis was developed by the Belgian biotech company Mithra Pharmaceuticals, and the drug is licensed for distribution in Australia and the United States by Mayne Pharma, with an expected launch at the end of June 2021.

The Food and Drug Administration has approved a new estrogen for the first time in more than 50 years.

The novel combined oral contraceptive, marketed as Nextstellis, contains 3 mg drospirenone (DRSP) and 14.2 mg of estetrol (E4) in tablet form. Estetrol is an estrogen that is naturally produced during pregnancy, but will now be produced from a plant source; it has not previously been used in oral contraceptives.

Approval of the unique estetrol/drospirenone combination was based on data from a pair of phase 3 clinical trials including 3,725 women. Overall, Nextstellis was safe and effective while meeting its primary endpoint of pregnancy prevention, according to a company press release. Participants also reported favorable results on secondary endpoints including cycle control, bleeding profile, safety, and tolerability.

Although many women take short-acting contraceptives containing estrogen and progestin, concerns persist about side effects, said Mitchell Creinin, MD, of the University of California, in the press release. In addition to providing effective contraception, the drug showed minimal impact on specific markers of concern, including triglycerides, cholesterol, and glucose, as well as weight and endocrine markers, Dr. Creinin said.

Nextstellis was developed by the Belgian biotech company Mithra Pharmaceuticals, and the drug is licensed for distribution in Australia and the United States by Mayne Pharma, with an expected launch at the end of June 2021.

The Food and Drug Administration has approved a new estrogen for the first time in more than 50 years.

The novel combined oral contraceptive, marketed as Nextstellis, contains 3 mg drospirenone (DRSP) and 14.2 mg of estetrol (E4) in tablet form. Estetrol is an estrogen that is naturally produced during pregnancy, but will now be produced from a plant source; it has not previously been used in oral contraceptives.

Approval of the unique estetrol/drospirenone combination was based on data from a pair of phase 3 clinical trials including 3,725 women. Overall, Nextstellis was safe and effective while meeting its primary endpoint of pregnancy prevention, according to a company press release. Participants also reported favorable results on secondary endpoints including cycle control, bleeding profile, safety, and tolerability.

Although many women take short-acting contraceptives containing estrogen and progestin, concerns persist about side effects, said Mitchell Creinin, MD, of the University of California, in the press release. In addition to providing effective contraception, the drug showed minimal impact on specific markers of concern, including triglycerides, cholesterol, and glucose, as well as weight and endocrine markers, Dr. Creinin said.

Nextstellis was developed by the Belgian biotech company Mithra Pharmaceuticals, and the drug is licensed for distribution in Australia and the United States by Mayne Pharma, with an expected launch at the end of June 2021.

Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.

The team was headed by Harald zur Hausen, MD, PhD, division of episomal-persistent DNA in cancer and chronic diseases, German Cancer Research Center, Heidelberg, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papillomaviruses in the development of cervical cancer.

The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published in the Proceedings of the National Academy of Sciences.

“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Dr. Hausen said in a related press statement.
 

Pathogenic agents, found in vicinity of tumors

BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.

A few years ago, Dr. Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.

They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.

The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.

In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.

The team found that BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of proinflammatory macrophages.

The researchers also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep versus just 1.7% of those in the control group.

In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.

“These oxygen radicals promote the development of genetic changes,” Dr. Hausen said.

The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.

“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Dr. Hausen explained.

He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.

The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.

The researchers stressed, however, that further study will be required to confirm the results.

They nevertheless believed that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.

Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers via the reduction of chronic inflammation.

This work was supported by an unrestricted grant from ORYX Alpha. One coauthor was supported by the EOS Foundation, the SFBTR-179 and 209, and a European Research Council consolidator grant. The other coauthors disclosed no relevant financial relationships.

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

Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.

The team was headed by Harald zur Hausen, MD, PhD, division of episomal-persistent DNA in cancer and chronic diseases, German Cancer Research Center, Heidelberg, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papillomaviruses in the development of cervical cancer.

The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published in the Proceedings of the National Academy of Sciences.

“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Dr. Hausen said in a related press statement.
 

Pathogenic agents, found in vicinity of tumors

BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.

A few years ago, Dr. Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.

They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.

The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.

In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.

The team found that BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of proinflammatory macrophages.

The researchers also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep versus just 1.7% of those in the control group.

In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.

“These oxygen radicals promote the development of genetic changes,” Dr. Hausen said.

The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.

“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Dr. Hausen explained.

He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.

The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.

The researchers stressed, however, that further study will be required to confirm the results.

They nevertheless believed that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.

Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers via the reduction of chronic inflammation.

This work was supported by an unrestricted grant from ORYX Alpha. One coauthor was supported by the EOS Foundation, the SFBTR-179 and 209, and a European Research Council consolidator grant. The other coauthors disclosed no relevant financial relationships.

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

Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.

The team was headed by Harald zur Hausen, MD, PhD, division of episomal-persistent DNA in cancer and chronic diseases, German Cancer Research Center, Heidelberg, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papillomaviruses in the development of cervical cancer.

The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published in the Proceedings of the National Academy of Sciences.

“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Dr. Hausen said in a related press statement.
 

Pathogenic agents, found in vicinity of tumors

BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.

A few years ago, Dr. Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.

They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.

The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.

In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.

The team found that BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of proinflammatory macrophages.

The researchers also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep versus just 1.7% of those in the control group.

In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.

“These oxygen radicals promote the development of genetic changes,” Dr. Hausen said.

The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.

“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Dr. Hausen explained.

He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.

The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.

The researchers stressed, however, that further study will be required to confirm the results.

They nevertheless believed that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.

Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers via the reduction of chronic inflammation.

This work was supported by an unrestricted grant from ORYX Alpha. One coauthor was supported by the EOS Foundation, the SFBTR-179 and 209, and a European Research Council consolidator grant. The other coauthors disclosed no relevant financial relationships.

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

Rare is the parent who has never so much as thought about spanking an unruly child. But a new study provides another reason to avoid corporal punishment: Spanking may cause changes in the same areas of a child’s brain that are affected by more severe physical and sexual abuse.

Previous research has consistently found links between spanking and behavioral problems, aggression, depression, and anxiety, says Jorge Cuartas, a doctoral candidate at the Harvard Graduate School of Education and first author of the study. “We wanted to look at one potential mechanism, brain development, that might explain how corporal punishment can impact children’s behavior and cognitive development.”

