Pulmonology

Two-thirds of patients hospitalized with pneumonia received an excess duration of antibiotics, according to a recent study of more than 6,000 patients.

Longer antibiotic courses did not increase the survival rate or prevent any subsequent health care utilization, authors said; instead, they increased the risk of patient-reported adverse events.

The findings bolster a growing body of evidence showing that short-course therapy for pneumonia is safe and that longer durations are not only unnecessary, but “potentially harmful,” said Valerie M. Vaughn, MD, assistant professor of medicine at the University of Michigan, Ann Arbor, and coinvestigators.

“Reducing excess treatment durations should be a top priority for antibiotic stewardship nationally,” the investigators wrote in their report, which appears in the Annals of Internal Medicine.

The primary analysis of their retrospective cohort study included 6,481 individuals with pneumonia treated at 43 hospitals participating in a statewide quality initiative designed to improve care for hospitalized medical patients at risk of adverse events. About half of the patients were women, and the median age was 70 years. Nearly 60% had severe pneumonia.

The primary outcome of the study was the rate of excess antibiotic therapy duration beyond the shortest expected treatment duration consistent with guidelines. Patients with community-acquired pneumonia (CAP), representing about three-quarters of the study cohort, were expected to have a treatment duration of at least 5 days, while patients with health care–acquired pneumonia (HCAP) were expected to have at least 7 days of treatment.

Overall, 4,391 patients (67.8%) had antibiotic courses longer than the shortest effective duration, with a median duration of 8 days, and a median excess duration of 2 days, the researchers noted.

The great majority of excess days (93.2%) were due to antibiotic prescribed at discharge, according to Dr. Vaughn and colleagues.

Excess treatment duration was not linked to any improvement in 30-day mortality, readmission rates, or subsequent emergency department visits, they found.

In a telephone call at 30 days, 38% of patients treated to excess said they had gone to the doctor for an antibiotic-associated adverse event, compared with 31% who received appropriate-length courses (P = .003).

Odds of a patient-reported adverse event were increased by 5% for every excess treatment day, the investigators wrote.

Taken together, these findings have implications for patient care, research efforts, and future guidelines, according to Dr. Vaughn and coinvestigators.

“The next iteration of CAP and HCAP guidelines should explicitly recommend (rather than imply) that providers prescribe the shortest effective duration,” they said in a discussion of their study results.

Dr. Vaughn reported no disclosures related to the study. Coauthors reported grants from Blue Cross Blue Shield of Michigan and the Agency for Healthcare Research and Quality, personal fees from Wiley Publishing, and royalties from Wolters Kluwer Publishing and Oxford University Press, among other disclosures.

SOURCE: Vaughn VM et al. Ann Intern Med. 2019;171:153-63. doi: 10.7326/M18-3640.

Two-thirds of patients hospitalized with pneumonia received an excess duration of antibiotics, according to a recent study of more than 6,000 patients.

Longer antibiotic courses did not increase the survival rate or prevent any subsequent health care utilization, authors said; instead, they increased the risk of patient-reported adverse events.

The findings bolster a growing body of evidence showing that short-course therapy for pneumonia is safe and that longer durations are not only unnecessary, but “potentially harmful,” said Valerie M. Vaughn, MD, assistant professor of medicine at the University of Michigan, Ann Arbor, and coinvestigators.

“Reducing excess treatment durations should be a top priority for antibiotic stewardship nationally,” the investigators wrote in their report, which appears in the Annals of Internal Medicine.

The primary analysis of their retrospective cohort study included 6,481 individuals with pneumonia treated at 43 hospitals participating in a statewide quality initiative designed to improve care for hospitalized medical patients at risk of adverse events. About half of the patients were women, and the median age was 70 years. Nearly 60% had severe pneumonia.

The primary outcome of the study was the rate of excess antibiotic therapy duration beyond the shortest expected treatment duration consistent with guidelines. Patients with community-acquired pneumonia (CAP), representing about three-quarters of the study cohort, were expected to have a treatment duration of at least 5 days, while patients with health care–acquired pneumonia (HCAP) were expected to have at least 7 days of treatment.

Overall, 4,391 patients (67.8%) had antibiotic courses longer than the shortest effective duration, with a median duration of 8 days, and a median excess duration of 2 days, the researchers noted.

