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Patients with hidradenitis suppurativa (HS) were found to be at a significantly higher risk of long-term opioid use compared with those who did not have HS, in a retrospective cohort study.

“These results suggest that periodic assessment of pain and screening for long-term opioid use may be warranted, particularly among patients who are older, who smoke tobacco, or who have depression and other medical comorbidities,” wrote the authors of the study (JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610).

Researchers led by Sarah Reddy, BA, of the Zucker School of Medicine at Hofstra/ Northwell, New Hyde Park, N.Y., used data from a health-care database that represents an estimated 17% of the U.S. population. They focused on opioid-naive adults who were in the database for at least 3 years from 2008-2018 and monitored whether they began opioid use and then maintained use for at least 1 year.

Nearly 829,000 patients were in the control group, and 22,277 were in the HS group. The mean age of those with HS was 41 years, 76% were women, and 59% were white.

Over 1 year, the crude incidence of long-term opioid use among HS patients who were opioid naive was 0.33%, compared with 0.14% of controls (P less than .001).

An analysis, adjusted for potential confounding factors, found that compared with controls, those with HS were more likely to develop long-term opioid use (odds ratio [OR], 1.53, 95% confidence interval, 1.20-1.95; P less than .001). In the adjusted analysis, long-term opioid use was increased among those in the HS group who had ever smoked tobacco (OR, 3.64, 95% CI, 2.06-6.41; P less than .001), compared with patients with HS who had never smoked; and those who had a history of depression (OR, 1.97, 95% CI, 1.21-3.19; P = .006), compared with HS patients who had not had depression.

The risk of long-term opioid use among those with HS increased by 2% with each additional year in age.

In addition, 5% of patients with HS and long-term opioid use were diagnosed with opioid use disorder over the study period. “Sex, race/ethnicity, disease duration, established dermatologic care, alcohol abuse, and nonopioid substance abuse were not associated with increased risk of long-term opioid use among patients with HS,” the authors wrote.

Emphasizing that these results “should not further stigmatize” people with HS, they said, “our hope is that the medical community, including dermatologists, will further embrace and engage in an integrated care plan that comprehensively supports the needs of patients with HS, including pain management.”

Future research, they added, “should include evaluating the association between disease severity and risk of opioid use, the role of disease-modifying therapies in reducing opioid use, and the development of effective and appropriate multimodal pain management strategies for HS.”

An educational grant to a study author from AbbVie partially funded the study. No other study funding was reported. Ms. Reddy had no disclosures; one author disclosed having received grants and personal fees from AbbVie and UCB during the study.

SOURCE: Reddy S et al. JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610.

Patients with hidradenitis suppurativa (HS) were found to be at a significantly higher risk of long-term opioid use compared with those who did not have HS, in a retrospective cohort study.

“These results suggest that periodic assessment of pain and screening for long-term opioid use may be warranted, particularly among patients who are older, who smoke tobacco, or who have depression and other medical comorbidities,” wrote the authors of the study (JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610).

Researchers led by Sarah Reddy, BA, of the Zucker School of Medicine at Hofstra/ Northwell, New Hyde Park, N.Y., used data from a health-care database that represents an estimated 17% of the U.S. population. They focused on opioid-naive adults who were in the database for at least 3 years from 2008-2018 and monitored whether they began opioid use and then maintained use for at least 1 year.

Nearly 829,000 patients were in the control group, and 22,277 were in the HS group. The mean age of those with HS was 41 years, 76% were women, and 59% were white.

Over 1 year, the crude incidence of long-term opioid use among HS patients who were opioid naive was 0.33%, compared with 0.14% of controls (P less than .001).

An analysis, adjusted for potential confounding factors, found that compared with controls, those with HS were more likely to develop long-term opioid use (odds ratio [OR], 1.53, 95% confidence interval, 1.20-1.95; P less than .001). In the adjusted analysis, long-term opioid use was increased among those in the HS group who had ever smoked tobacco (OR, 3.64, 95% CI, 2.06-6.41; P less than .001), compared with patients with HS who had never smoked; and those who had a history of depression (OR, 1.97, 95% CI, 1.21-3.19; P = .006), compared with HS patients who had not had depression.

The risk of long-term opioid use among those with HS increased by 2% with each additional year in age.

In addition, 5% of patients with HS and long-term opioid use were diagnosed with opioid use disorder over the study period. “Sex, race/ethnicity, disease duration, established dermatologic care, alcohol abuse, and nonopioid substance abuse were not associated with increased risk of long-term opioid use among patients with HS,” the authors wrote.

Emphasizing that these results “should not further stigmatize” people with HS, they said, “our hope is that the medical community, including dermatologists, will further embrace and engage in an integrated care plan that comprehensively supports the needs of patients with HS, including pain management.”

Future research, they added, “should include evaluating the association between disease severity and risk of opioid use, the role of disease-modifying therapies in reducing opioid use, and the development of effective and appropriate multimodal pain management strategies for HS.”

An educational grant to a study author from AbbVie partially funded the study. No other study funding was reported. Ms. Reddy had no disclosures; one author disclosed having received grants and personal fees from AbbVie and UCB during the study.

SOURCE: Reddy S et al. JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610.

Patients with hidradenitis suppurativa (HS) were found to be at a significantly higher risk of long-term opioid use compared with those who did not have HS, in a retrospective cohort study.

“These results suggest that periodic assessment of pain and screening for long-term opioid use may be warranted, particularly among patients who are older, who smoke tobacco, or who have depression and other medical comorbidities,” wrote the authors of the study (JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610).

Researchers led by Sarah Reddy, BA, of the Zucker School of Medicine at Hofstra/ Northwell, New Hyde Park, N.Y., used data from a health-care database that represents an estimated 17% of the U.S. population. They focused on opioid-naive adults who were in the database for at least 3 years from 2008-2018 and monitored whether they began opioid use and then maintained use for at least 1 year.

Nearly 829,000 patients were in the control group, and 22,277 were in the HS group. The mean age of those with HS was 41 years, 76% were women, and 59% were white.

Over 1 year, the crude incidence of long-term opioid use among HS patients who were opioid naive was 0.33%, compared with 0.14% of controls (P less than .001).

An analysis, adjusted for potential confounding factors, found that compared with controls, those with HS were more likely to develop long-term opioid use (odds ratio [OR], 1.53, 95% confidence interval, 1.20-1.95; P less than .001). In the adjusted analysis, long-term opioid use was increased among those in the HS group who had ever smoked tobacco (OR, 3.64, 95% CI, 2.06-6.41; P less than .001), compared with patients with HS who had never smoked; and those who had a history of depression (OR, 1.97, 95% CI, 1.21-3.19; P = .006), compared with HS patients who had not had depression.

The risk of long-term opioid use among those with HS increased by 2% with each additional year in age.

In addition, 5% of patients with HS and long-term opioid use were diagnosed with opioid use disorder over the study period. “Sex, race/ethnicity, disease duration, established dermatologic care, alcohol abuse, and nonopioid substance abuse were not associated with increased risk of long-term opioid use among patients with HS,” the authors wrote.

Emphasizing that these results “should not further stigmatize” people with HS, they said, “our hope is that the medical community, including dermatologists, will further embrace and engage in an integrated care plan that comprehensively supports the needs of patients with HS, including pain management.”

Future research, they added, “should include evaluating the association between disease severity and risk of opioid use, the role of disease-modifying therapies in reducing opioid use, and the development of effective and appropriate multimodal pain management strategies for HS.”

An educational grant to a study author from AbbVie partially funded the study. No other study funding was reported. Ms. Reddy had no disclosures; one author disclosed having received grants and personal fees from AbbVie and UCB during the study.

SOURCE: Reddy S et al. JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610.

Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

MADRID – In patients with fibrosing lung diseases other than idiopathic pulmonary fibrosis (IPF), nintedanib, a tyrosine kinase inhibitor, substantially reduced the rate of decline in lung function, according to findings from a phase 3, placebo-controlled trial presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

The trial, called INBUILD, enrolled patients who had a progressive lung disease with a fibrosing phenotype, such as interstitial pneumonia with autoimmune features (IPAF) or noninterstitial pneumonia (NSIP), on the premise that these conditions might share a pathology responsive to a common therapy, explained Kevin R. Flaherty, MD, of National Jewish Health, Denver. The INBUILD trial was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries. A total of 663 patients underwent randomization and received at least one dose of nintedanib (332) or placebo (331).

Patients with fibrosing lung disease affecting more than 10% of lung volume were randomized to 150 mg twice daily of nintedanib, which inhibits intracellular growth factors implicated in fibrosis and is already indicated for IPF, or matching placebo.

On the primary endpoint of change in forced vital capacity (FVC) at 52 weeks, those in the nintedanib arm lost lung function at a rate that was less than half that of those randomized to placebo (–80.8 vs. –187.8 mL/year; P less than .001).

In a preplanned stratification, the protection from nintedanib against a decline in lung function was found to be at least as good in those with a usual interstitial pneumonia (UIP-like) pattern of fibrosis on baseline imaging (–82.9 vs. –211.1 mL/year), compared with those with other fibrotic patterns (–79.0 vs. –154.2 mL/year). The UIP-like subgroup represented about 60% of those enrolled.

“The relative protection from decline in lung function supports the hypothesis that progressive fibrosing interstitial lung diseases have a similar pathobiologic mechanism,” said Dr. Flaherty. Results from the INBUILD were published simultaneously with his ERS presentation (N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681).

The curves documenting change of lung function in favor of nintedanib relative to placebo separated within 12 weeks of treatment initiation, according to Dr. Flaherty. The ERS-invited discussant, Martin Kolb, MD, PhD, professor of respirology, McMaster University, Hamilton, Ont., called the reductions in loss of lung function “profound” and “very impactful.”

However, despite these reductions, there was no significant difference in quality of life as measured with the King’s Brief Interstitial Lung Disease (KBILD) questionnaire, which was a secondary outcome. The problem was that there was little change in KBILD in either group at 52 weeks, limiting the ability to show differences.

The rates of death were numerically lower at 52 weeks in the nintedanib arm for the study overall (4.8% vs. 5.1%) and for the UIP-like subgroup (5.3% vs. 7.8%), but the differences did not reach statistical significance.

A suggestion of benefit was derived from a design feature of INBUILD that called for patients to remain on blinded therapy until all enrolled patients completed the trial. When the effect of nintedanib was evaluated in this extended analysis, the event curves for the combined endpoint of interstitial lung disease or death separated and approached significance.

In this extended analysis, which suggests that clinical benefit is likely to accrue after longer periods of treatment, “we saw similar trends when we looked at mortality as an independent outcome,” Dr. Flaherty reported.

More patients in the nintedanib group discontinued therapy because of adverse events (19.6% vs. 10.3%), but Dr. Flaherty characterized the rate of serious adverse events as “similar.” He made this statement even though several adverse events, particularly those involving the gastrointestinal tract, such as diarrhea (66.9% vs. 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% vs. 5.1%), and abdominal pain (10.2% vs. 2.4%), were higher in the nintedanib arm.