The study, published in Child Development, used functional MRIs to map brain changes in 147 tweens who’d never experienced physical or sexual abuse. Researchers tracked which parts of the children’s brains activated in response to neutral or fearful facial expressions. When shown pictures of someone looking fearful, kids who reported having been spanked had a larger response in certain parts of the brain than kids who hadn’t been. Those areas drive the response to environmental cues, recognizing threats and reacting to them. If a child’s brain overreacts, behavioral challenges can result.

“We saw those changes in the same areas as more severe forms of abuse or domestic violence. It suggests the difference is of degree rather than type,” Mr. Cuartas says. As far as a child’s brain is concerned, “It’s all violence.”

It’s a significant finding because many parents don’t think of spanking as being violent, says Vincent J. Palusci, MD, a pediatrician and editor-in-chief of the journal Child Maltreatment. “We want to raise kids who are happy and healthy, and many parents who use spanking are doing it with that goal.”
 

Spanking in the U.S.

Around the world, 62 states and countries have outlawed corporal punishment. While the U.S. has no such protections, both the American Academy of Pediatrics and the American Psychological Association have condemned the practice. Acceptance of spanking seems to be shrinking: The percentage of parents in this country who say they spank their children is trending downward. In 1993, 50% of parents surveyed said they did, but by 2017 that number had fallen to 35%. Still far too many, Mr. Cuartas and Dr. Palusci say, but a promising trend.

“While we wouldn’t as parents want to hurt our kids,” Dr. Palusci says, “we need to understand that spanking can be just as bad as things we’d never do.”
 

Discipline vs. punishment

For some parents, it may require a shift in thinking, differentiating between discipline and punishment. “Discipline changes behavior – it teaches positive behavior, empathy, essential social skills. But that’s different from punishment,” Mr. Cuartas says. “That makes somebody feel pain or shame. We have to start thinking about spanking as punishment.”

That can be difficult, especially for adults who’ve been spanked themselves. They may believe that since they turned out fine, spanking must be fine, too. But the study doesn’t suggest that every child who’s spanked will have these difficulties – it just shows they happen, Mr. Cuartas says. “Compare this to smoking. We all know someone who smokes who’s healthy, but that doesn’t mean smoking is good,” he says. “Individual cases aren’t enough to understand whether certain experiences are good or bad.”

Dr. Palusci draws parallels to the advice pregnant women receive about taking medications: If it hasn’t been tested in pregnancy specifically, no amount can be considered safe. “We don’t have the studies to say how much spanking is dangerous, so we have to think that any amount has this potential.”

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

Rare is the parent who has never so much as thought about spanking an unruly child. But a new study provides another reason to avoid corporal punishment: Spanking may cause changes in the same areas of a child’s brain that are affected by more severe physical and sexual abuse.

Previous research has consistently found links between spanking and behavioral problems, aggression, depression, and anxiety, says Jorge Cuartas, a doctoral candidate at the Harvard Graduate School of Education and first author of the study. “We wanted to look at one potential mechanism, brain development, that might explain how corporal punishment can impact children’s behavior and cognitive development.”

The study, published in Child Development, used functional MRIs to map brain changes in 147 tweens who’d never experienced physical or sexual abuse. Researchers tracked which parts of the children’s brains activated in response to neutral or fearful facial expressions. When shown pictures of someone looking fearful, kids who reported having been spanked had a larger response in certain parts of the brain than kids who hadn’t been. Those areas drive the response to environmental cues, recognizing threats and reacting to them. If a child’s brain overreacts, behavioral challenges can result.

“We saw those changes in the same areas as more severe forms of abuse or domestic violence. It suggests the difference is of degree rather than type,” Mr. Cuartas says. As far as a child’s brain is concerned, “It’s all violence.”

It’s a significant finding because many parents don’t think of spanking as being violent, says Vincent J. Palusci, MD, a pediatrician and editor-in-chief of the journal Child Maltreatment. “We want to raise kids who are happy and healthy, and many parents who use spanking are doing it with that goal.”
 

Spanking in the U.S.

Around the world, 62 states and countries have outlawed corporal punishment. While the U.S. has no such protections, both the American Academy of Pediatrics and the American Psychological Association have condemned the practice. Acceptance of spanking seems to be shrinking: The percentage of parents in this country who say they spank their children is trending downward. In 1993, 50% of parents surveyed said they did, but by 2017 that number had fallen to 35%. Still far too many, Mr. Cuartas and Dr. Palusci say, but a promising trend.

“While we wouldn’t as parents want to hurt our kids,” Dr. Palusci says, “we need to understand that spanking can be just as bad as things we’d never do.”
 

Discipline vs. punishment

For some parents, it may require a shift in thinking, differentiating between discipline and punishment. “Discipline changes behavior – it teaches positive behavior, empathy, essential social skills. But that’s different from punishment,” Mr. Cuartas says. “That makes somebody feel pain or shame. We have to start thinking about spanking as punishment.”

That can be difficult, especially for adults who’ve been spanked themselves. They may believe that since they turned out fine, spanking must be fine, too. But the study doesn’t suggest that every child who’s spanked will have these difficulties – it just shows they happen, Mr. Cuartas says. “Compare this to smoking. We all know someone who smokes who’s healthy, but that doesn’t mean smoking is good,” he says. “Individual cases aren’t enough to understand whether certain experiences are good or bad.”

Dr. Palusci draws parallels to the advice pregnant women receive about taking medications: If it hasn’t been tested in pregnancy specifically, no amount can be considered safe. “We don’t have the studies to say how much spanking is dangerous, so we have to think that any amount has this potential.”

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

Rare is the parent who has never so much as thought about spanking an unruly child. But a new study provides another reason to avoid corporal punishment: Spanking may cause changes in the same areas of a child’s brain that are affected by more severe physical and sexual abuse.

Previous research has consistently found links between spanking and behavioral problems, aggression, depression, and anxiety, says Jorge Cuartas, a doctoral candidate at the Harvard Graduate School of Education and first author of the study. “We wanted to look at one potential mechanism, brain development, that might explain how corporal punishment can impact children’s behavior and cognitive development.”

The study, published in Child Development, used functional MRIs to map brain changes in 147 tweens who’d never experienced physical or sexual abuse. Researchers tracked which parts of the children’s brains activated in response to neutral or fearful facial expressions. When shown pictures of someone looking fearful, kids who reported having been spanked had a larger response in certain parts of the brain than kids who hadn’t been. Those areas drive the response to environmental cues, recognizing threats and reacting to them. If a child’s brain overreacts, behavioral challenges can result.