The great majority of excess days (93.2%) were due to antibiotic prescribed at discharge, according to Dr. Vaughn and colleagues.

Excess treatment duration was not linked to any improvement in 30-day mortality, readmission rates, or subsequent emergency department visits, they found.

In a telephone call at 30 days, 38% of patients treated to excess said they had gone to the doctor for an antibiotic-associated adverse event, compared with 31% who received appropriate-length courses (P = .003).

Odds of a patient-reported adverse event were increased by 5% for every excess treatment day, the investigators wrote.

Taken together, these findings have implications for patient care, research efforts, and future guidelines, according to Dr. Vaughn and coinvestigators.

“The next iteration of CAP and HCAP guidelines should explicitly recommend (rather than imply) that providers prescribe the shortest effective duration,” they said in a discussion of their study results.

Dr. Vaughn reported no disclosures related to the study. Coauthors reported grants from Blue Cross Blue Shield of Michigan and the Agency for Healthcare Research and Quality, personal fees from Wiley Publishing, and royalties from Wolters Kluwer Publishing and Oxford University Press, among other disclosures.

SOURCE: Vaughn VM et al. Ann Intern Med. 2019;171:153-63. doi: 10.7326/M18-3640.

Two-thirds of patients hospitalized with pneumonia received an excess duration of antibiotics, according to a recent study of more than 6,000 patients.

Longer antibiotic courses did not increase the survival rate or prevent any subsequent health care utilization, authors said; instead, they increased the risk of patient-reported adverse events.

The findings bolster a growing body of evidence showing that short-course therapy for pneumonia is safe and that longer durations are not only unnecessary, but “potentially harmful,” said Valerie M. Vaughn, MD, assistant professor of medicine at the University of Michigan, Ann Arbor, and coinvestigators.

“Reducing excess treatment durations should be a top priority for antibiotic stewardship nationally,” the investigators wrote in their report, which appears in the Annals of Internal Medicine.

The primary analysis of their retrospective cohort study included 6,481 individuals with pneumonia treated at 43 hospitals participating in a statewide quality initiative designed to improve care for hospitalized medical patients at risk of adverse events. About half of the patients were women, and the median age was 70 years. Nearly 60% had severe pneumonia.

The primary outcome of the study was the rate of excess antibiotic therapy duration beyond the shortest expected treatment duration consistent with guidelines. Patients with community-acquired pneumonia (CAP), representing about three-quarters of the study cohort, were expected to have a treatment duration of at least 5 days, while patients with health care–acquired pneumonia (HCAP) were expected to have at least 7 days of treatment.

Overall, 4,391 patients (67.8%) had antibiotic courses longer than the shortest effective duration, with a median duration of 8 days, and a median excess duration of 2 days, the researchers noted.

The great majority of excess days (93.2%) were due to antibiotic prescribed at discharge, according to Dr. Vaughn and colleagues.

Excess treatment duration was not linked to any improvement in 30-day mortality, readmission rates, or subsequent emergency department visits, they found.

In a telephone call at 30 days, 38% of patients treated to excess said they had gone to the doctor for an antibiotic-associated adverse event, compared with 31% who received appropriate-length courses (P = .003).

Odds of a patient-reported adverse event were increased by 5% for every excess treatment day, the investigators wrote.

Taken together, these findings have implications for patient care, research efforts, and future guidelines, according to Dr. Vaughn and coinvestigators.

“The next iteration of CAP and HCAP guidelines should explicitly recommend (rather than imply) that providers prescribe the shortest effective duration,” they said in a discussion of their study results.

Dr. Vaughn reported no disclosures related to the study. Coauthors reported grants from Blue Cross Blue Shield of Michigan and the Agency for Healthcare Research and Quality, personal fees from Wiley Publishing, and royalties from Wolters Kluwer Publishing and Oxford University Press, among other disclosures.

SOURCE: Vaughn VM et al. Ann Intern Med. 2019;171:153-63. doi: 10.7326/M18-3640.

Most infants are vulnerable to measles, mumps, and rubella viruses between the disappearance of antibodies acquired during gestation and their first MMR vaccination, according to results of a study in Vaccine.