The INBUILD trial demonstrates that nintedanib preserves lung function in fibrosing lung diseases other than IPF. In his review of this paper, Dr. Kolb pointed out that non-IPF etiologies represent about 75% of interstitial lung diseases. For these patients “we have no drugs, so there is a big medical need.”

Dr. Flaherty reports no potential conflicts of interest. The study was funded by Boehringer-Ingelheim, which produces nintedanib.

SOURCE: Flaherty KR et al. N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681.

MADRID – In patients with fibrosing lung diseases other than idiopathic pulmonary fibrosis (IPF), nintedanib, a tyrosine kinase inhibitor, substantially reduced the rate of decline in lung function, according to findings from a phase 3, placebo-controlled trial presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

The trial, called INBUILD, enrolled patients who had a progressive lung disease with a fibrosing phenotype, such as interstitial pneumonia with autoimmune features (IPAF) or noninterstitial pneumonia (NSIP), on the premise that these conditions might share a pathology responsive to a common therapy, explained Kevin R. Flaherty, MD, of National Jewish Health, Denver. The INBUILD trial was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries. A total of 663 patients underwent randomization and received at least one dose of nintedanib (332) or placebo (331).

Patients with fibrosing lung disease affecting more than 10% of lung volume were randomized to 150 mg twice daily of nintedanib, which inhibits intracellular growth factors implicated in fibrosis and is already indicated for IPF, or matching placebo.

On the primary endpoint of change in forced vital capacity (FVC) at 52 weeks, those in the nintedanib arm lost lung function at a rate that was less than half that of those randomized to placebo (–80.8 vs. –187.8 mL/year; P less than .001).

In a preplanned stratification, the protection from nintedanib against a decline in lung function was found to be at least as good in those with a usual interstitial pneumonia (UIP-like) pattern of fibrosis on baseline imaging (–82.9 vs. –211.1 mL/year), compared with those with other fibrotic patterns (–79.0 vs. –154.2 mL/year). The UIP-like subgroup represented about 60% of those enrolled.

“The relative protection from decline in lung function supports the hypothesis that progressive fibrosing interstitial lung diseases have a similar pathobiologic mechanism,” said Dr. Flaherty. Results from the INBUILD were published simultaneously with his ERS presentation (N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681).

The curves documenting change of lung function in favor of nintedanib relative to placebo separated within 12 weeks of treatment initiation, according to Dr. Flaherty. The ERS-invited discussant, Martin Kolb, MD, PhD, professor of respirology, McMaster University, Hamilton, Ont., called the reductions in loss of lung function “profound” and “very impactful.”

However, despite these reductions, there was no significant difference in quality of life as measured with the King’s Brief Interstitial Lung Disease (KBILD) questionnaire, which was a secondary outcome. The problem was that there was little change in KBILD in either group at 52 weeks, limiting the ability to show differences.

The rates of death were numerically lower at 52 weeks in the nintedanib arm for the study overall (4.8% vs. 5.1%) and for the UIP-like subgroup (5.3% vs. 7.8%), but the differences did not reach statistical significance.

A suggestion of benefit was derived from a design feature of INBUILD that called for patients to remain on blinded therapy until all enrolled patients completed the trial. When the effect of nintedanib was evaluated in this extended analysis, the event curves for the combined endpoint of interstitial lung disease or death separated and approached significance.

In this extended analysis, which suggests that clinical benefit is likely to accrue after longer periods of treatment, “we saw similar trends when we looked at mortality as an independent outcome,” Dr. Flaherty reported.

More patients in the nintedanib group discontinued therapy because of adverse events (19.6% vs. 10.3%), but Dr. Flaherty characterized the rate of serious adverse events as “similar.” He made this statement even though several adverse events, particularly those involving the gastrointestinal tract, such as diarrhea (66.9% vs. 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% vs. 5.1%), and abdominal pain (10.2% vs. 2.4%), were higher in the nintedanib arm.

The INBUILD trial demonstrates that nintedanib preserves lung function in fibrosing lung diseases other than IPF. In his review of this paper, Dr. Kolb pointed out that non-IPF etiologies represent about 75% of interstitial lung diseases. For these patients “we have no drugs, so there is a big medical need.”

Dr. Flaherty reports no potential conflicts of interest. The study was funded by Boehringer-Ingelheim, which produces nintedanib.

SOURCE: Flaherty KR et al. N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681.

MADRID – In patients with fibrosing lung diseases other than idiopathic pulmonary fibrosis (IPF), nintedanib, a tyrosine kinase inhibitor, substantially reduced the rate of decline in lung function, according to findings from a phase 3, placebo-controlled trial presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

The trial, called INBUILD, enrolled patients who had a progressive lung disease with a fibrosing phenotype, such as interstitial pneumonia with autoimmune features (IPAF) or noninterstitial pneumonia (NSIP), on the premise that these conditions might share a pathology responsive to a common therapy, explained Kevin R. Flaherty, MD, of National Jewish Health, Denver. The INBUILD trial was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries. A total of 663 patients underwent randomization and received at least one dose of nintedanib (332) or placebo (331).

Patients with fibrosing lung disease affecting more than 10% of lung volume were randomized to 150 mg twice daily of nintedanib, which inhibits intracellular growth factors implicated in fibrosis and is already indicated for IPF, or matching placebo.

On the primary endpoint of change in forced vital capacity (FVC) at 52 weeks, those in the nintedanib arm lost lung function at a rate that was less than half that of those randomized to placebo (–80.8 vs. –187.8 mL/year; P less than .001).

In a preplanned stratification, the protection from nintedanib against a decline in lung function was found to be at least as good in those with a usual interstitial pneumonia (UIP-like) pattern of fibrosis on baseline imaging (–82.9 vs. –211.1 mL/year), compared with those with other fibrotic patterns (–79.0 vs. –154.2 mL/year). The UIP-like subgroup represented about 60% of those enrolled.

“The relative protection from decline in lung function supports the hypothesis that progressive fibrosing interstitial lung diseases have a similar pathobiologic mechanism,” said Dr. Flaherty. Results from the INBUILD were published simultaneously with his ERS presentation (N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681).

The curves documenting change of lung function in favor of nintedanib relative to placebo separated within 12 weeks of treatment initiation, according to Dr. Flaherty. The ERS-invited discussant, Martin Kolb, MD, PhD, professor of respirology, McMaster University, Hamilton, Ont., called the reductions in loss of lung function “profound” and “very impactful.”

However, despite these reductions, there was no significant difference in quality of life as measured with the King’s Brief Interstitial Lung Disease (KBILD) questionnaire, which was a secondary outcome. The problem was that there was little change in KBILD in either group at 52 weeks, limiting the ability to show differences.

The rates of death were numerically lower at 52 weeks in the nintedanib arm for the study overall (4.8% vs. 5.1%) and for the UIP-like subgroup (5.3% vs. 7.8%), but the differences did not reach statistical significance.

A suggestion of benefit was derived from a design feature of INBUILD that called for patients to remain on blinded therapy until all enrolled patients completed the trial. When the effect of nintedanib was evaluated in this extended analysis, the event curves for the combined endpoint of interstitial lung disease or death separated and approached significance.

In this extended analysis, which suggests that clinical benefit is likely to accrue after longer periods of treatment, “we saw similar trends when we looked at mortality as an independent outcome,” Dr. Flaherty reported.

More patients in the nintedanib group discontinued therapy because of adverse events (19.6% vs. 10.3%), but Dr. Flaherty characterized the rate of serious adverse events as “similar.” He made this statement even though several adverse events, particularly those involving the gastrointestinal tract, such as diarrhea (66.9% vs. 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% vs. 5.1%), and abdominal pain (10.2% vs. 2.4%), were higher in the nintedanib arm.

The INBUILD trial demonstrates that nintedanib preserves lung function in fibrosing lung diseases other than IPF. In his review of this paper, Dr. Kolb pointed out that non-IPF etiologies represent about 75% of interstitial lung diseases. For these patients “we have no drugs, so there is a big medical need.”

Dr. Flaherty reports no potential conflicts of interest. The study was funded by Boehringer-Ingelheim, which produces nintedanib.

SOURCE: Flaherty KR et al. N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681.

When an emergency department (ED) closes, neighboring hospitals—“bystander hospitals”—feel the effects, especially if they are already near or at full capacity: The health outcomes for their patients worsen, according to findings from a study funded by the National Heart, Lung, and Blood Institute (NHLBI).

The researchers examined outcomes for more than 1 million patients at nearly 4,000 hospitals in both urban and rural areas who had been affected by the closure or opening of an ED. The primary measures were 30-day, 90-day, and 1-year mortality rates, and 30-day readmission rates for heart attack. The researchers chose heart attacks because of the known benefits of timely treatment.

The researchers used changes in driving time between an ED and the next-closest one as a proxy for a closure or opening. If driving time increased, it meant a nearby ED had closed.

They found that when it took an additional 30 minutes or more to get to another hospital, the 1-year mortality rate in those receiving hospitals increased by 8% and the 30-day readmission rate by 6%. The likelihood of patients receiving an angioplasty or stent dropped by 4%.

However, the researchers also found that when an ED opened, the patients in the bystander hospitals benefited, experiencing a reduction in 1-year mortality by 5%. And the likelihood of their receiving percutaneous coronary intervention improved by 12%.

The study is believed to be the first to evaluate the impact of ED openings and closures on other hospitals. The lead author of the study, Renee Hsia, MD, said, “We now have evidence that hospital closures affect other hospitals, and they do so in different ways. Hospitals that are already crowded will likely be unable to maintain the same quality when a nearby emergency department closes.”

Limited resources at high-occupancy hospitals make them “sensitive to changes” in neighboring communities, the researchers say. “Hospital closures stress the health care infrastructure,” says Nicole Redmond, MD, PhD, MPH, a medical officer at NHLBI, “especially if the hospital is already caring for a socially and medically complex patient population and working at full capacity. As a result, such closures may inadvertently increase the health disparities that we are trying to mitigate.”

When an emergency department (ED) closes, neighboring hospitals—“bystander hospitals”—feel the effects, especially if they are already near or at full capacity: The health outcomes for their patients worsen, according to findings from a study funded by the National Heart, Lung, and Blood Institute (NHLBI).

The researchers examined outcomes for more than 1 million patients at nearly 4,000 hospitals in both urban and rural areas who had been affected by the closure or opening of an ED. The primary measures were 30-day, 90-day, and 1-year mortality rates, and 30-day readmission rates for heart attack. The researchers chose heart attacks because of the known benefits of timely treatment.

The researchers used changes in driving time between an ED and the next-closest one as a proxy for a closure or opening. If driving time increased, it meant a nearby ED had closed.

They found that when it took an additional 30 minutes or more to get to another hospital, the 1-year mortality rate in those receiving hospitals increased by 8% and the 30-day readmission rate by 6%. The likelihood of patients receiving an angioplasty or stent dropped by 4%.