“We saw those changes in the same areas as more severe forms of abuse or domestic violence. It suggests the difference is of degree rather than type,” Mr. Cuartas says. As far as a child’s brain is concerned, “It’s all violence.”

It’s a significant finding because many parents don’t think of spanking as being violent, says Vincent J. Palusci, MD, a pediatrician and editor-in-chief of the journal Child Maltreatment. “We want to raise kids who are happy and healthy, and many parents who use spanking are doing it with that goal.”
 

Spanking in the U.S.

Around the world, 62 states and countries have outlawed corporal punishment. While the U.S. has no such protections, both the American Academy of Pediatrics and the American Psychological Association have condemned the practice. Acceptance of spanking seems to be shrinking: The percentage of parents in this country who say they spank their children is trending downward. In 1993, 50% of parents surveyed said they did, but by 2017 that number had fallen to 35%. Still far too many, Mr. Cuartas and Dr. Palusci say, but a promising trend.

“While we wouldn’t as parents want to hurt our kids,” Dr. Palusci says, “we need to understand that spanking can be just as bad as things we’d never do.”
 

Discipline vs. punishment

For some parents, it may require a shift in thinking, differentiating between discipline and punishment. “Discipline changes behavior – it teaches positive behavior, empathy, essential social skills. But that’s different from punishment,” Mr. Cuartas says. “That makes somebody feel pain or shame. We have to start thinking about spanking as punishment.”

That can be difficult, especially for adults who’ve been spanked themselves. They may believe that since they turned out fine, spanking must be fine, too. But the study doesn’t suggest that every child who’s spanked will have these difficulties – it just shows they happen, Mr. Cuartas says. “Compare this to smoking. We all know someone who smokes who’s healthy, but that doesn’t mean smoking is good,” he says. “Individual cases aren’t enough to understand whether certain experiences are good or bad.”

Dr. Palusci draws parallels to the advice pregnant women receive about taking medications: If it hasn’t been tested in pregnancy specifically, no amount can be considered safe. “We don’t have the studies to say how much spanking is dangerous, so we have to think that any amount has this potential.”

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

The first artificial intelligence (AI) endoscopy module developed specifically to help detect adenomas during routine colonoscopy is making its debut following approval by the Food and Drug Administration on April 9.

The GI Genius module is the first and only commercially available computer-aided detection system that uses AI to identify colorectal polyps during routine colonoscopy.

The technology is compatible with most standard video endoscopy systems and has been “trained” to identify colonic lesions that are possibly cancerous, according to Medtronic, the distributor of the device.

“I think that anything we can do within a reasonable cost that enhances quality and patient outcomes during colonoscopy warrants very close consideration,” David Johnson, MD, professor of medicine and chief of gastroenterology, Eastern Virginia Medical School, Norfolk, said in an interview.

He was not involved with the development of the GI Genius system but has worked with a similar AI device that is used in conjunction with colonoscopy.

“The whole development of the technology for AI is done by inputting repetitive images into the computer, where it develops what is called the ‘neural network,’ ” he explained.

The computer then draws upon the “education” of this neural network to identify different types of colonic lesions, “and the more inputs that are put into the computer to enhance the neural network, the more capable the program becomes in the identification of variants and lesion size and characteristics,” Dr. Johnson added.

During routine colonoscopy, the GI Genius system generates visual markers – essentially, small green squares – and a low-volume sound whenever the software detects a region of interest.

These squares are superimposed on the video generated by the endoscope camera to alert the colonoscopist to regions that may require closer assessment, either visually, by tissue sampling, or by removal of the lesion itself.

“Colonoscopy is a durable screening and surveillance strategy, but it’s not perfect [because] it depends on a physician’s skill and their ability to pick up polyps in the colon,” Jeremy Glissen Brown, MD, of Beth Israel Deaconess Medical Center, Boston, said in an interview. He has also worked with an AI device.

Studies of adenoma detection during “all-comer” colonoscopies show that the rate of missed lesions ranges from a low of 6% to 40%, “so polyps are still missed during colonoscopy, and any technology that can solve parts of that problem is welcome,” Dr. Glissen Brown commented.
 

Clinical trial data that led to approval

The recent FDA approval of the GI Genius device was based on a prospective, randomized trial that was published in Gastroenterology in 2020. That trial involved 700 patients who were being screened or followed with colonoscopy every 3 years or longer. Participants underwent either white-light standard colonoscopy with the assistance of the GI Genius technology or standard white-light colonoscopy alone.

Results showed that the combination of standard colonoscopy and the GI Genius module identified laboratory-confirmed adenomas or carcinomas in 54.8% of patients, compared with 40.4% of patients who underwent colonoscopy alone.

In the Gastroenterology article, the authors wrote that the “14% absolute increase in adenoma detection rate obtained by computer-aided detection (CADe) in our study indicates that failure in polyp recognition is a clinically relevant cause of miss rate. Of note, the efficacy of CADe in reversing such miss rate also indicates that the same operator who missed the lesion in the first place was able to correctly diagnose it when the lesion was presented by the CADe. This underlines that the main cognitive challenge in polyp recognition is the discrimination between the candidate lesion and the surrounding healthy mucosa, whereas its correct characterization as neoplastic tissue that occurs after CADe detection is apparently a much easier task.”

The authors also noted that they did “not assess the actual number of false-positive activations by the system, as this would have altered the routine setting of our study,” but they refer to a study published in Gut in 2020 in which false-positive frames were seen in fewer than 1% of frames from the whole colonoscopy.

Because the new device improves on the ability of colonoscopy to detect lesions overall, it may reduce the risk of interval cancers between colonoscopies, Medtronic suggests.

Previous research has shown that every 1% increase in the adenoma detection rate results in a 3% decrease in the risk for colorectal cancer.

“More than 19 million screening colonoscopies are performed in the United State each year. ... Detection of adenomas during colonoscopy is an important quality metric,” James Weber, MD, a gastroenterologist affiliated with Texas Digestive Disease Consultants, Southlake, commented in a Medtronic press release.

“The addition of AI can increase the quality of colonoscopies, potentially improving diagnosis and outcomes for colon cancer patients,” he added.

Dr. Weber is also the CEO of GI Alliance, a physician-led national health care platform of independent GI practices in six states in the United States.
 

Computer-aided detection

Unlike other computer-aided detection technologies, GI Genius does not characterize or “diagnose” a lesion, nor does it replace laboratory sampling as a means of confirming a cancer diagnosis.

The technology acts essentially as an extra set of expert “eyes” to detect suspicious lesions during colonoscopy, which should prove helpful, Dr. Johnson and Dr. Glissen Brown both commented.