Yarinca/istockphoto

María José Cilleruelo, PhD, of Hospital Universitario Puerta de Hierro in Majadahonda, Spain, and colleagues showed that, although most infants acquire some protective antibodies against MMR from their mothers during gestation, most have lost this protection as early as 3 months of age. This single-center, observational, prospective study was conducted between October 2013 and December 2014, and it began with 146 mother-child pairs, with 99 remaining in follow-up at 3 months, 77 at 6 months, 63 at 9 months, and 30 at 12 months. For measles, 88% of newborns were seropositive, but only 19% were at 3 months; for mumps, 70% of newborns were seropositive, but only 11% were at 3 months; and for rubella, 91% of newborns were seropositive, but only 13% were at 3 months. No infants were seropositive for mumps or rubella at 9 months, and only 2% were for measles. No infants were seropositive for any of these viruses by 12 months of age.

The investigators noted that, given Spain (where the study was conducted) is a country that gives the first MMR vaccine at 12 months of life, these declining titers can leave most infants vulnerable to those viruses before then.

“We suggest that it may be worth considering administering the first dose of MMR vaccine before 12 months of age,” the investigators concluded, although they advised studies be undertaken into the efficacy and safety of administration of that vaccine in infants younger than 12 months. They noted that the biggest limitation of this study was the high percentage of loss to follow-up, which limited the statistical power to make comparisons.

The study was funded by the Fondo de Investigación Sanitaria, and one of the authors was funded by CIBER de Epidemiología y Salud Pública. The authors declared that there are no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Cilleruelo MJ et al. Vaccine. 2019;37:4164-71.

Most infants are vulnerable to measles, mumps, and rubella viruses between the disappearance of antibodies acquired during gestation and their first MMR vaccination, according to results of a study in Vaccine.

Yarinca/istockphoto

María José Cilleruelo, PhD, of Hospital Universitario Puerta de Hierro in Majadahonda, Spain, and colleagues showed that, although most infants acquire some protective antibodies against MMR from their mothers during gestation, most have lost this protection as early as 3 months of age. This single-center, observational, prospective study was conducted between October 2013 and December 2014, and it began with 146 mother-child pairs, with 99 remaining in follow-up at 3 months, 77 at 6 months, 63 at 9 months, and 30 at 12 months. For measles, 88% of newborns were seropositive, but only 19% were at 3 months; for mumps, 70% of newborns were seropositive, but only 11% were at 3 months; and for rubella, 91% of newborns were seropositive, but only 13% were at 3 months. No infants were seropositive for mumps or rubella at 9 months, and only 2% were for measles. No infants were seropositive for any of these viruses by 12 months of age.

The investigators noted that, given Spain (where the study was conducted) is a country that gives the first MMR vaccine at 12 months of life, these declining titers can leave most infants vulnerable to those viruses before then.

“We suggest that it may be worth considering administering the first dose of MMR vaccine before 12 months of age,” the investigators concluded, although they advised studies be undertaken into the efficacy and safety of administration of that vaccine in infants younger than 12 months. They noted that the biggest limitation of this study was the high percentage of loss to follow-up, which limited the statistical power to make comparisons.

The study was funded by the Fondo de Investigación Sanitaria, and one of the authors was funded by CIBER de Epidemiología y Salud Pública. The authors declared that there are no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Cilleruelo MJ et al. Vaccine. 2019;37:4164-71.

Most infants are vulnerable to measles, mumps, and rubella viruses between the disappearance of antibodies acquired during gestation and their first MMR vaccination, according to results of a study in Vaccine.

Yarinca/istockphoto

María José Cilleruelo, PhD, of Hospital Universitario Puerta de Hierro in Majadahonda, Spain, and colleagues showed that, although most infants acquire some protective antibodies against MMR from their mothers during gestation, most have lost this protection as early as 3 months of age. This single-center, observational, prospective study was conducted between October 2013 and December 2014, and it began with 146 mother-child pairs, with 99 remaining in follow-up at 3 months, 77 at 6 months, 63 at 9 months, and 30 at 12 months. For measles, 88% of newborns were seropositive, but only 19% were at 3 months; for mumps, 70% of newborns were seropositive, but only 11% were at 3 months; and for rubella, 91% of newborns were seropositive, but only 13% were at 3 months. No infants were seropositive for mumps or rubella at 9 months, and only 2% were for measles. No infants were seropositive for any of these viruses by 12 months of age.