However, the researchers also found that when an ED opened, the patients in the bystander hospitals benefited, experiencing a reduction in 1-year mortality by 5%. And the likelihood of their receiving percutaneous coronary intervention improved by 12%.

The study is believed to be the first to evaluate the impact of ED openings and closures on other hospitals. The lead author of the study, Renee Hsia, MD, said, “We now have evidence that hospital closures affect other hospitals, and they do so in different ways. Hospitals that are already crowded will likely be unable to maintain the same quality when a nearby emergency department closes.”

Limited resources at high-occupancy hospitals make them “sensitive to changes” in neighboring communities, the researchers say. “Hospital closures stress the health care infrastructure,” says Nicole Redmond, MD, PhD, MPH, a medical officer at NHLBI, “especially if the hospital is already caring for a socially and medically complex patient population and working at full capacity. As a result, such closures may inadvertently increase the health disparities that we are trying to mitigate.”

When an emergency department (ED) closes, neighboring hospitals—“bystander hospitals”—feel the effects, especially if they are already near or at full capacity: The health outcomes for their patients worsen, according to findings from a study funded by the National Heart, Lung, and Blood Institute (NHLBI).

The researchers examined outcomes for more than 1 million patients at nearly 4,000 hospitals in both urban and rural areas who had been affected by the closure or opening of an ED. The primary measures were 30-day, 90-day, and 1-year mortality rates, and 30-day readmission rates for heart attack. The researchers chose heart attacks because of the known benefits of timely treatment.

The researchers used changes in driving time between an ED and the next-closest one as a proxy for a closure or opening. If driving time increased, it meant a nearby ED had closed.

They found that when it took an additional 30 minutes or more to get to another hospital, the 1-year mortality rate in those receiving hospitals increased by 8% and the 30-day readmission rate by 6%. The likelihood of patients receiving an angioplasty or stent dropped by 4%.

However, the researchers also found that when an ED opened, the patients in the bystander hospitals benefited, experiencing a reduction in 1-year mortality by 5%. And the likelihood of their receiving percutaneous coronary intervention improved by 12%.

The study is believed to be the first to evaluate the impact of ED openings and closures on other hospitals. The lead author of the study, Renee Hsia, MD, said, “We now have evidence that hospital closures affect other hospitals, and they do so in different ways. Hospitals that are already crowded will likely be unable to maintain the same quality when a nearby emergency department closes.”

Limited resources at high-occupancy hospitals make them “sensitive to changes” in neighboring communities, the researchers say. “Hospital closures stress the health care infrastructure,” says Nicole Redmond, MD, PhD, MPH, a medical officer at NHLBI, “especially if the hospital is already caring for a socially and medically complex patient population and working at full capacity. As a result, such closures may inadvertently increase the health disparities that we are trying to mitigate.”

More than 75% of patients with vaping-related lung injuries used at least one tetrahydrocannabinol (THC)–containing product before they developed symptoms, and most products used were prepackaged, prefilled cartridges, according to new data released by the Centers for Disease Control and Prevention.

mauro grigollo/Thinkstock

The majority of these products (66%) were THC-containing cartridges marketed under the brand name Dank. Dank cartridges are available at legal dispensaries and online in areas where they are legal. The Dank company posted a statement on its website warning buyers about fake cartridges and showing images of genuine cartridges. However, 89% of the cartridges were obtained on the street, from dealers, online, or from friends or social contacts, Jennifer Layden, MD, of the Illinois Department of Public Health said during a CDC telebriefing.

The illness was first recognized in Wisconsin and Illinois. Marijuana is illegal in Wisconsin; Illinois licensed recreational marijuana in 2009.

Other commonalties among cases have also emerged, Anne Schuchat, MD, deputy director of CDC, said during the call. More than two-thirds of the 805 confirmed or probable cases were male, and the median age was 23 years. The illness crosses age barriers, she said. About 62% were 18-24 years of age, and 54% under age 25. However, among the 12 deaths so far reported, the median age was 50 years. The age range was wide, from 27 to 71 years. Dr. Schuchat said data about medical comorbidities potentially linking the deaths is not yet available, although it is part of the ongoing investigation.

Other clinical commonalities included intensive use of THC-containing products and, in a small number of cases, concomitant use of benzodiazepenes, opioids, and narcotics.

Cases have now emerged in 46 states and in the U.S. Virgin Islands, although the number reported each week is dropping. However, this decrease may not represent a drop in newly occurring cases, but instead reflect delays in clinical recognition or reporting to local health departments, Dr. Schuchat said.

Regardless of the recent decline in reported cases, she said, the epidemic is serious, far reaching, and ongoing.

“I want to stress that this is a serious, life-threatening disease occurring mostly in otherwise healthy young people. These illnesses and deaths are occurring in the context of a dynamic marketplace with mix of products with mixes of ingredients, including potentially illicit substances. Users don’t know what’s in them and cannot tell from the ingredients listed on the packaging.”

msullivan@mdedge.com

More than 75% of patients with vaping-related lung injuries used at least one tetrahydrocannabinol (THC)–containing product before they developed symptoms, and most products used were prepackaged, prefilled cartridges, according to new data released by the Centers for Disease Control and Prevention.

mauro grigollo/Thinkstock

The majority of these products (66%) were THC-containing cartridges marketed under the brand name Dank. Dank cartridges are available at legal dispensaries and online in areas where they are legal. The Dank company posted a statement on its website warning buyers about fake cartridges and showing images of genuine cartridges. However, 89% of the cartridges were obtained on the street, from dealers, online, or from friends or social contacts, Jennifer Layden, MD, of the Illinois Department of Public Health said during a CDC telebriefing.

The illness was first recognized in Wisconsin and Illinois. Marijuana is illegal in Wisconsin; Illinois licensed recreational marijuana in 2009.

Other commonalties among cases have also emerged, Anne Schuchat, MD, deputy director of CDC, said during the call. More than two-thirds of the 805 confirmed or probable cases were male, and the median age was 23 years. The illness crosses age barriers, she said. About 62% were 18-24 years of age, and 54% under age 25. However, among the 12 deaths so far reported, the median age was 50 years. The age range was wide, from 27 to 71 years. Dr. Schuchat said data about medical comorbidities potentially linking the deaths is not yet available, although it is part of the ongoing investigation.

Other clinical commonalities included intensive use of THC-containing products and, in a small number of cases, concomitant use of benzodiazepenes, opioids, and narcotics.

Cases have now emerged in 46 states and in the U.S. Virgin Islands, although the number reported each week is dropping. However, this decrease may not represent a drop in newly occurring cases, but instead reflect delays in clinical recognition or reporting to local health departments, Dr. Schuchat said.

Regardless of the recent decline in reported cases, she said, the epidemic is serious, far reaching, and ongoing.

“I want to stress that this is a serious, life-threatening disease occurring mostly in otherwise healthy young people. These illnesses and deaths are occurring in the context of a dynamic marketplace with mix of products with mixes of ingredients, including potentially illicit substances. Users don’t know what’s in them and cannot tell from the ingredients listed on the packaging.”

msullivan@mdedge.com

More than 75% of patients with vaping-related lung injuries used at least one tetrahydrocannabinol (THC)–containing product before they developed symptoms, and most products used were prepackaged, prefilled cartridges, according to new data released by the Centers for Disease Control and Prevention.

mauro grigollo/Thinkstock

The majority of these products (66%) were THC-containing cartridges marketed under the brand name Dank. Dank cartridges are available at legal dispensaries and online in areas where they are legal. The Dank company posted a statement on its website warning buyers about fake cartridges and showing images of genuine cartridges. However, 89% of the cartridges were obtained on the street, from dealers, online, or from friends or social contacts, Jennifer Layden, MD, of the Illinois Department of Public Health said during a CDC telebriefing.

The illness was first recognized in Wisconsin and Illinois. Marijuana is illegal in Wisconsin; Illinois licensed recreational marijuana in 2009.

Other commonalties among cases have also emerged, Anne Schuchat, MD, deputy director of CDC, said during the call. More than two-thirds of the 805 confirmed or probable cases were male, and the median age was 23 years. The illness crosses age barriers, she said. About 62% were 18-24 years of age, and 54% under age 25. However, among the 12 deaths so far reported, the median age was 50 years. The age range was wide, from 27 to 71 years. Dr. Schuchat said data about medical comorbidities potentially linking the deaths is not yet available, although it is part of the ongoing investigation.

Other clinical commonalities included intensive use of THC-containing products and, in a small number of cases, concomitant use of benzodiazepenes, opioids, and narcotics.

Cases have now emerged in 46 states and in the U.S. Virgin Islands, although the number reported each week is dropping. However, this decrease may not represent a drop in newly occurring cases, but instead reflect delays in clinical recognition or reporting to local health departments, Dr. Schuchat said.

Regardless of the recent decline in reported cases, she said, the epidemic is serious, far reaching, and ongoing.

“I want to stress that this is a serious, life-threatening disease occurring mostly in otherwise healthy young people. These illnesses and deaths are occurring in the context of a dynamic marketplace with mix of products with mixes of ingredients, including potentially illicit substances. Users don’t know what’s in them and cannot tell from the ingredients listed on the packaging.”

msullivan@mdedge.com

Elevated serum levels of circulating sex hormones were found to be associated with lower odds of asthma in women, possibly explaining in part the different prevalence of asthma in men and women, according to the findings of a large cross-sectional population based study.

Yueh-Ying Han, PhD, of the Children’s Hospital of Pittsburgh and colleagues investigated the role of free testosterone and estradiol levels and current asthma among adults. The impact of obesity on that association was also examined. The investigators analyzed data from 7,615 adults (3,953 men and 3,662 women) who participated in the 2013-2014 and 2015-2016 U.S. National Health and Nutrition Examination Survey. The data included health interviews, examination components, and laboratory tests on each patient. Serum samples were analyzed by the division of laboratory sciences of the Centers for Disease Control and Prevention. Logistic regression was used for the multivariable analysis of sex hormone levels (as quartiles) and current asthma, and the analysis was done separately on men and women. Pregnant women were excluded, in addition to individuals with incomplete data. The exclusions tended to be Hispanic, former smokers, lower income, and lacking private insurance. The overall prevalence of current asthma in the sample was 9% (6% in men and 13% in women).

Three models were generated based on serum levels in women and in men.

For model 1 (unadjusted for estradiol), women whose serum testosterone levels were in the second and fourth quartiles had 30%-45% significantly lower odds of having current asthma than those whose serum testosterone level was in the lowest quartile. Among men, those whose serum testosterone levels were in the second and fourth quartiles had 12%-13% lower odds for current asthma.

For model 2 (unadjusted for free testosterone), women whose serum estradiol levels were in the third quartile had 34% significantly lower odds of having current asthma than those whose estradiol levels were in the lowest quartile. The findings were similar for men, that is, those whose serum estradiol levels were in the third quartile had 30% lower odds for having asthma, compared with those with in the lowest quartile.