“When a gastroenterologist looks at the video image, typically, our eyes are focused in the center of that image – that’s where our 20/20 vision is,” Dr. Johnson explained.

The computer has 20/20 vision over the whole image, including the periphery, “so the technology really gives an extremely expanded acuity of vision and highlights areas that we may need to investigate further,” he added.

Dr. Glissen Brown was involved in a trial of another AI device – the real-time automatic polyp detection system (Shanghai Wision AI). That study showed an increase in colonoscopic polyp and adenoma detection rates, but this was mainly because of a higher number of diminutive adenomas detected by the automatic detection system, Dr. Gliseen Brown said. There was no important difference in the number of larger adenomas detected with the device and the number detected without it.

However, there was a significant increase in the detection of hyperplastic polyps when the automatic detection system was used. “We definitely want to look at the false positive rate – both the false positive rate under the camera when we are doing colonoscopy and under the microscope when we do biopsies,” Dr. Glissen Brown acknowledged.

In numerous prospective studies of various computer-aided detection technologies such as the GI Genius system, the false positive rate resulting in the performance of biopsy of insignificant lesions is relatively low, he said.

“Ultimately, the decision to remove or biopsy a lesion is with the physician, because the GI Genius technology just points the provider to the area of concern, and then it’s up to them to look at it and decide whether it needs to be biopsied or not,” Dr. Glissen Brown said.

“So the technology serves more as a digital safety net and points the physician in the right direction, so it shouldn’t lead to much in the way of histologic false positives,” he noted.

The only potential disadvantage to using an AI system such as the GI Genius module is the time it might take for endoscopists to learn how to use it and how much the technology might increase the time required to perform the procedure, he added.

For about 18 months, Dr. Johnson has been running a clinical trial with a similar type of AI technology during colonoscopy. He has found that the learning curve for using these systems is “inordinately short.” Dr. Glissen Brown agreed and suggested that, if physicians are already performing colonoscopies regularly, they could probably learn to use an AI system such as GI Genius in about a week.

In his experience, Dr. Johnson has found that the delay caused by use of an AI system during colonoscopy is “minimal.”

If there is any delay at all, “we know that time in the colon on withdrawal increases the detection of polyps, so more time during withdrawal may be a good thing,” he added. It should be noted that endoscopy societies recommend a withdrawal time of at least 6 minutes, which is one of the metrics used to ensure the quality of a colonoscopy, Dr. Glissen Brown explained.

Indeed, the pivotal study upon which the FDA approved the GI Genius module required a minimum withdrawal time of 6 minutes. Participants said they did not find that using the GI Genius increased withdrawal time, he added.

“I think there is enough prospective evidence at this point to suggest that this technology may really be of benefit to clinicians with a lot of different skill levels, so I would be eager to know how clinicians interact with it in the clinical setting,” Dr. Glissen Brown commented.

Dr. Johnson agreed, noting that “even the good can get better.”

Dr. Johnson disclosed relationships with this news organization, CRH Medical, the American College of Gastroenterology Research Institute, and HyGIeaCare. Dr. Glissen Brown disclosed no relevant financial relationships.

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

Article updated April 21, 2021.

The first artificial intelligence (AI) endoscopy module developed specifically to help detect adenomas during routine colonoscopy is making its debut following approval by the Food and Drug Administration on April 9.

The GI Genius module is the first and only commercially available computer-aided detection system that uses AI to identify colorectal polyps during routine colonoscopy.

The technology is compatible with most standard video endoscopy systems and has been “trained” to identify colonic lesions that are possibly cancerous, according to Medtronic, the distributor of the device.

“I think that anything we can do within a reasonable cost that enhances quality and patient outcomes during colonoscopy warrants very close consideration,” David Johnson, MD, professor of medicine and chief of gastroenterology, Eastern Virginia Medical School, Norfolk, said in an interview.

He was not involved with the development of the GI Genius system but has worked with a similar AI device that is used in conjunction with colonoscopy.

“The whole development of the technology for AI is done by inputting repetitive images into the computer, where it develops what is called the ‘neural network,’ ” he explained.

The computer then draws upon the “education” of this neural network to identify different types of colonic lesions, “and the more inputs that are put into the computer to enhance the neural network, the more capable the program becomes in the identification of variants and lesion size and characteristics,” Dr. Johnson added.

During routine colonoscopy, the GI Genius system generates visual markers – essentially, small green squares – and a low-volume sound whenever the software detects a region of interest.

These squares are superimposed on the video generated by the endoscope camera to alert the colonoscopist to regions that may require closer assessment, either visually, by tissue sampling, or by removal of the lesion itself.

“Colonoscopy is a durable screening and surveillance strategy, but it’s not perfect [because] it depends on a physician’s skill and their ability to pick up polyps in the colon,” Jeremy Glissen Brown, MD, of Beth Israel Deaconess Medical Center, Boston, said in an interview. He has also worked with an AI device.

Studies of adenoma detection during “all-comer” colonoscopies show that the rate of missed lesions ranges from a low of 6% to 40%, “so polyps are still missed during colonoscopy, and any technology that can solve parts of that problem is welcome,” Dr. Glissen Brown commented.
 

Clinical trial data that led to approval

The recent FDA approval of the GI Genius device was based on a prospective, randomized trial that was published in Gastroenterology in 2020. That trial involved 700 patients who were being screened or followed with colonoscopy every 3 years or longer. Participants underwent either white-light standard colonoscopy with the assistance of the GI Genius technology or standard white-light colonoscopy alone.

Results showed that the combination of standard colonoscopy and the GI Genius module identified laboratory-confirmed adenomas or carcinomas in 54.8% of patients, compared with 40.4% of patients who underwent colonoscopy alone.

In the Gastroenterology article, the authors wrote that the “14% absolute increase in adenoma detection rate obtained by computer-aided detection (CADe) in our study indicates that failure in polyp recognition is a clinically relevant cause of miss rate. Of note, the efficacy of CADe in reversing such miss rate also indicates that the same operator who missed the lesion in the first place was able to correctly diagnose it when the lesion was presented by the CADe. This underlines that the main cognitive challenge in polyp recognition is the discrimination between the candidate lesion and the surrounding healthy mucosa, whereas its correct characterization as neoplastic tissue that occurs after CADe detection is apparently a much easier task.”

The authors also noted that they did “not assess the actual number of false-positive activations by the system, as this would have altered the routine setting of our study,” but they refer to a study published in Gut in 2020 in which false-positive frames were seen in fewer than 1% of frames from the whole colonoscopy.