The investigators noted that, given Spain (where the study was conducted) is a country that gives the first MMR vaccine at 12 months of life, these declining titers can leave most infants vulnerable to those viruses before then.

“We suggest that it may be worth considering administering the first dose of MMR vaccine before 12 months of age,” the investigators concluded, although they advised studies be undertaken into the efficacy and safety of administration of that vaccine in infants younger than 12 months. They noted that the biggest limitation of this study was the high percentage of loss to follow-up, which limited the statistical power to make comparisons.

The study was funded by the Fondo de Investigación Sanitaria, and one of the authors was funded by CIBER de Epidemiología y Salud Pública. The authors declared that there are no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Cilleruelo MJ et al. Vaccine. 2019;37:4164-71.

SAN DIEGO – The prevalence of obstructive sleep apnea (OSA) is substantially lower using the Centers for Medicare & Medicaid Services apnea-hypopnea index definition of OSA than using the one recommended by the American Academy of Sleep Medicine.

Doug Brunk/MDedge News

In addition, among individuals who did not have OSA using the CMS definition but met criteria using the AASM definition of OSA, an apnea-hypopnea index (AHI) of five events or greater per hour was associated with a greater likelihood of having hypertension.

The findings come from an analysis which set out to assess the relationship between OSA and hypertension using the AASM-recommended definition and the 2018 American Heart Association/American College of Cardiology blood pressure guidelines, and to determine if there is an association between hypertension and OSA among individuals who did not meet the CMS definition of OSA.

“Given the substantial morbidity associated with hypertension, these results suggest that universal adoption of the AASM AHI definition would be a reasonable step in ensuring appropriate diagnosis and treatment of OSA,” lead study author Stuart F. Quan, MD, said at the annual meeting of the Associated Professional Sleep Societies.

Dr. Quan, of the division of sleep and circadian disorders at Brigham and Women’s Hospital in Boston, noted that a number of studies have demonstrated that OSA is a risk factor for hypertension and a variety of other medical conditions. “Rightly or wrongly, the most important metric for determining whether OSA is present and determining its severity, is the apnea-hypopnea index,” he said. “It’s the most common metric used for determining OSA severity, and mostly importantly, Medicare and some other insurers use this metric to determine whether a person is eligible for treatment. If a person falls above the line, they can get continuous positive airway pressure, for example. If they’re below the line, that’s too bad; they don’t have OSA insofar as the insurance company is concerned.”

There is no controversy as to what constitutes apnea, he continued, but some disagreement exists on the definition of hypopnea. The AASM recommends using a 3% oxygen desaturation or an arousal, while Medicare uses a definition of hypopnea requiring only a 4% oxygen desaturation. Hypertension definitions have changed recently as well. Before 2018, the definition of hypertension was greater than 140/90 mm Hg for people younger than age 65 years and 150/80 mm Hg for people age 65 years and older. In 2018, the AHA and ACC changed the hypertension guidelines, defining normal as less than 120/80 mm Hg.

“Previous studies linking OSA and hypertension used older definitions, but to my knowledge there are no current studies examining the association between OSA and hypertension using new definitions,” Dr. Quan said.

He reported on results from an analysis of 6,307 participants in the Sleep Heart Health Study who underwent home polysomnography. Their AHI defined by a 3% oxygen desaturation or an arousal was classified into four categories of OSA severity: fewer than 5 events per hour (normal sleep), 5-14 events per hour (mild sleep apnea), 15-29 events per hour (moderate sleep apnea), and 30 or more events per hour (severe sleep apnea).

The researchers used three definitions of dichotomous BP elevation: elevated (greater than 120/80 mm Hg or use of hypertension medications [meds]), stage 1 (greater than 130/80 mm Hg or meds), or stage 2 (greater than 140/90 mm Hg or meds). They used logistic regression to assess the association between elevated BP and/or hypertension and OSA severity, controlling for demographics and body mass index. Additional analyses utilized multiple linear regression to determine the relationship between natural log AHI and systolic and diastolic BP, controlling for the same covariates.