For model 3 (a multivariable model including serum levels of both estradiol and free testosterone), women whose serum testosterone levels were in the second and fourth quartiles had 30% and 44% lower odds of current asthma than those whose serum testosterone levels were in the lowest quartile. But in this multivariable model, the association between serum estradiol and current asthma was not significant. Among men (models 1-3), the magnitude of the estimated effect of serum testosterone and serum estradiol on current asthma was similar to that observed in female participants, but neither serum testosterone nor serum estradiol was significantly associated with current asthma.

The investigators then analyzed the impact of obesity on the relationship between serum hormone levels and obesity. Obesity was defined as body mass index equal to or greater than 30 kg/m². A total of 1,370 men and 1,653 women were included in this analysis. In multivariable analyses of the obese participants, adjustment without (model 1) and with (model 3) serum estradiol, serum free-testosterone levels in the highest (fourth) quartile were significantly associated with reduced odds of asthma in obese women. In multivariable analyses without (model 2) and with (model 3), serum estradiol levels above the first quartile were significantly associated with reduced odds of current asthma in obese women.

In contrast to the results in obese women, neither serum free testosterone nor serum estradiol was significantly associated with current asthma in obese men or nonobese women.

Dr. Han and coauthors suggested a possible mechanism of the role of sex hormones in asthma. “Androgens such as testosterone may reduce innate and adaptive immune responses, while estrogen and progesterone may enhance T-helper cell type 2 allergic airway inflammation.”

They concluded: “We found that elevated serum levels of both free testosterone and estradiol were significantly associated with reduced odds of asthma in obese women, and that elevated levels of serum estradiol were significantly associated with reduced odds of asthma in nonobese men. Our findings further suggest that sex steroid hormones play a role in known sex differences in asthma among adults.”

One coauthor has received research materials from Merck and GlaxoSmithKline (inhaled steroids), as well as Pharmavite (vitamin D and placebo capsules), to provide medications free of cost to participants in National Institutes for Health–funded studies, unrelated to the current work. The other authors reported no conflicts of interest.

tborden@mdedge.com

SOURCE: Han Y-Y et al. J Respir Crit Care Med. 2019 Sep 16. doi: 10.1164/rccm.201905-0996OC.

Elevated serum levels of circulating sex hormones were found to be associated with lower odds of asthma in women, possibly explaining in part the different prevalence of asthma in men and women, according to the findings of a large cross-sectional population based study.

Yueh-Ying Han, PhD, of the Children’s Hospital of Pittsburgh and colleagues investigated the role of free testosterone and estradiol levels and current asthma among adults. The impact of obesity on that association was also examined. The investigators analyzed data from 7,615 adults (3,953 men and 3,662 women) who participated in the 2013-2014 and 2015-2016 U.S. National Health and Nutrition Examination Survey. The data included health interviews, examination components, and laboratory tests on each patient. Serum samples were analyzed by the division of laboratory sciences of the Centers for Disease Control and Prevention. Logistic regression was used for the multivariable analysis of sex hormone levels (as quartiles) and current asthma, and the analysis was done separately on men and women. Pregnant women were excluded, in addition to individuals with incomplete data. The exclusions tended to be Hispanic, former smokers, lower income, and lacking private insurance. The overall prevalence of current asthma in the sample was 9% (6% in men and 13% in women).

Three models were generated based on serum levels in women and in men.

For model 1 (unadjusted for estradiol), women whose serum testosterone levels were in the second and fourth quartiles had 30%-45% significantly lower odds of having current asthma than those whose serum testosterone level was in the lowest quartile. Among men, those whose serum testosterone levels were in the second and fourth quartiles had 12%-13% lower odds for current asthma.

For model 2 (unadjusted for free testosterone), women whose serum estradiol levels were in the third quartile had 34% significantly lower odds of having current asthma than those whose estradiol levels were in the lowest quartile. The findings were similar for men, that is, those whose serum estradiol levels were in the third quartile had 30% lower odds for having asthma, compared with those with in the lowest quartile.

For model 3 (a multivariable model including serum levels of both estradiol and free testosterone), women whose serum testosterone levels were in the second and fourth quartiles had 30% and 44% lower odds of current asthma than those whose serum testosterone levels were in the lowest quartile. But in this multivariable model, the association between serum estradiol and current asthma was not significant. Among men (models 1-3), the magnitude of the estimated effect of serum testosterone and serum estradiol on current asthma was similar to that observed in female participants, but neither serum testosterone nor serum estradiol was significantly associated with current asthma.

The investigators then analyzed the impact of obesity on the relationship between serum hormone levels and obesity. Obesity was defined as body mass index equal to or greater than 30 kg/m². A total of 1,370 men and 1,653 women were included in this analysis. In multivariable analyses of the obese participants, adjustment without (model 1) and with (model 3) serum estradiol, serum free-testosterone levels in the highest (fourth) quartile were significantly associated with reduced odds of asthma in obese women. In multivariable analyses without (model 2) and with (model 3), serum estradiol levels above the first quartile were significantly associated with reduced odds of current asthma in obese women.

In contrast to the results in obese women, neither serum free testosterone nor serum estradiol was significantly associated with current asthma in obese men or nonobese women.

Dr. Han and coauthors suggested a possible mechanism of the role of sex hormones in asthma. “Androgens such as testosterone may reduce innate and adaptive immune responses, while estrogen and progesterone may enhance T-helper cell type 2 allergic airway inflammation.”

They concluded: “We found that elevated serum levels of both free testosterone and estradiol were significantly associated with reduced odds of asthma in obese women, and that elevated levels of serum estradiol were significantly associated with reduced odds of asthma in nonobese men. Our findings further suggest that sex steroid hormones play a role in known sex differences in asthma among adults.”

One coauthor has received research materials from Merck and GlaxoSmithKline (inhaled steroids), as well as Pharmavite (vitamin D and placebo capsules), to provide medications free of cost to participants in National Institutes for Health–funded studies, unrelated to the current work. The other authors reported no conflicts of interest.

tborden@mdedge.com

SOURCE: Han Y-Y et al. J Respir Crit Care Med. 2019 Sep 16. doi: 10.1164/rccm.201905-0996OC.

Elevated serum levels of circulating sex hormones were found to be associated with lower odds of asthma in women, possibly explaining in part the different prevalence of asthma in men and women, according to the findings of a large cross-sectional population based study.

Yueh-Ying Han, PhD, of the Children’s Hospital of Pittsburgh and colleagues investigated the role of free testosterone and estradiol levels and current asthma among adults. The impact of obesity on that association was also examined. The investigators analyzed data from 7,615 adults (3,953 men and 3,662 women) who participated in the 2013-2014 and 2015-2016 U.S. National Health and Nutrition Examination Survey. The data included health interviews, examination components, and laboratory tests on each patient. Serum samples were analyzed by the division of laboratory sciences of the Centers for Disease Control and Prevention. Logistic regression was used for the multivariable analysis of sex hormone levels (as quartiles) and current asthma, and the analysis was done separately on men and women. Pregnant women were excluded, in addition to individuals with incomplete data. The exclusions tended to be Hispanic, former smokers, lower income, and lacking private insurance. The overall prevalence of current asthma in the sample was 9% (6% in men and 13% in women).

Three models were generated based on serum levels in women and in men.

For model 1 (unadjusted for estradiol), women whose serum testosterone levels were in the second and fourth quartiles had 30%-45% significantly lower odds of having current asthma than those whose serum testosterone level was in the lowest quartile. Among men, those whose serum testosterone levels were in the second and fourth quartiles had 12%-13% lower odds for current asthma.

For model 2 (unadjusted for free testosterone), women whose serum estradiol levels were in the third quartile had 34% significantly lower odds of having current asthma than those whose estradiol levels were in the lowest quartile. The findings were similar for men, that is, those whose serum estradiol levels were in the third quartile had 30% lower odds for having asthma, compared with those with in the lowest quartile.

For model 3 (a multivariable model including serum levels of both estradiol and free testosterone), women whose serum testosterone levels were in the second and fourth quartiles had 30% and 44% lower odds of current asthma than those whose serum testosterone levels were in the lowest quartile. But in this multivariable model, the association between serum estradiol and current asthma was not significant. Among men (models 1-3), the magnitude of the estimated effect of serum testosterone and serum estradiol on current asthma was similar to that observed in female participants, but neither serum testosterone nor serum estradiol was significantly associated with current asthma.

The investigators then analyzed the impact of obesity on the relationship between serum hormone levels and obesity. Obesity was defined as body mass index equal to or greater than 30 kg/m². A total of 1,370 men and 1,653 women were included in this analysis. In multivariable analyses of the obese participants, adjustment without (model 1) and with (model 3) serum estradiol, serum free-testosterone levels in the highest (fourth) quartile were significantly associated with reduced odds of asthma in obese women. In multivariable analyses without (model 2) and with (model 3), serum estradiol levels above the first quartile were significantly associated with reduced odds of current asthma in obese women.

In contrast to the results in obese women, neither serum free testosterone nor serum estradiol was significantly associated with current asthma in obese men or nonobese women.

Dr. Han and coauthors suggested a possible mechanism of the role of sex hormones in asthma. “Androgens such as testosterone may reduce innate and adaptive immune responses, while estrogen and progesterone may enhance T-helper cell type 2 allergic airway inflammation.”

They concluded: “We found that elevated serum levels of both free testosterone and estradiol were significantly associated with reduced odds of asthma in obese women, and that elevated levels of serum estradiol were significantly associated with reduced odds of asthma in nonobese men. Our findings further suggest that sex steroid hormones play a role in known sex differences in asthma among adults.”

One coauthor has received research materials from Merck and GlaxoSmithKline (inhaled steroids), as well as Pharmavite (vitamin D and placebo capsules), to provide medications free of cost to participants in National Institutes for Health–funded studies, unrelated to the current work. The other authors reported no conflicts of interest.

tborden@mdedge.com

SOURCE: Han Y-Y et al. J Respir Crit Care Med. 2019 Sep 16. doi: 10.1164/rccm.201905-0996OC.

Almost half of black children with poorly controlled asthma showed a superior response to increased inhaled glucocorticoids over long-acting beta-agonists, based on data from 280 children aged 5-11 years with at least one grandparent identified as black.

Previous studies have suggested that long-acting beta₂-agonists (LABAs) may be more effective for patients with poorly controlled asthma, but such step-up therapy has not been well studied in black patients, wrote Michael E. Wechsler, MD, of National Jewish Health, Denver, and colleagues.

In a study published in the New England Journal of Medicine, the researchers reported results of two parallel BARD (Best African American Response to Asthma Drugs) trials conducted at nine centers between January 2014 and March 2016 of individuals with poorly controlled asthma. One trial included 280 children aged 5-11 years (average age, 8.5 years); the second trial included adolescents aged 12 years and older and adults (average age, 37 years) who had family backgrounds that were similar to those of the children.