Because the new device improves on the ability of colonoscopy to detect lesions overall, it may reduce the risk of interval cancers between colonoscopies, Medtronic suggests.

Previous research has shown that every 1% increase in the adenoma detection rate results in a 3% decrease in the risk for colorectal cancer.

“More than 19 million screening colonoscopies are performed in the United State each year. ... Detection of adenomas during colonoscopy is an important quality metric,” James Weber, MD, a gastroenterologist affiliated with Texas Digestive Disease Consultants, Southlake, commented in a Medtronic press release.

“The addition of AI can increase the quality of colonoscopies, potentially improving diagnosis and outcomes for colon cancer patients,” he added.

Dr. Weber is also the CEO of GI Alliance, a physician-led national health care platform of independent GI practices in six states in the United States.
 

Computer-aided detection

Unlike other computer-aided detection technologies, GI Genius does not characterize or “diagnose” a lesion, nor does it replace laboratory sampling as a means of confirming a cancer diagnosis.

The technology acts essentially as an extra set of expert “eyes” to detect suspicious lesions during colonoscopy, which should prove helpful, Dr. Johnson and Dr. Glissen Brown both commented.

“When a gastroenterologist looks at the video image, typically, our eyes are focused in the center of that image – that’s where our 20/20 vision is,” Dr. Johnson explained.

The computer has 20/20 vision over the whole image, including the periphery, “so the technology really gives an extremely expanded acuity of vision and highlights areas that we may need to investigate further,” he added.

Dr. Glissen Brown was involved in a trial of another AI device – the real-time automatic polyp detection system (Shanghai Wision AI). That study showed an increase in colonoscopic polyp and adenoma detection rates, but this was mainly because of a higher number of diminutive adenomas detected by the automatic detection system, Dr. Gliseen Brown said. There was no important difference in the number of larger adenomas detected with the device and the number detected without it.

However, there was a significant increase in the detection of hyperplastic polyps when the automatic detection system was used. “We definitely want to look at the false positive rate – both the false positive rate under the camera when we are doing colonoscopy and under the microscope when we do biopsies,” Dr. Glissen Brown acknowledged.

In numerous prospective studies of various computer-aided detection technologies such as the GI Genius system, the false positive rate resulting in the performance of biopsy of insignificant lesions is relatively low, he said.

“Ultimately, the decision to remove or biopsy a lesion is with the physician, because the GI Genius technology just points the provider to the area of concern, and then it’s up to them to look at it and decide whether it needs to be biopsied or not,” Dr. Glissen Brown said.

“So the technology serves more as a digital safety net and points the physician in the right direction, so it shouldn’t lead to much in the way of histologic false positives,” he noted.

The only potential disadvantage to using an AI system such as the GI Genius module is the time it might take for endoscopists to learn how to use it and how much the technology might increase the time required to perform the procedure, he added.

For about 18 months, Dr. Johnson has been running a clinical trial with a similar type of AI technology during colonoscopy. He has found that the learning curve for using these systems is “inordinately short.” Dr. Glissen Brown agreed and suggested that, if physicians are already performing colonoscopies regularly, they could probably learn to use an AI system such as GI Genius in about a week.

In his experience, Dr. Johnson has found that the delay caused by use of an AI system during colonoscopy is “minimal.”

If there is any delay at all, “we know that time in the colon on withdrawal increases the detection of polyps, so more time during withdrawal may be a good thing,” he added. It should be noted that endoscopy societies recommend a withdrawal time of at least 6 minutes, which is one of the metrics used to ensure the quality of a colonoscopy, Dr. Glissen Brown explained.

Indeed, the pivotal study upon which the FDA approved the GI Genius module required a minimum withdrawal time of 6 minutes. Participants said they did not find that using the GI Genius increased withdrawal time, he added.

“I think there is enough prospective evidence at this point to suggest that this technology may really be of benefit to clinicians with a lot of different skill levels, so I would be eager to know how clinicians interact with it in the clinical setting,” Dr. Glissen Brown commented.

Dr. Johnson agreed, noting that “even the good can get better.”

Dr. Johnson disclosed relationships with this news organization, CRH Medical, the American College of Gastroenterology Research Institute, and HyGIeaCare. Dr. Glissen Brown disclosed no relevant financial relationships.

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

Article updated April 21, 2021.

The first artificial intelligence (AI) endoscopy module developed specifically to help detect adenomas during routine colonoscopy is making its debut following approval by the Food and Drug Administration on April 9.

The GI Genius module is the first and only commercially available computer-aided detection system that uses AI to identify colorectal polyps during routine colonoscopy.

The technology is compatible with most standard video endoscopy systems and has been “trained” to identify colonic lesions that are possibly cancerous, according to Medtronic, the distributor of the device.

“I think that anything we can do within a reasonable cost that enhances quality and patient outcomes during colonoscopy warrants very close consideration,” David Johnson, MD, professor of medicine and chief of gastroenterology, Eastern Virginia Medical School, Norfolk, said in an interview.

He was not involved with the development of the GI Genius system but has worked with a similar AI device that is used in conjunction with colonoscopy.

“The whole development of the technology for AI is done by inputting repetitive images into the computer, where it develops what is called the ‘neural network,’ ” he explained.

The computer then draws upon the “education” of this neural network to identify different types of colonic lesions, “and the more inputs that are put into the computer to enhance the neural network, the more capable the program becomes in the identification of variants and lesion size and characteristics,” Dr. Johnson added.

During routine colonoscopy, the GI Genius system generates visual markers – essentially, small green squares – and a low-volume sound whenever the software detects a region of interest.

These squares are superimposed on the video generated by the endoscope camera to alert the colonoscopist to regions that may require closer assessment, either visually, by tissue sampling, or by removal of the lesion itself.

“Colonoscopy is a durable screening and surveillance strategy, but it’s not perfect [because] it depends on a physician’s skill and their ability to pick up polyps in the colon,” Jeremy Glissen Brown, MD, of Beth Israel Deaconess Medical Center, Boston, said in an interview. He has also worked with an AI device.

Studies of adenoma detection during “all-comer” colonoscopies show that the rate of missed lesions ranges from a low of 6% to 40%, “so polyps are still missed during colonoscopy, and any technology that can solve parts of that problem is welcome,” Dr. Glissen Brown commented.
 

Clinical trial data that led to approval

The recent FDA approval of the GI Genius device was based on a prospective, randomized trial that was published in Gastroenterology in 2020. That trial involved 700 patients who were being screened or followed with colonoscopy every 3 years or longer. Participants underwent either white-light standard colonoscopy with the assistance of the GI Genius technology or standard white-light colonoscopy alone.