For all definitions of elevated BP, increasing OSA severity was associated with greater likelihood of an elevated or hypertensive status in fully adjusted models. Specifically, the odds ratios among those with elevated BP was 1.30 (95% confidence interval, 1.10-1.54), 1.41 (95% CI, 1.15-1.72), and 1.69 (95% CI, 1.32-2.17) for mild, moderate, and severe sleep apnea, respectively. The ORs among those with stage 1 BP was 1.27 (95% CI, 1.09-1.49), 1.36 (95% CI, 1.13-1.63), 1.58 (95% CI, 1.27-1.97) for mild, moderate, and severe sleep apnea, while the OR among those with stage 2 BP was 1.07 (95% CI, 0.92-1.26), 1.22 (95% CI, 1.02-1.45), 1.38 (95% CI, 1.12-1.69) for mild, moderate, and severe sleep apnea. Linear regression found that AHI was associated with both systolic and diastolic BP in fully adjusted models.

“Using the AASM and CMS AHI definitions, increasing severity of AHI is associated with greater likelihood of having an elevated blood pressure or hypertension,” Dr. Quan concluded. “However, the prevalence of OSA was substantially lower using the CMS definition of OSA. In fact, 218 of these individuals had moderate to severe OSA when the AASM definition was applied.”

He characterized the study as “a practical analysis, a way to help identify patients who might benefit from treatment. This is not the issue of whether the science of 3% AHI is better than 4%.”

The Sleep Heart Health Study was supported by the National Heart, Lung, and Blood Institute. Dr. Quan reported that he helped draft the AASM AHI recommendations but had no other relevant disclosures.

dbrunk@mdedge.com

SOURCE: Quan SF et al. SLEEP 2019, Abstract 0501.

SAN DIEGO – The prevalence of obstructive sleep apnea (OSA) is substantially lower using the Centers for Medicare & Medicaid Services apnea-hypopnea index definition of OSA than using the one recommended by the American Academy of Sleep Medicine.

Doug Brunk/MDedge News

In addition, among individuals who did not have OSA using the CMS definition but met criteria using the AASM definition of OSA, an apnea-hypopnea index (AHI) of five events or greater per hour was associated with a greater likelihood of having hypertension.

The findings come from an analysis which set out to assess the relationship between OSA and hypertension using the AASM-recommended definition and the 2018 American Heart Association/American College of Cardiology blood pressure guidelines, and to determine if there is an association between hypertension and OSA among individuals who did not meet the CMS definition of OSA.

“Given the substantial morbidity associated with hypertension, these results suggest that universal adoption of the AASM AHI definition would be a reasonable step in ensuring appropriate diagnosis and treatment of OSA,” lead study author Stuart F. Quan, MD, said at the annual meeting of the Associated Professional Sleep Societies.

Dr. Quan, of the division of sleep and circadian disorders at Brigham and Women’s Hospital in Boston, noted that a number of studies have demonstrated that OSA is a risk factor for hypertension and a variety of other medical conditions. “Rightly or wrongly, the most important metric for determining whether OSA is present and determining its severity, is the apnea-hypopnea index,” he said. “It’s the most common metric used for determining OSA severity, and mostly importantly, Medicare and some other insurers use this metric to determine whether a person is eligible for treatment. If a person falls above the line, they can get continuous positive airway pressure, for example. If they’re below the line, that’s too bad; they don’t have OSA insofar as the insurance company is concerned.”

There is no controversy as to what constitutes apnea, he continued, but some disagreement exists on the definition of hypopnea. The AASM recommends using a 3% oxygen desaturation or an arousal, while Medicare uses a definition of hypopnea requiring only a 4% oxygen desaturation. Hypertension definitions have changed recently as well. Before 2018, the definition of hypertension was greater than 140/90 mm Hg for people younger than age 65 years and 150/80 mm Hg for people age 65 years and older. In 2018, the AHA and ACC changed the hypertension guidelines, defining normal as less than 120/80 mm Hg.

“Previous studies linking OSA and hypertension used older definitions, but to my knowledge there are no current studies examining the association between OSA and hypertension using new definitions,” Dr. Quan said.

He reported on results from an analysis of 6,307 participants in the Sleep Heart Health Study who underwent home polysomnography. Their AHI defined by a 3% oxygen desaturation or an arousal was classified into four categories of OSA severity: fewer than 5 events per hour (normal sleep), 5-14 events per hour (mild sleep apnea), 15-29 events per hour (moderate sleep apnea), and 30 or more events per hour (severe sleep apnea).