The researchers randomized the children to four groups to compare the following protocols: doubling the dose of a glucocorticoid (fluticasone propionate) to a dose of 100 mcg, twice daily (the double-fluticasone group); doubling the dose of fluticasone to 100 mcg and adding 50 mcg of the LABA salmeterol (the salmeterol/double-fluticasone group); quintupling the dose of fluticasone to 250 mcg (the quintuple-fluticasone group); or quintupling the dose of fluticasone to 250 mcg and adding 50 mcg of salmeterol (the salmeterol/quintuple-fluticasone group). The trial consisted of a four-way crossover design with each treatment period lasting 14 weeks.

The primary outcome was a composite measure including asthma exacerbations, asthma control days, and percentage of predicted forced expiratory volume in the first second at the end of each treatment.

Overall, a superior response occurred in 53% of the salmeterol/double-fluticasone group, 41% of the double-fluticasone group, 43% of the salmeterol/quintuple fluticasone group, and 47% of the quintuple-fluticasone group.

The superior response was 46% for both groups when the researchers compared a quintupled dose of fluticasone propionate (250 mcg) with a two step–up strategy of adding salmeterol at a dose of 50 mcg and increasing the dose of fluticasone to 100 mcg.

“In contrast to black adults and white persons of all ages, almost half the children who had at least one grandparent who identified as black and who had poorly controlled asthma had a superior response to an increased dose of an inhaled glucocorticoid over the addition of a LABA,” Dr. Wechsler and coauthors wrote. No more than 12% of the children in any treatment group did not have a superior response. No significant differences in reports of respiratory tract infections or pneumonia were seen between the groups. Children younger than 8 years showed a decrease in the ratio of urinary cortisol to creatinine with an increased dose of inhaled glucocorticoids.

In the adolescent and adult study using the same treatment protocols, 20%-25% of patients did not have a differential outcome between treatments. “In adolescents and adults, the addition of a LABA was more likely to produce superior responses than increasing the dose of an inhaled glucocorticoid,” Dr. Wechsler and coauthors wrote.

The study findings were limited by several factors, including the inability to assess long-term effects on growth and inability to detect biomarkers associated with responses to specific therapies, the researchers noted. However, the results suggest that black children with poorly controlled asthma can benefit from additional inhaled glucocorticoids, and larger studies are needed to identify the best treatment for this patient population.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Wechsler reported relationships with companies including AstraZeneca, Equillium, Genentech, GlaxoSmithKline, Mylan, Novartis, Regeneron, resTORbio, Sanofi, and others. Coauthors identified relationships with numerous pharmaceutical companies.

SOURCE: Wechsler ME et al. N Engl J Med. 2019 Sep 25. doi: 10.1056/NEJMoa1905560.

Almost half of black children with poorly controlled asthma showed a superior response to increased inhaled glucocorticoids over long-acting beta-agonists, based on data from 280 children aged 5-11 years with at least one grandparent identified as black.

Previous studies have suggested that long-acting beta₂-agonists (LABAs) may be more effective for patients with poorly controlled asthma, but such step-up therapy has not been well studied in black patients, wrote Michael E. Wechsler, MD, of National Jewish Health, Denver, and colleagues.

In a study published in the New England Journal of Medicine, the researchers reported results of two parallel BARD (Best African American Response to Asthma Drugs) trials conducted at nine centers between January 2014 and March 2016 of individuals with poorly controlled asthma. One trial included 280 children aged 5-11 years (average age, 8.5 years); the second trial included adolescents aged 12 years and older and adults (average age, 37 years) who had family backgrounds that were similar to those of the children.

The researchers randomized the children to four groups to compare the following protocols: doubling the dose of a glucocorticoid (fluticasone propionate) to a dose of 100 mcg, twice daily (the double-fluticasone group); doubling the dose of fluticasone to 100 mcg and adding 50 mcg of the LABA salmeterol (the salmeterol/double-fluticasone group); quintupling the dose of fluticasone to 250 mcg (the quintuple-fluticasone group); or quintupling the dose of fluticasone to 250 mcg and adding 50 mcg of salmeterol (the salmeterol/quintuple-fluticasone group). The trial consisted of a four-way crossover design with each treatment period lasting 14 weeks.

The primary outcome was a composite measure including asthma exacerbations, asthma control days, and percentage of predicted forced expiratory volume in the first second at the end of each treatment.

Overall, a superior response occurred in 53% of the salmeterol/double-fluticasone group, 41% of the double-fluticasone group, 43% of the salmeterol/quintuple fluticasone group, and 47% of the quintuple-fluticasone group.

The superior response was 46% for both groups when the researchers compared a quintupled dose of fluticasone propionate (250 mcg) with a two step–up strategy of adding salmeterol at a dose of 50 mcg and increasing the dose of fluticasone to 100 mcg.

“In contrast to black adults and white persons of all ages, almost half the children who had at least one grandparent who identified as black and who had poorly controlled asthma had a superior response to an increased dose of an inhaled glucocorticoid over the addition of a LABA,” Dr. Wechsler and coauthors wrote. No more than 12% of the children in any treatment group did not have a superior response. No significant differences in reports of respiratory tract infections or pneumonia were seen between the groups. Children younger than 8 years showed a decrease in the ratio of urinary cortisol to creatinine with an increased dose of inhaled glucocorticoids.

In the adolescent and adult study using the same treatment protocols, 20%-25% of patients did not have a differential outcome between treatments. “In adolescents and adults, the addition of a LABA was more likely to produce superior responses than increasing the dose of an inhaled glucocorticoid,” Dr. Wechsler and coauthors wrote.

The study findings were limited by several factors, including the inability to assess long-term effects on growth and inability to detect biomarkers associated with responses to specific therapies, the researchers noted. However, the results suggest that black children with poorly controlled asthma can benefit from additional inhaled glucocorticoids, and larger studies are needed to identify the best treatment for this patient population.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Wechsler reported relationships with companies including AstraZeneca, Equillium, Genentech, GlaxoSmithKline, Mylan, Novartis, Regeneron, resTORbio, Sanofi, and others. Coauthors identified relationships with numerous pharmaceutical companies.

SOURCE: Wechsler ME et al. N Engl J Med. 2019 Sep 25. doi: 10.1056/NEJMoa1905560.

Almost half of black children with poorly controlled asthma showed a superior response to increased inhaled glucocorticoids over long-acting beta-agonists, based on data from 280 children aged 5-11 years with at least one grandparent identified as black.

Previous studies have suggested that long-acting beta₂-agonists (LABAs) may be more effective for patients with poorly controlled asthma, but such step-up therapy has not been well studied in black patients, wrote Michael E. Wechsler, MD, of National Jewish Health, Denver, and colleagues.

In a study published in the New England Journal of Medicine, the researchers reported results of two parallel BARD (Best African American Response to Asthma Drugs) trials conducted at nine centers between January 2014 and March 2016 of individuals with poorly controlled asthma. One trial included 280 children aged 5-11 years (average age, 8.5 years); the second trial included adolescents aged 12 years and older and adults (average age, 37 years) who had family backgrounds that were similar to those of the children.

The researchers randomized the children to four groups to compare the following protocols: doubling the dose of a glucocorticoid (fluticasone propionate) to a dose of 100 mcg, twice daily (the double-fluticasone group); doubling the dose of fluticasone to 100 mcg and adding 50 mcg of the LABA salmeterol (the salmeterol/double-fluticasone group); quintupling the dose of fluticasone to 250 mcg (the quintuple-fluticasone group); or quintupling the dose of fluticasone to 250 mcg and adding 50 mcg of salmeterol (the salmeterol/quintuple-fluticasone group). The trial consisted of a four-way crossover design with each treatment period lasting 14 weeks.

The primary outcome was a composite measure including asthma exacerbations, asthma control days, and percentage of predicted forced expiratory volume in the first second at the end of each treatment.

Overall, a superior response occurred in 53% of the salmeterol/double-fluticasone group, 41% of the double-fluticasone group, 43% of the salmeterol/quintuple fluticasone group, and 47% of the quintuple-fluticasone group.

The superior response was 46% for both groups when the researchers compared a quintupled dose of fluticasone propionate (250 mcg) with a two step–up strategy of adding salmeterol at a dose of 50 mcg and increasing the dose of fluticasone to 100 mcg.

“In contrast to black adults and white persons of all ages, almost half the children who had at least one grandparent who identified as black and who had poorly controlled asthma had a superior response to an increased dose of an inhaled glucocorticoid over the addition of a LABA,” Dr. Wechsler and coauthors wrote. No more than 12% of the children in any treatment group did not have a superior response. No significant differences in reports of respiratory tract infections or pneumonia were seen between the groups. Children younger than 8 years showed a decrease in the ratio of urinary cortisol to creatinine with an increased dose of inhaled glucocorticoids.

In the adolescent and adult study using the same treatment protocols, 20%-25% of patients did not have a differential outcome between treatments. “In adolescents and adults, the addition of a LABA was more likely to produce superior responses than increasing the dose of an inhaled glucocorticoid,” Dr. Wechsler and coauthors wrote.

The study findings were limited by several factors, including the inability to assess long-term effects on growth and inability to detect biomarkers associated with responses to specific therapies, the researchers noted. However, the results suggest that black children with poorly controlled asthma can benefit from additional inhaled glucocorticoids, and larger studies are needed to identify the best treatment for this patient population.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Wechsler reported relationships with companies including AstraZeneca, Equillium, Genentech, GlaxoSmithKline, Mylan, Novartis, Regeneron, resTORbio, Sanofi, and others. Coauthors identified relationships with numerous pharmaceutical companies.

SOURCE: Wechsler ME et al. N Engl J Med. 2019 Sep 25. doi: 10.1056/NEJMoa1905560.

Norman E. Sharpless, MD, acting commissioner of the Food and Drug Administration, has issued remarks that were prepared for a testimony before a U.S. House Energy and Commerce subcommittee on FDA regulation of electronic nicotine delivery systems and investigation of vaping illnesses.

Dr. Sharpless’s statement focuses on two priorities: the continuing investigation into the cause of lung injury associated with the use of vaping products and the FDA’s ongoing efforts to address an epidemic of youth use of electronic nicotine delivery systems (ENDS). In regards to lung injuries associated with vaping, Dr. Sharpless said that the FDA and Centers for Disease Control and Prevention, in conjunction with state partners, have been investigating the outbreak and noted that, while most cases have involved tetrahydrocannabinol, there is as of yet no common cause or product linked to all cases.

The FDA is not currently pursuing any legal action against personal usage of vaping products, but “if we determine that someone is manufacturing or distributing illicit, adulterated vaping products that caused illness and death for personal profit, we would consider that to be a criminal act,” Dr. Sharpless said.

Research from the 2018 and 2019 National Youth Tobacco Surveys has indicated that ENDS usage among youth has risen dramatically in recent years, Dr. Sharpless continued in the statement. The FDA has pursued several courses of action, including the issue of a warning letter to Juul for marketing unauthorized modified-risk tobacco products to children.

However, he noted, youth e-cigarette use continues to rise, which is the reason for the FDA’s intention to finalize a compliance policy related to flavored ENDS, a policy supported by President TRump.