Results showed that the combination of standard colonoscopy and the GI Genius module identified laboratory-confirmed adenomas or carcinomas in 54.8% of patients, compared with 40.4% of patients who underwent colonoscopy alone.

In the Gastroenterology article, the authors wrote that the “14% absolute increase in adenoma detection rate obtained by computer-aided detection (CADe) in our study indicates that failure in polyp recognition is a clinically relevant cause of miss rate. Of note, the efficacy of CADe in reversing such miss rate also indicates that the same operator who missed the lesion in the first place was able to correctly diagnose it when the lesion was presented by the CADe. This underlines that the main cognitive challenge in polyp recognition is the discrimination between the candidate lesion and the surrounding healthy mucosa, whereas its correct characterization as neoplastic tissue that occurs after CADe detection is apparently a much easier task.”

The authors also noted that they did “not assess the actual number of false-positive activations by the system, as this would have altered the routine setting of our study,” but they refer to a study published in Gut in 2020 in which false-positive frames were seen in fewer than 1% of frames from the whole colonoscopy.

Because the new device improves on the ability of colonoscopy to detect lesions overall, it may reduce the risk of interval cancers between colonoscopies, Medtronic suggests.

Previous research has shown that every 1% increase in the adenoma detection rate results in a 3% decrease in the risk for colorectal cancer.

“More than 19 million screening colonoscopies are performed in the United State each year. ... Detection of adenomas during colonoscopy is an important quality metric,” James Weber, MD, a gastroenterologist affiliated with Texas Digestive Disease Consultants, Southlake, commented in a Medtronic press release.

“The addition of AI can increase the quality of colonoscopies, potentially improving diagnosis and outcomes for colon cancer patients,” he added.

Dr. Weber is also the CEO of GI Alliance, a physician-led national health care platform of independent GI practices in six states in the United States.
 

Computer-aided detection

Unlike other computer-aided detection technologies, GI Genius does not characterize or “diagnose” a lesion, nor does it replace laboratory sampling as a means of confirming a cancer diagnosis.

The technology acts essentially as an extra set of expert “eyes” to detect suspicious lesions during colonoscopy, which should prove helpful, Dr. Johnson and Dr. Glissen Brown both commented.

“When a gastroenterologist looks at the video image, typically, our eyes are focused in the center of that image – that’s where our 20/20 vision is,” Dr. Johnson explained.

The computer has 20/20 vision over the whole image, including the periphery, “so the technology really gives an extremely expanded acuity of vision and highlights areas that we may need to investigate further,” he added.

Dr. Glissen Brown was involved in a trial of another AI device – the real-time automatic polyp detection system (Shanghai Wision AI). That study showed an increase in colonoscopic polyp and adenoma detection rates, but this was mainly because of a higher number of diminutive adenomas detected by the automatic detection system, Dr. Gliseen Brown said. There was no important difference in the number of larger adenomas detected with the device and the number detected without it.

However, there was a significant increase in the detection of hyperplastic polyps when the automatic detection system was used. “We definitely want to look at the false positive rate – both the false positive rate under the camera when we are doing colonoscopy and under the microscope when we do biopsies,” Dr. Glissen Brown acknowledged.

In numerous prospective studies of various computer-aided detection technologies such as the GI Genius system, the false positive rate resulting in the performance of biopsy of insignificant lesions is relatively low, he said.

“Ultimately, the decision to remove or biopsy a lesion is with the physician, because the GI Genius technology just points the provider to the area of concern, and then it’s up to them to look at it and decide whether it needs to be biopsied or not,” Dr. Glissen Brown said.

“So the technology serves more as a digital safety net and points the physician in the right direction, so it shouldn’t lead to much in the way of histologic false positives,” he noted.

The only potential disadvantage to using an AI system such as the GI Genius module is the time it might take for endoscopists to learn how to use it and how much the technology might increase the time required to perform the procedure, he added.

For about 18 months, Dr. Johnson has been running a clinical trial with a similar type of AI technology during colonoscopy. He has found that the learning curve for using these systems is “inordinately short.” Dr. Glissen Brown agreed and suggested that, if physicians are already performing colonoscopies regularly, they could probably learn to use an AI system such as GI Genius in about a week.

In his experience, Dr. Johnson has found that the delay caused by use of an AI system during colonoscopy is “minimal.”

If there is any delay at all, “we know that time in the colon on withdrawal increases the detection of polyps, so more time during withdrawal may be a good thing,” he added. It should be noted that endoscopy societies recommend a withdrawal time of at least 6 minutes, which is one of the metrics used to ensure the quality of a colonoscopy, Dr. Glissen Brown explained.

Indeed, the pivotal study upon which the FDA approved the GI Genius module required a minimum withdrawal time of 6 minutes. Participants said they did not find that using the GI Genius increased withdrawal time, he added.

“I think there is enough prospective evidence at this point to suggest that this technology may really be of benefit to clinicians with a lot of different skill levels, so I would be eager to know how clinicians interact with it in the clinical setting,” Dr. Glissen Brown commented.

Dr. Johnson agreed, noting that “even the good can get better.”

Dr. Johnson disclosed relationships with this news organization, CRH Medical, the American College of Gastroenterology Research Institute, and HyGIeaCare. Dr. Glissen Brown disclosed no relevant financial relationships.

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

Article updated April 21, 2021.

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

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

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

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

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

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

The scientific evidence for airborne transmission of the SARS-CoV-2 virus from different researchers all point in the same direction – that infectious aerosols are the principal means of person-to-person transmission, according to experts.

Not that it’s without controversy.

The science backing aerosol transmission “is clear-cut, but it is not accepted in many circles,” Trisha Greenhalgh, PhD, said in an interview.

“In particular, some in the evidence-based medicine movement and some infectious diseases clinicians are remarkably resistant to the evidence,” added Dr. Greenhalgh, professor of primary care health sciences at the University of Oxford (England).

“It’s very hard to see why, since the evidence all stacks up,” Dr. Greenhalgh said.

“The scientific evidence on spread from both near-field and far-field aerosols has been clear since early on in the pandemic, but there was resistance to acknowledging this in some circles, including the medical journals,” Joseph G. Allen, DSc, MPH, told this news organization when asked to comment.

“This is the week the dam broke. Three new commentaries came out … in top medical journals – BMJ, The Lancet, JAMA – all making the same point that aerosols are the dominant mode of transmission,” added Dr. Allen, associate professor of exposure assessment science at the Harvard T.H. Chan School of Public Health in Boston.