The researchers used three definitions of dichotomous BP elevation: elevated (greater than 120/80 mm Hg or use of hypertension medications [meds]), stage 1 (greater than 130/80 mm Hg or meds), or stage 2 (greater than 140/90 mm Hg or meds). They used logistic regression to assess the association between elevated BP and/or hypertension and OSA severity, controlling for demographics and body mass index. Additional analyses utilized multiple linear regression to determine the relationship between natural log AHI and systolic and diastolic BP, controlling for the same covariates.

For all definitions of elevated BP, increasing OSA severity was associated with greater likelihood of an elevated or hypertensive status in fully adjusted models. Specifically, the odds ratios among those with elevated BP was 1.30 (95% confidence interval, 1.10-1.54), 1.41 (95% CI, 1.15-1.72), and 1.69 (95% CI, 1.32-2.17) for mild, moderate, and severe sleep apnea, respectively. The ORs among those with stage 1 BP was 1.27 (95% CI, 1.09-1.49), 1.36 (95% CI, 1.13-1.63), 1.58 (95% CI, 1.27-1.97) for mild, moderate, and severe sleep apnea, while the OR among those with stage 2 BP was 1.07 (95% CI, 0.92-1.26), 1.22 (95% CI, 1.02-1.45), 1.38 (95% CI, 1.12-1.69) for mild, moderate, and severe sleep apnea. Linear regression found that AHI was associated with both systolic and diastolic BP in fully adjusted models.

“Using the AASM and CMS AHI definitions, increasing severity of AHI is associated with greater likelihood of having an elevated blood pressure or hypertension,” Dr. Quan concluded. “However, the prevalence of OSA was substantially lower using the CMS definition of OSA. In fact, 218 of these individuals had moderate to severe OSA when the AASM definition was applied.”

He characterized the study as “a practical analysis, a way to help identify patients who might benefit from treatment. This is not the issue of whether the science of 3% AHI is better than 4%.”

The Sleep Heart Health Study was supported by the National Heart, Lung, and Blood Institute. Dr. Quan reported that he helped draft the AASM AHI recommendations but had no other relevant disclosures.

dbrunk@mdedge.com

SOURCE: Quan SF et al. SLEEP 2019, Abstract 0501.

SAN DIEGO – The prevalence of obstructive sleep apnea (OSA) is substantially lower using the Centers for Medicare & Medicaid Services apnea-hypopnea index definition of OSA than using the one recommended by the American Academy of Sleep Medicine.

Doug Brunk/MDedge News

In addition, among individuals who did not have OSA using the CMS definition but met criteria using the AASM definition of OSA, an apnea-hypopnea index (AHI) of five events or greater per hour was associated with a greater likelihood of having hypertension.

The findings come from an analysis which set out to assess the relationship between OSA and hypertension using the AASM-recommended definition and the 2018 American Heart Association/American College of Cardiology blood pressure guidelines, and to determine if there is an association between hypertension and OSA among individuals who did not meet the CMS definition of OSA.

“Given the substantial morbidity associated with hypertension, these results suggest that universal adoption of the AASM AHI definition would be a reasonable step in ensuring appropriate diagnosis and treatment of OSA,” lead study author Stuart F. Quan, MD, said at the annual meeting of the Associated Professional Sleep Societies.

Dr. Quan, of the division of sleep and circadian disorders at Brigham and Women’s Hospital in Boston, noted that a number of studies have demonstrated that OSA is a risk factor for hypertension and a variety of other medical conditions. “Rightly or wrongly, the most important metric for determining whether OSA is present and determining its severity, is the apnea-hypopnea index,” he said. “It’s the most common metric used for determining OSA severity, and mostly importantly, Medicare and some other insurers use this metric to determine whether a person is eligible for treatment. If a person falls above the line, they can get continuous positive airway pressure, for example. If they’re below the line, that’s too bad; they don’t have OSA insofar as the insurance company is concerned.”

There is no controversy as to what constitutes apnea, he continued, but some disagreement exists on the definition of hypopnea. The AASM recommends using a 3% oxygen desaturation or an arousal, while Medicare uses a definition of hypopnea requiring only a 4% oxygen desaturation. Hypertension definitions have changed recently as well. Before 2018, the definition of hypertension was greater than 140/90 mm Hg for people younger than age 65 years and 150/80 mm Hg for people age 65 years and older. In 2018, the AHA and ACC changed the hypertension guidelines, defining normal as less than 120/80 mm Hg.