“FDA is not ‘banning’ flavors, as has been described in some news reports. Rather, FDA intends to enforce existing law that limits the marketing of such products,” Dr. Sharpless said. “This policy would not mean that flavored e-cigarettes could never be marketed. If a company can show through an application to FDA that a specific product meets the standard set forth by Congress, then the FDA would authorize that ENDS product for sale.”

Find the full statement on the FDA website.

lfranki@mdedge.com

Norman E. Sharpless, MD, acting commissioner of the Food and Drug Administration, has issued remarks that were prepared for a testimony before a U.S. House Energy and Commerce subcommittee on FDA regulation of electronic nicotine delivery systems and investigation of vaping illnesses.

Dr. Sharpless’s statement focuses on two priorities: the continuing investigation into the cause of lung injury associated with the use of vaping products and the FDA’s ongoing efforts to address an epidemic of youth use of electronic nicotine delivery systems (ENDS). In regards to lung injuries associated with vaping, Dr. Sharpless said that the FDA and Centers for Disease Control and Prevention, in conjunction with state partners, have been investigating the outbreak and noted that, while most cases have involved tetrahydrocannabinol, there is as of yet no common cause or product linked to all cases.

The FDA is not currently pursuing any legal action against personal usage of vaping products, but “if we determine that someone is manufacturing or distributing illicit, adulterated vaping products that caused illness and death for personal profit, we would consider that to be a criminal act,” Dr. Sharpless said.

Research from the 2018 and 2019 National Youth Tobacco Surveys has indicated that ENDS usage among youth has risen dramatically in recent years, Dr. Sharpless continued in the statement. The FDA has pursued several courses of action, including the issue of a warning letter to Juul for marketing unauthorized modified-risk tobacco products to children.

However, he noted, youth e-cigarette use continues to rise, which is the reason for the FDA’s intention to finalize a compliance policy related to flavored ENDS, a policy supported by President TRump.

“FDA is not ‘banning’ flavors, as has been described in some news reports. Rather, FDA intends to enforce existing law that limits the marketing of such products,” Dr. Sharpless said. “This policy would not mean that flavored e-cigarettes could never be marketed. If a company can show through an application to FDA that a specific product meets the standard set forth by Congress, then the FDA would authorize that ENDS product for sale.”

Find the full statement on the FDA website.

lfranki@mdedge.com

Norman E. Sharpless, MD, acting commissioner of the Food and Drug Administration, has issued remarks that were prepared for a testimony before a U.S. House Energy and Commerce subcommittee on FDA regulation of electronic nicotine delivery systems and investigation of vaping illnesses.

Dr. Sharpless’s statement focuses on two priorities: the continuing investigation into the cause of lung injury associated with the use of vaping products and the FDA’s ongoing efforts to address an epidemic of youth use of electronic nicotine delivery systems (ENDS). In regards to lung injuries associated with vaping, Dr. Sharpless said that the FDA and Centers for Disease Control and Prevention, in conjunction with state partners, have been investigating the outbreak and noted that, while most cases have involved tetrahydrocannabinol, there is as of yet no common cause or product linked to all cases.

The FDA is not currently pursuing any legal action against personal usage of vaping products, but “if we determine that someone is manufacturing or distributing illicit, adulterated vaping products that caused illness and death for personal profit, we would consider that to be a criminal act,” Dr. Sharpless said.

Research from the 2018 and 2019 National Youth Tobacco Surveys has indicated that ENDS usage among youth has risen dramatically in recent years, Dr. Sharpless continued in the statement. The FDA has pursued several courses of action, including the issue of a warning letter to Juul for marketing unauthorized modified-risk tobacco products to children.

However, he noted, youth e-cigarette use continues to rise, which is the reason for the FDA’s intention to finalize a compliance policy related to flavored ENDS, a policy supported by President TRump.

“FDA is not ‘banning’ flavors, as has been described in some news reports. Rather, FDA intends to enforce existing law that limits the marketing of such products,” Dr. Sharpless said. “This policy would not mean that flavored e-cigarettes could never be marketed. If a company can show through an application to FDA that a specific product meets the standard set forth by Congress, then the FDA would authorize that ENDS product for sale.”

Find the full statement on the FDA website.

lfranki@mdedge.com

Pregnant women should be screened for asymptomatic bacteriuria using urine culture because the benefit of reducing pyelonephritis during pregnancy slightly but significantly outweighs the risks of maternal and fetal antibiotic exposure, according to new recommendations set forth by the United States Preventive Services Task Force (USPSTF).

toeytoey2530/Thinkstock

However, the investigating committee reported, there is evidence against screening nonpregnant women and adult men. In fact, the committee found “adequate” evidence of potential harm associated with treating asymptomatic bacteriuria in adults of both sexes, including adverse effects of antibiotics and on the microbiome.

The new document downgrades from A to B the group’s prior recommendation that urine culture screening for asymptomatic bacteriuria should be performed among pregnant women at 12-16 weeks’ gestation or at their first prenatal visit. The USPSTF recommendation to not screen nonpregnant adults retained its D rating, Jerome A. Leis, MD and Christine Soong, MD said in an accompanying editorial.

“Not screening or treating asymptomatic bacteriuria in this population has long been an ironclad recommendation endorsed by the Infectious Diseases Society of America, as well as numerous professional societies as part of the Choosing Wisely campaign,” wrote Dr. Leis of Sunnybrook Health Sciences Centre, Toronto, and Dr. Soong of the University of Toronto. “Restating this steadfast and pervasive recommendation may seem unremarkable and almost pedantic, yet it remains stubbornly disregarded by clinicians across multiple settings.”

The new recommendations were based on a review of 19 studies involving almost 8,500 pregnant and nonpregnant women, as well as a small number of adult men. Most were carried out in the 1960s or 1970s. The most recent ones were published in 2002 and 2015. The dearth of more recent data may have limited some conclusions and certainly highlighted the need for more research, said Jillian T. Henderson, PhD, chair of the committee assigned to investigate the evidence.

“Few studies of asymptomatic bacteriuria screening or treatment in pregnant populations have been conducted in the past 40 years,” wrote Dr. Henderson of Kaiser Permanente Northwest, Portland, and associates. “Historical evidence established asymptomatic bacteriuria screening and treatment as standard obstetric practice in the United States.” But these trials typically were less rigorous than modern studies, and the results are out of touch with modern clinical settings and treatment protocols, the team noted.

Additionally, Dr. Henderson and coauthors said, rates of pyelonephritis were about 10 times higher then than they are now. In the more recent studies, pyelonephritis rates in control groups were 2.2% and 2.5%; in most of the older studies, control group rates ranged from 33% to 36%.

In commissioning the investigation, the task force looked at the following four questions:

Does screening improve health outcomes?

Neither of two studies involving 5,289 women, one from Spain and one from Turkey, addressed this question in nonpregnant women; however, studies that looked at pregnant women generally found that screening did reduce the risk of pyelonephritis by about 70%. The investigators cautioned that these studies were out of date and perhaps methodologically flawed.

The only study that looked at newborn outcomes found no difference in birth weights or premature births between the screened and unscreened cohorts.

No study examined this question in nonpregnant women or men.
 

What are the harms of such screening?

A single study of 372 pregnant women described potential prenatal and perinatal harms associated with screening and treatment. It found a slight increase in congenital abnormalities in the screened cohort (1.6%), compared with those who were not screened (1.1%). However, those who were not screened were presumably not prescribed antibiotics.

Does treatment of screening-detected asymptomatic bacteriuria improve health outcomes?

Twelve trials of pregnant women (2,377) addressed this issue. All but two were conducted in the 1960s and 1970s. Treatment varied widely; sulfonamides were the most common, including the now discarded sulfamethazine and sulfadimethoxine. Dosages and duration of treatment also were considerably higher and longer than current practice.

In all but one study, there were higher rates of pyelonephritis in the control group. A pooled risk analysis indicated that treatment reduced the risk of pyelonephritis by nearly 80% (relative risk, 0.24).

Seven studies found higher rates of low birth weight in infants born to mothers who were treated, but two studies reported a significant reduction in the risk of low birth weight.

Among the six trials that examined perinatal mortality, none found significant associations with treatment.

Five studies examined treatment in nonpregnant women with screening-detected asymptomatic bacteriuria, and one included men as well. Of the four that reported the rate of symptomatic infection or pyelonephritis, none found a significant difference between treatment and control groups. The single study that included men also found no significant difference between treatment and control groups.

Among the three studies that focused on older adults, there also were no significant between-group differences in outcomes.

What harms are associated with treatment of screening-detected asymptomatic bacteriuria?

Seven studies comprised pregnant women. Five reported congenital malformations in the intervention and control groups. Overall, there were very few cases of malformations, with more – although not significantly more – in the control groups.

Evidence related to other infant and maternal harms was “sparsely and inconsistently reported,” Dr. Henderson and coauthors noted, “and there was a lack of evidence on long-term neonatal outcomes after antibiotic treatment of asymptomatic bacteriuria in pregnancy.”

Two studies listed maternal adverse events associated with different treatments including vaginitis and diarrhea with ampicillin and rashes and nausea with nalidixic acid.

In terms of nonpregnant women and men, four studies reported adverse events. None occurred with nitrofurantoin or trimethoprim treatment; however, one study that included daily treatment with ofloxacin noted that 6% withdrew because of adverse events – vertigo and gastrointestinal symptoms.

Treatments didn’t affect hematocrit, bilirubin, serum urea, or nitrogen, although some studies found a slight reduction in serum creatinine.

Although there’s a need for additional research into this question, the new recommendations provide a good reason to further reduce unnecessary antibiotic exposure, Lindsey E. Nicolle, MD, wrote in a second commentary.

These updated recommendations “contribute to the evolution of management of asymptomatic bacteriuria in healthy women,” wrote Dr. Nicolle of the University of Manitoba, Winnipeg. “However, questions remain about the risks and benefits of universal screening for and treatment of asymptomatic bacteriuria in pregnant women in the context of current clinical practice. The effects of changes in fetal-maternal care, of low- compared with high-risk pregnancies, and of health care access need to be understood. In the short term, application of current diagnostic recommendations for identification of persistent symptomatic bacteriuria with a second urine culture may provide an immediate opportunity to limit unnecessary antimicrobial use for some pregnant women.”

No conflicts of interest were reported by the USPSTF authors, nor by Dr. Leis, Dr. Soong, or Dr. Nicolle. The USPSTF report was funded by the Agency for Healthcare Research and Quality.
 

SOURCES: U.S. Preventive Services Task Force. JAMA. 2019;322(12):1188-94; Henderson JT et al. JAMA. 2019;322(12):1195-205; Leis JA and Soong C. JAMA. 2019. doi: 10.1001/jamainternmed.2019.4515; Nicolle LE. JAMA. 2019;322(12):1152-4.