Dr. Greenhalgh and colleagues point to an increase in COVID-19 cases in the aftermath of so-called “super-spreader” events, spread of SARS-CoV-2 to people across different hotel rooms, and the relatively lower transmission detected after outdoor events.
 

Top 10 reasons

They outlined 10 scientific reasons backing airborne transmission in a commentary published online April 15 in The Lancet:

• The dominance of airborne transmission is supported by long-range transmission observed at super-spreader events.
• Long-range transmission has been reported among rooms at COVID-19 quarantine hotels, settings where infected people never spent time in the same room.
• Asymptomatic individuals account for an estimated 33%-59% of SARS-CoV-2 transmission, and could be spreading the virus through speaking, which produces thousands of aerosol particles and few large droplets.
• Transmission outdoors and in well-ventilated indoor spaces is lower than in enclosed spaces.
• Nosocomial infections are reported in health care settings where protective measures address large droplets but not aerosols.
• Viable SARS-CoV-2 has been detected in the air of hospital rooms and in the car of an infected person.
• Investigators found SARS-CoV-2 in hospital air filters and building ducts.
• It’s not just humans – infected animals can infect animals in other cages connected only through an air duct.
• No strong evidence refutes airborne transmission, and contact tracing supports secondary transmission in crowded, poorly ventilated indoor spaces.
• Only limited evidence supports other means of SARS-CoV-2 transmission, including through fomites or large droplets.

“We thought we’d summarize [the evidence] to clarify the arguments for and against. We looked hard for evidence against but found none,” Dr. Greenhalgh said.

“Although other routes can contribute, we believe that the airborne route is likely to be dominant,” the authors note.

The evidence on airborne transmission was there very early on but the Centers for Disease Control and Prevention, World Health Organization, and others repeated the message that the primary concern was droplets and fomites.
 

Response to a review

The top 10 list is also part rebuttal of a systematic review funded by the WHO and published last month that points to inconclusive evidence for airborne transmission. The researchers involved with that review state that “the lack of recoverable viral culture samples of SARS-CoV-2 prevents firm conclusions to be drawn about airborne transmission.”

However, Dr. Greenhalgh and colleagues note that “this conclusion, and the wide circulation of the review’s findings, is concerning because of the public health implications.”

The current authors also argue that enough evidence already exists on airborne transmission. “Policy should change. We don’t need more research on this topic; we need different policy,” Dr. Greenhalgh said. “We need ventilation front and center, air filtration when necessary, and better-fitting masks worn whenever indoors.”

Dr. Allen agreed that guidance hasn’t always kept pace with the science. “With all of the new evidence accumulated on airborne transmission since last winter, there is still widespread confusion in the public about modes of transmission,” he said. Dr. Allen also serves as commissioner of The Lancet COVID-19 Commission and is chair of the commission’s Task Force on Safe Work, Safe Schools, and Safe Travel.

“It was only just last week that CDC pulled back on guidance on ‘deep cleaning’ and in its place correctly said that the risk from touching surfaces is low,” he added. “The science has been clear on this for over a year, but official guidance was only recently updated.”

As a result, many companies and organizations continued to focus on “hygiene theatre,” Dr. Allen said, “wasting resources on overcleaning surfaces. Unbelievably, many schools still close for an entire day each week for deep cleaning and some still quarantine library books. The message that shared air is the problem, not shared surfaces, is a message that still needs to be reinforced.”

The National Institute for Health Research, Economic and Social Research Council, and Wellcome support Dr. Greenhalgh’s research. Dr. Greenhalgh and Dr. Allen had no relevant financial relationships to disclose.

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

The scientific evidence for airborne transmission of the SARS-CoV-2 virus from different researchers all point in the same direction – that infectious aerosols are the principal means of person-to-person transmission, according to experts.

Not that it’s without controversy.

The science backing aerosol transmission “is clear-cut, but it is not accepted in many circles,” Trisha Greenhalgh, PhD, said in an interview.

“In particular, some in the evidence-based medicine movement and some infectious diseases clinicians are remarkably resistant to the evidence,” added Dr. Greenhalgh, professor of primary care health sciences at the University of Oxford (England).

“It’s very hard to see why, since the evidence all stacks up,” Dr. Greenhalgh said.

“The scientific evidence on spread from both near-field and far-field aerosols has been clear since early on in the pandemic, but there was resistance to acknowledging this in some circles, including the medical journals,” Joseph G. Allen, DSc, MPH, told this news organization when asked to comment.

“This is the week the dam broke. Three new commentaries came out … in top medical journals – BMJ, The Lancet, JAMA – all making the same point that aerosols are the dominant mode of transmission,” added Dr. Allen, associate professor of exposure assessment science at the Harvard T.H. Chan School of Public Health in Boston.

Dr. Greenhalgh and colleagues point to an increase in COVID-19 cases in the aftermath of so-called “super-spreader” events, spread of SARS-CoV-2 to people across different hotel rooms, and the relatively lower transmission detected after outdoor events.
 

Top 10 reasons

They outlined 10 scientific reasons backing airborne transmission in a commentary published online April 15 in The Lancet:

• The dominance of airborne transmission is supported by long-range transmission observed at super-spreader events.
• Long-range transmission has been reported among rooms at COVID-19 quarantine hotels, settings where infected people never spent time in the same room.
• Asymptomatic individuals account for an estimated 33%-59% of SARS-CoV-2 transmission, and could be spreading the virus through speaking, which produces thousands of aerosol particles and few large droplets.
• Transmission outdoors and in well-ventilated indoor spaces is lower than in enclosed spaces.
• Nosocomial infections are reported in health care settings where protective measures address large droplets but not aerosols.
• Viable SARS-CoV-2 has been detected in the air of hospital rooms and in the car of an infected person.
• Investigators found SARS-CoV-2 in hospital air filters and building ducts.
• It’s not just humans – infected animals can infect animals in other cages connected only through an air duct.
• No strong evidence refutes airborne transmission, and contact tracing supports secondary transmission in crowded, poorly ventilated indoor spaces.
• Only limited evidence supports other means of SARS-CoV-2 transmission, including through fomites or large droplets.

“We thought we’d summarize [the evidence] to clarify the arguments for and against. We looked hard for evidence against but found none,” Dr. Greenhalgh said.

“Although other routes can contribute, we believe that the airborne route is likely to be dominant,” the authors note.

The evidence on airborne transmission was there very early on but the Centers for Disease Control and Prevention, World Health Organization, and others repeated the message that the primary concern was droplets and fomites.
 