Pregnant women should be screened for asymptomatic bacteriuria using urine culture because the benefit of reducing pyelonephritis during pregnancy slightly but significantly outweighs the risks of maternal and fetal antibiotic exposure, according to new recommendations set forth by the United States Preventive Services Task Force (USPSTF).

toeytoey2530/Thinkstock

However, the investigating committee reported, there is evidence against screening nonpregnant women and adult men. In fact, the committee found “adequate” evidence of potential harm associated with treating asymptomatic bacteriuria in adults of both sexes, including adverse effects of antibiotics and on the microbiome.

The new document downgrades from A to B the group’s prior recommendation that urine culture screening for asymptomatic bacteriuria should be performed among pregnant women at 12-16 weeks’ gestation or at their first prenatal visit. The USPSTF recommendation to not screen nonpregnant adults retained its D rating, Jerome A. Leis, MD and Christine Soong, MD said in an accompanying editorial.

“Not screening or treating asymptomatic bacteriuria in this population has long been an ironclad recommendation endorsed by the Infectious Diseases Society of America, as well as numerous professional societies as part of the Choosing Wisely campaign,” wrote Dr. Leis of Sunnybrook Health Sciences Centre, Toronto, and Dr. Soong of the University of Toronto. “Restating this steadfast and pervasive recommendation may seem unremarkable and almost pedantic, yet it remains stubbornly disregarded by clinicians across multiple settings.”

The new recommendations were based on a review of 19 studies involving almost 8,500 pregnant and nonpregnant women, as well as a small number of adult men. Most were carried out in the 1960s or 1970s. The most recent ones were published in 2002 and 2015. The dearth of more recent data may have limited some conclusions and certainly highlighted the need for more research, said Jillian T. Henderson, PhD, chair of the committee assigned to investigate the evidence.

“Few studies of asymptomatic bacteriuria screening or treatment in pregnant populations have been conducted in the past 40 years,” wrote Dr. Henderson of Kaiser Permanente Northwest, Portland, and associates. “Historical evidence established asymptomatic bacteriuria screening and treatment as standard obstetric practice in the United States.” But these trials typically were less rigorous than modern studies, and the results are out of touch with modern clinical settings and treatment protocols, the team noted.

Additionally, Dr. Henderson and coauthors said, rates of pyelonephritis were about 10 times higher then than they are now. In the more recent studies, pyelonephritis rates in control groups were 2.2% and 2.5%; in most of the older studies, control group rates ranged from 33% to 36%.

In commissioning the investigation, the task force looked at the following four questions:

Does screening improve health outcomes?

Neither of two studies involving 5,289 women, one from Spain and one from Turkey, addressed this question in nonpregnant women; however, studies that looked at pregnant women generally found that screening did reduce the risk of pyelonephritis by about 70%. The investigators cautioned that these studies were out of date and perhaps methodologically flawed.

The only study that looked at newborn outcomes found no difference in birth weights or premature births between the screened and unscreened cohorts.

No study examined this question in nonpregnant women or men.
 

What are the harms of such screening?

A single study of 372 pregnant women described potential prenatal and perinatal harms associated with screening and treatment. It found a slight increase in congenital abnormalities in the screened cohort (1.6%), compared with those who were not screened (1.1%). However, those who were not screened were presumably not prescribed antibiotics.

Does treatment of screening-detected asymptomatic bacteriuria improve health outcomes?

Twelve trials of pregnant women (2,377) addressed this issue. All but two were conducted in the 1960s and 1970s. Treatment varied widely; sulfonamides were the most common, including the now discarded sulfamethazine and sulfadimethoxine. Dosages and duration of treatment also were considerably higher and longer than current practice.

In all but one study, there were higher rates of pyelonephritis in the control group. A pooled risk analysis indicated that treatment reduced the risk of pyelonephritis by nearly 80% (relative risk, 0.24).

Seven studies found higher rates of low birth weight in infants born to mothers who were treated, but two studies reported a significant reduction in the risk of low birth weight.

Among the six trials that examined perinatal mortality, none found significant associations with treatment.

Five studies examined treatment in nonpregnant women with screening-detected asymptomatic bacteriuria, and one included men as well. Of the four that reported the rate of symptomatic infection or pyelonephritis, none found a significant difference between treatment and control groups. The single study that included men also found no significant difference between treatment and control groups.

Among the three studies that focused on older adults, there also were no significant between-group differences in outcomes.

What harms are associated with treatment of screening-detected asymptomatic bacteriuria?

Seven studies comprised pregnant women. Five reported congenital malformations in the intervention and control groups. Overall, there were very few cases of malformations, with more – although not significantly more – in the control groups.

Evidence related to other infant and maternal harms was “sparsely and inconsistently reported,” Dr. Henderson and coauthors noted, “and there was a lack of evidence on long-term neonatal outcomes after antibiotic treatment of asymptomatic bacteriuria in pregnancy.”

Two studies listed maternal adverse events associated with different treatments including vaginitis and diarrhea with ampicillin and rashes and nausea with nalidixic acid.

In terms of nonpregnant women and men, four studies reported adverse events. None occurred with nitrofurantoin or trimethoprim treatment; however, one study that included daily treatment with ofloxacin noted that 6% withdrew because of adverse events – vertigo and gastrointestinal symptoms.

Treatments didn’t affect hematocrit, bilirubin, serum urea, or nitrogen, although some studies found a slight reduction in serum creatinine.

Although there’s a need for additional research into this question, the new recommendations provide a good reason to further reduce unnecessary antibiotic exposure, Lindsey E. Nicolle, MD, wrote in a second commentary.

These updated recommendations “contribute to the evolution of management of asymptomatic bacteriuria in healthy women,” wrote Dr. Nicolle of the University of Manitoba, Winnipeg. “However, questions remain about the risks and benefits of universal screening for and treatment of asymptomatic bacteriuria in pregnant women in the context of current clinical practice. The effects of changes in fetal-maternal care, of low- compared with high-risk pregnancies, and of health care access need to be understood. In the short term, application of current diagnostic recommendations for identification of persistent symptomatic bacteriuria with a second urine culture may provide an immediate opportunity to limit unnecessary antimicrobial use for some pregnant women.”

No conflicts of interest were reported by the USPSTF authors, nor by Dr. Leis, Dr. Soong, or Dr. Nicolle. The USPSTF report was funded by the Agency for Healthcare Research and Quality.
 

SOURCES: U.S. Preventive Services Task Force. JAMA. 2019;322(12):1188-94; Henderson JT et al. JAMA. 2019;322(12):1195-205; Leis JA and Soong C. JAMA. 2019. doi: 10.1001/jamainternmed.2019.4515; Nicolle LE. JAMA. 2019;322(12):1152-4.

Pregnant women should be screened for asymptomatic bacteriuria using urine culture because the benefit of reducing pyelonephritis during pregnancy slightly but significantly outweighs the risks of maternal and fetal antibiotic exposure, according to new recommendations set forth by the United States Preventive Services Task Force (USPSTF).

toeytoey2530/Thinkstock

However, the investigating committee reported, there is evidence against screening nonpregnant women and adult men. In fact, the committee found “adequate” evidence of potential harm associated with treating asymptomatic bacteriuria in adults of both sexes, including adverse effects of antibiotics and on the microbiome.

The new document downgrades from A to B the group’s prior recommendation that urine culture screening for asymptomatic bacteriuria should be performed among pregnant women at 12-16 weeks’ gestation or at their first prenatal visit. The USPSTF recommendation to not screen nonpregnant adults retained its D rating, Jerome A. Leis, MD and Christine Soong, MD said in an accompanying editorial.

“Not screening or treating asymptomatic bacteriuria in this population has long been an ironclad recommendation endorsed by the Infectious Diseases Society of America, as well as numerous professional societies as part of the Choosing Wisely campaign,” wrote Dr. Leis of Sunnybrook Health Sciences Centre, Toronto, and Dr. Soong of the University of Toronto. “Restating this steadfast and pervasive recommendation may seem unremarkable and almost pedantic, yet it remains stubbornly disregarded by clinicians across multiple settings.”

The new recommendations were based on a review of 19 studies involving almost 8,500 pregnant and nonpregnant women, as well as a small number of adult men. Most were carried out in the 1960s or 1970s. The most recent ones were published in 2002 and 2015. The dearth of more recent data may have limited some conclusions and certainly highlighted the need for more research, said Jillian T. Henderson, PhD, chair of the committee assigned to investigate the evidence.

“Few studies of asymptomatic bacteriuria screening or treatment in pregnant populations have been conducted in the past 40 years,” wrote Dr. Henderson of Kaiser Permanente Northwest, Portland, and associates. “Historical evidence established asymptomatic bacteriuria screening and treatment as standard obstetric practice in the United States.” But these trials typically were less rigorous than modern studies, and the results are out of touch with modern clinical settings and treatment protocols, the team noted.

Additionally, Dr. Henderson and coauthors said, rates of pyelonephritis were about 10 times higher then than they are now. In the more recent studies, pyelonephritis rates in control groups were 2.2% and 2.5%; in most of the older studies, control group rates ranged from 33% to 36%.

In commissioning the investigation, the task force looked at the following four questions:

Does screening improve health outcomes?

Neither of two studies involving 5,289 women, one from Spain and one from Turkey, addressed this question in nonpregnant women; however, studies that looked at pregnant women generally found that screening did reduce the risk of pyelonephritis by about 70%. The investigators cautioned that these studies were out of date and perhaps methodologically flawed.

The only study that looked at newborn outcomes found no difference in birth weights or premature births between the screened and unscreened cohorts.

No study examined this question in nonpregnant women or men.
 

What are the harms of such screening?

A single study of 372 pregnant women described potential prenatal and perinatal harms associated with screening and treatment. It found a slight increase in congenital abnormalities in the screened cohort (1.6%), compared with those who were not screened (1.1%). However, those who were not screened were presumably not prescribed antibiotics.

Does treatment of screening-detected asymptomatic bacteriuria improve health outcomes?

Twelve trials of pregnant women (2,377) addressed this issue. All but two were conducted in the 1960s and 1970s. Treatment varied widely; sulfonamides were the most common, including the now discarded sulfamethazine and sulfadimethoxine. Dosages and duration of treatment also were considerably higher and longer than current practice.

In all but one study, there were higher rates of pyelonephritis in the control group. A pooled risk analysis indicated that treatment reduced the risk of pyelonephritis by nearly 80% (relative risk, 0.24).

Seven studies found higher rates of low birth weight in infants born to mothers who were treated, but two studies reported a significant reduction in the risk of low birth weight.

Among the six trials that examined perinatal mortality, none found significant associations with treatment.

Five studies examined treatment in nonpregnant women with screening-detected asymptomatic bacteriuria, and one included men as well. Of the four that reported the rate of symptomatic infection or pyelonephritis, none found a significant difference between treatment and control groups. The single study that included men also found no significant difference between treatment and control groups.

Among the three studies that focused on older adults, there also were no significant between-group differences in outcomes.

What harms are associated with treatment of screening-detected asymptomatic bacteriuria?

Seven studies comprised pregnant women. Five reported congenital malformations in the intervention and control groups. Overall, there were very few cases of malformations, with more – although not significantly more – in the control groups.