Response to a review

The top 10 list is also part rebuttal of a systematic review funded by the WHO and published last month that points to inconclusive evidence for airborne transmission. The researchers involved with that review state that “the lack of recoverable viral culture samples of SARS-CoV-2 prevents firm conclusions to be drawn about airborne transmission.”

However, Dr. Greenhalgh and colleagues note that “this conclusion, and the wide circulation of the review’s findings, is concerning because of the public health implications.”

The current authors also argue that enough evidence already exists on airborne transmission. “Policy should change. We don’t need more research on this topic; we need different policy,” Dr. Greenhalgh said. “We need ventilation front and center, air filtration when necessary, and better-fitting masks worn whenever indoors.”

Dr. Allen agreed that guidance hasn’t always kept pace with the science. “With all of the new evidence accumulated on airborne transmission since last winter, there is still widespread confusion in the public about modes of transmission,” he said. Dr. Allen also serves as commissioner of The Lancet COVID-19 Commission and is chair of the commission’s Task Force on Safe Work, Safe Schools, and Safe Travel.

“It was only just last week that CDC pulled back on guidance on ‘deep cleaning’ and in its place correctly said that the risk from touching surfaces is low,” he added. “The science has been clear on this for over a year, but official guidance was only recently updated.”

As a result, many companies and organizations continued to focus on “hygiene theatre,” Dr. Allen said, “wasting resources on overcleaning surfaces. Unbelievably, many schools still close for an entire day each week for deep cleaning and some still quarantine library books. The message that shared air is the problem, not shared surfaces, is a message that still needs to be reinforced.”

The National Institute for Health Research, Economic and Social Research Council, and Wellcome support Dr. Greenhalgh’s research. Dr. Greenhalgh and Dr. Allen had no relevant financial relationships to disclose.

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

The scientific evidence for airborne transmission of the SARS-CoV-2 virus from different researchers all point in the same direction – that infectious aerosols are the principal means of person-to-person transmission, according to experts.

Not that it’s without controversy.

The science backing aerosol transmission “is clear-cut, but it is not accepted in many circles,” Trisha Greenhalgh, PhD, said in an interview.

“In particular, some in the evidence-based medicine movement and some infectious diseases clinicians are remarkably resistant to the evidence,” added Dr. Greenhalgh, professor of primary care health sciences at the University of Oxford (England).

“It’s very hard to see why, since the evidence all stacks up,” Dr. Greenhalgh said.

“The scientific evidence on spread from both near-field and far-field aerosols has been clear since early on in the pandemic, but there was resistance to acknowledging this in some circles, including the medical journals,” Joseph G. Allen, DSc, MPH, told this news organization when asked to comment.

“This is the week the dam broke. Three new commentaries came out … in top medical journals – BMJ, The Lancet, JAMA – all making the same point that aerosols are the dominant mode of transmission,” added Dr. Allen, associate professor of exposure assessment science at the Harvard T.H. Chan School of Public Health in Boston.

Dr. Greenhalgh and colleagues point to an increase in COVID-19 cases in the aftermath of so-called “super-spreader” events, spread of SARS-CoV-2 to people across different hotel rooms, and the relatively lower transmission detected after outdoor events.
 

Top 10 reasons

They outlined 10 scientific reasons backing airborne transmission in a commentary published online April 15 in The Lancet:

• The dominance of airborne transmission is supported by long-range transmission observed at super-spreader events.
• Long-range transmission has been reported among rooms at COVID-19 quarantine hotels, settings where infected people never spent time in the same room.
• Asymptomatic individuals account for an estimated 33%-59% of SARS-CoV-2 transmission, and could be spreading the virus through speaking, which produces thousands of aerosol particles and few large droplets.
• Transmission outdoors and in well-ventilated indoor spaces is lower than in enclosed spaces.
• Nosocomial infections are reported in health care settings where protective measures address large droplets but not aerosols.
• Viable SARS-CoV-2 has been detected in the air of hospital rooms and in the car of an infected person.
• Investigators found SARS-CoV-2 in hospital air filters and building ducts.
• It’s not just humans – infected animals can infect animals in other cages connected only through an air duct.
• No strong evidence refutes airborne transmission, and contact tracing supports secondary transmission in crowded, poorly ventilated indoor spaces.
• Only limited evidence supports other means of SARS-CoV-2 transmission, including through fomites or large droplets.

“We thought we’d summarize [the evidence] to clarify the arguments for and against. We looked hard for evidence against but found none,” Dr. Greenhalgh said.

“Although other routes can contribute, we believe that the airborne route is likely to be dominant,” the authors note.

The evidence on airborne transmission was there very early on but the Centers for Disease Control and Prevention, World Health Organization, and others repeated the message that the primary concern was droplets and fomites.
 

Response to a review

The top 10 list is also part rebuttal of a systematic review funded by the WHO and published last month that points to inconclusive evidence for airborne transmission. The researchers involved with that review state that “the lack of recoverable viral culture samples of SARS-CoV-2 prevents firm conclusions to be drawn about airborne transmission.”

However, Dr. Greenhalgh and colleagues note that “this conclusion, and the wide circulation of the review’s findings, is concerning because of the public health implications.”

The current authors also argue that enough evidence already exists on airborne transmission. “Policy should change. We don’t need more research on this topic; we need different policy,” Dr. Greenhalgh said. “We need ventilation front and center, air filtration when necessary, and better-fitting masks worn whenever indoors.”

Dr. Allen agreed that guidance hasn’t always kept pace with the science. “With all of the new evidence accumulated on airborne transmission since last winter, there is still widespread confusion in the public about modes of transmission,” he said. Dr. Allen also serves as commissioner of The Lancet COVID-19 Commission and is chair of the commission’s Task Force on Safe Work, Safe Schools, and Safe Travel.

“It was only just last week that CDC pulled back on guidance on ‘deep cleaning’ and in its place correctly said that the risk from touching surfaces is low,” he added. “The science has been clear on this for over a year, but official guidance was only recently updated.”

As a result, many companies and organizations continued to focus on “hygiene theatre,” Dr. Allen said, “wasting resources on overcleaning surfaces. Unbelievably, many schools still close for an entire day each week for deep cleaning and some still quarantine library books. The message that shared air is the problem, not shared surfaces, is a message that still needs to be reinforced.”

The National Institute for Health Research, Economic and Social Research Council, and Wellcome support Dr. Greenhalgh’s research. Dr. Greenhalgh and Dr. Allen had no relevant financial relationships to disclose.

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