Evidence related to other infant and maternal harms was “sparsely and inconsistently reported,” Dr. Henderson and coauthors noted, “and there was a lack of evidence on long-term neonatal outcomes after antibiotic treatment of asymptomatic bacteriuria in pregnancy.”

Two studies listed maternal adverse events associated with different treatments including vaginitis and diarrhea with ampicillin and rashes and nausea with nalidixic acid.

In terms of nonpregnant women and men, four studies reported adverse events. None occurred with nitrofurantoin or trimethoprim treatment; however, one study that included daily treatment with ofloxacin noted that 6% withdrew because of adverse events – vertigo and gastrointestinal symptoms.

Treatments didn’t affect hematocrit, bilirubin, serum urea, or nitrogen, although some studies found a slight reduction in serum creatinine.

Although there’s a need for additional research into this question, the new recommendations provide a good reason to further reduce unnecessary antibiotic exposure, Lindsey E. Nicolle, MD, wrote in a second commentary.

These updated recommendations “contribute to the evolution of management of asymptomatic bacteriuria in healthy women,” wrote Dr. Nicolle of the University of Manitoba, Winnipeg. “However, questions remain about the risks and benefits of universal screening for and treatment of asymptomatic bacteriuria in pregnant women in the context of current clinical practice. The effects of changes in fetal-maternal care, of low- compared with high-risk pregnancies, and of health care access need to be understood. In the short term, application of current diagnostic recommendations for identification of persistent symptomatic bacteriuria with a second urine culture may provide an immediate opportunity to limit unnecessary antimicrobial use for some pregnant women.”

No conflicts of interest were reported by the USPSTF authors, nor by Dr. Leis, Dr. Soong, or Dr. Nicolle. The USPSTF report was funded by the Agency for Healthcare Research and Quality.
 

SOURCES: U.S. Preventive Services Task Force. JAMA. 2019;322(12):1188-94; Henderson JT et al. JAMA. 2019;322(12):1195-205; Leis JA and Soong C. JAMA. 2019. doi: 10.1001/jamainternmed.2019.4515; Nicolle LE. JAMA. 2019;322(12):1152-4.

Among preschool children with cystic fibrosis, airway disease as measured by the Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) accurately predicts bronchiectasis in grade school, reported Nynke R. Bouma, BSc, and colleagues.

“Even though bronchiectasis is present in 60% to 80% of children with CF in school age, the extent and severity of bronchiectasis in preschool children are generally lower ... however, diffuse airway abnormalities such as airway wall thickening and mucus plugging are observed in many preschool children. It is hypothesized that these preschool airway changes reflect diffuse airway disease that eventually will result in bronchiectasis in school age,” they noted.

The PRAGMA-CF image scoring system can measure airway disease and can also be used to monitor disease progression, noted Ms. Bouma of Sophia Children’s Hospital, Rotterdam, and colleagues. The study was published in Pediatric Pulmonology. PRAGMA-CF is a composite score of airway wall thickening, mucus plugging, and bronchiectasis as percent disease (%disease). “In preschool children, %disease measured by PRAGMA-CF on chest CT allows quantification of early clinically relevant morphological features of CF airway disease and it is associated with later school-age bronchiectasis,” the team wrote. “These findings support the use of %disease as a clinically relevant outcome measure in early CF lung disease.”

The team conducted a prospective cohort study of 61 children (mean age 4 years) with cystic fibrosis, following them for a mean of 5 years. A total of 122 CT scans were available from this group, in addition to spirometry data and cystic fibrosis quality of life scores.

From preschool age to school age, the %disease on PRAGMA-CF increased significantly, from a mean of 0.7% to 1.73%. Scores on another composite measuring tool (%MUPAT, a composite score of airway wall thickening and mucus plugging) went from 0.46 to 0.58 – not a significant difference.

A multivariate analysis corrected for age in each school group and the type of scanner used to acquire the images. That analysis determined that each 1% increase in %disease at preschool age resulted in an increase of 1.18% of bronchiectasis at school age.

A cross-sectional analysis of the group at school age found significant associations between the %disease and percent of forced expiratory volume and the cystic fibrosis quality of life score.

At least one pulmonary exacerbation requiring intravenous antibiotics occurred in 19 of the patients. However, the investigators didn’t find any significant interactions between the %disease in preschool and these exacerbations..

“These findings are in line with previous studies in school‐aged children that showed that mucus plugging is associated with inflammation and airway wall thickening, and that these are thought to be risk factors for later bronchiectasis,” they concluded. “On the basis of our findings, we suggest that %disease and %MUPAT could be used as a clinically relevant outcome measure in clinical studies in preschool patients with cystic fibrosis, as these measures predict later bronchiectasis. Percent disease may be preferred as it captures all the principal features of CF airways disease including bronchiectasis.”

Ms. Bouma had no financial disclosures.

msullivan@mdedge.com

SOURCE: Bouma NR et al. Pediatr Pulmonol. 2019 Sep 9 doi: 10.1002/ppul.24498; Rosenow et al. Am J Respir Crit Care Med. 2015 May 15. doi: 10.1164/rccm.201501-0061OC.

Among preschool children with cystic fibrosis, airway disease as measured by the Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) accurately predicts bronchiectasis in grade school, reported Nynke R. Bouma, BSc, and colleagues.

“Even though bronchiectasis is present in 60% to 80% of children with CF in school age, the extent and severity of bronchiectasis in preschool children are generally lower ... however, diffuse airway abnormalities such as airway wall thickening and mucus plugging are observed in many preschool children. It is hypothesized that these preschool airway changes reflect diffuse airway disease that eventually will result in bronchiectasis in school age,” they noted.

The PRAGMA-CF image scoring system can measure airway disease and can also be used to monitor disease progression, noted Ms. Bouma of Sophia Children’s Hospital, Rotterdam, and colleagues. The study was published in Pediatric Pulmonology. PRAGMA-CF is a composite score of airway wall thickening, mucus plugging, and bronchiectasis as percent disease (%disease). “In preschool children, %disease measured by PRAGMA-CF on chest CT allows quantification of early clinically relevant morphological features of CF airway disease and it is associated with later school-age bronchiectasis,” the team wrote. “These findings support the use of %disease as a clinically relevant outcome measure in early CF lung disease.”

The team conducted a prospective cohort study of 61 children (mean age 4 years) with cystic fibrosis, following them for a mean of 5 years. A total of 122 CT scans were available from this group, in addition to spirometry data and cystic fibrosis quality of life scores.

From preschool age to school age, the %disease on PRAGMA-CF increased significantly, from a mean of 0.7% to 1.73%. Scores on another composite measuring tool (%MUPAT, a composite score of airway wall thickening and mucus plugging) went from 0.46 to 0.58 – not a significant difference.

A multivariate analysis corrected for age in each school group and the type of scanner used to acquire the images. That analysis determined that each 1% increase in %disease at preschool age resulted in an increase of 1.18% of bronchiectasis at school age.

A cross-sectional analysis of the group at school age found significant associations between the %disease and percent of forced expiratory volume and the cystic fibrosis quality of life score.

At least one pulmonary exacerbation requiring intravenous antibiotics occurred in 19 of the patients. However, the investigators didn’t find any significant interactions between the %disease in preschool and these exacerbations..

“These findings are in line with previous studies in school‐aged children that showed that mucus plugging is associated with inflammation and airway wall thickening, and that these are thought to be risk factors for later bronchiectasis,” they concluded. “On the basis of our findings, we suggest that %disease and %MUPAT could be used as a clinically relevant outcome measure in clinical studies in preschool patients with cystic fibrosis, as these measures predict later bronchiectasis. Percent disease may be preferred as it captures all the principal features of CF airways disease including bronchiectasis.”

Ms. Bouma had no financial disclosures.

msullivan@mdedge.com

SOURCE: Bouma NR et al. Pediatr Pulmonol. 2019 Sep 9 doi: 10.1002/ppul.24498; Rosenow et al. Am J Respir Crit Care Med. 2015 May 15. doi: 10.1164/rccm.201501-0061OC.

Among preschool children with cystic fibrosis, airway disease as measured by the Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) accurately predicts bronchiectasis in grade school, reported Nynke R. Bouma, BSc, and colleagues.

“Even though bronchiectasis is present in 60% to 80% of children with CF in school age, the extent and severity of bronchiectasis in preschool children are generally lower ... however, diffuse airway abnormalities such as airway wall thickening and mucus plugging are observed in many preschool children. It is hypothesized that these preschool airway changes reflect diffuse airway disease that eventually will result in bronchiectasis in school age,” they noted.

The PRAGMA-CF image scoring system can measure airway disease and can also be used to monitor disease progression, noted Ms. Bouma of Sophia Children’s Hospital, Rotterdam, and colleagues. The study was published in Pediatric Pulmonology. PRAGMA-CF is a composite score of airway wall thickening, mucus plugging, and bronchiectasis as percent disease (%disease). “In preschool children, %disease measured by PRAGMA-CF on chest CT allows quantification of early clinically relevant morphological features of CF airway disease and it is associated with later school-age bronchiectasis,” the team wrote. “These findings support the use of %disease as a clinically relevant outcome measure in early CF lung disease.”

The team conducted a prospective cohort study of 61 children (mean age 4 years) with cystic fibrosis, following them for a mean of 5 years. A total of 122 CT scans were available from this group, in addition to spirometry data and cystic fibrosis quality of life scores.

From preschool age to school age, the %disease on PRAGMA-CF increased significantly, from a mean of 0.7% to 1.73%. Scores on another composite measuring tool (%MUPAT, a composite score of airway wall thickening and mucus plugging) went from 0.46 to 0.58 – not a significant difference.

A multivariate analysis corrected for age in each school group and the type of scanner used to acquire the images. That analysis determined that each 1% increase in %disease at preschool age resulted in an increase of 1.18% of bronchiectasis at school age.

A cross-sectional analysis of the group at school age found significant associations between the %disease and percent of forced expiratory volume and the cystic fibrosis quality of life score.

At least one pulmonary exacerbation requiring intravenous antibiotics occurred in 19 of the patients. However, the investigators didn’t find any significant interactions between the %disease in preschool and these exacerbations..

“These findings are in line with previous studies in school‐aged children that showed that mucus plugging is associated with inflammation and airway wall thickening, and that these are thought to be risk factors for later bronchiectasis,” they concluded. “On the basis of our findings, we suggest that %disease and %MUPAT could be used as a clinically relevant outcome measure in clinical studies in preschool patients with cystic fibrosis, as these measures predict later bronchiectasis. Percent disease may be preferred as it captures all the principal features of CF airways disease including bronchiectasis.”

Ms. Bouma had no financial disclosures.

msullivan@mdedge.com

SOURCE: Bouma NR et al. Pediatr Pulmonol. 2019 Sep 9 doi: 10.1002/ppul.24498; Rosenow et al. Am J Respir Crit Care Med. 2015 May 15. doi: 10.1164/rccm.201501-0061OC.