“Previous studies linking OSA and hypertension used older definitions, but to my knowledge there are no current studies examining the association between OSA and hypertension using new definitions,” Dr. Quan said.

He reported on results from an analysis of 6,307 participants in the Sleep Heart Health Study who underwent home polysomnography. Their AHI defined by a 3% oxygen desaturation or an arousal was classified into four categories of OSA severity: fewer than 5 events per hour (normal sleep), 5-14 events per hour (mild sleep apnea), 15-29 events per hour (moderate sleep apnea), and 30 or more events per hour (severe sleep apnea).

The researchers used three definitions of dichotomous BP elevation: elevated (greater than 120/80 mm Hg or use of hypertension medications [meds]), stage 1 (greater than 130/80 mm Hg or meds), or stage 2 (greater than 140/90 mm Hg or meds). They used logistic regression to assess the association between elevated BP and/or hypertension and OSA severity, controlling for demographics and body mass index. Additional analyses utilized multiple linear regression to determine the relationship between natural log AHI and systolic and diastolic BP, controlling for the same covariates.

For all definitions of elevated BP, increasing OSA severity was associated with greater likelihood of an elevated or hypertensive status in fully adjusted models. Specifically, the odds ratios among those with elevated BP was 1.30 (95% confidence interval, 1.10-1.54), 1.41 (95% CI, 1.15-1.72), and 1.69 (95% CI, 1.32-2.17) for mild, moderate, and severe sleep apnea, respectively. The ORs among those with stage 1 BP was 1.27 (95% CI, 1.09-1.49), 1.36 (95% CI, 1.13-1.63), 1.58 (95% CI, 1.27-1.97) for mild, moderate, and severe sleep apnea, while the OR among those with stage 2 BP was 1.07 (95% CI, 0.92-1.26), 1.22 (95% CI, 1.02-1.45), 1.38 (95% CI, 1.12-1.69) for mild, moderate, and severe sleep apnea. Linear regression found that AHI was associated with both systolic and diastolic BP in fully adjusted models.

“Using the AASM and CMS AHI definitions, increasing severity of AHI is associated with greater likelihood of having an elevated blood pressure or hypertension,” Dr. Quan concluded. “However, the prevalence of OSA was substantially lower using the CMS definition of OSA. In fact, 218 of these individuals had moderate to severe OSA when the AASM definition was applied.”

He characterized the study as “a practical analysis, a way to help identify patients who might benefit from treatment. This is not the issue of whether the science of 3% AHI is better than 4%.”

The Sleep Heart Health Study was supported by the National Heart, Lung, and Blood Institute. Dr. Quan reported that he helped draft the AASM AHI recommendations but had no other relevant disclosures.

dbrunk@mdedge.com

SOURCE: Quan SF et al. SLEEP 2019, Abstract 0501.

SAN ANTONIO – Patients with obstructive sleep apnea who complain of feeling tired when they wake up, being sleepy during the day, and have a high score on the Epworth Sleepiness Scale face an increased risk for cardiovascular disease, results from a population-based analysis suggest.

Doug Brunk/MDedge News

“OSA is a highly heterogeneous disease, with multiple clinical presentations and consequences,” the study’s first author, Diego R. Mazzotti, PhD, said at the annual meeting of the Associated Professional Sleep Societies. “These patients also have diverse comorbidities, and there are arbitrary severity definitions and variable therapeutic responses. It’s difficult to lump these patients together.”

Symptom subtypes of OSA were originally described in the Icelandic Sleep Apnea Cohort, and defined as excessively sleepy, minimally symptomatic, and disturbed sleep (Eur Respir J. 2014; 44[6]:1600-7). These distinct clusters were identified based on symptom experiences and the existence of major comorbidities. “This concept is more popular today, trying to identify symptom clusters, or groups of individuals, that share similar polysomnographic data, and then compare differences in prevalence or incidence of cardiovascular disease,” said Dr. Mazzotti, a research associate at the University of Pennsylvania, Philadelphia. “That’s a concept that needs to be moving forward.”

Dr. Mazzotti and colleagues set out to determine if OSA symptom subtypes are present in the Sleep Heart Health Study, a multicenter, prospective, community-based cohort of individuals aged 40 years and older designed to assess the cardiovascular (CV) consequences of OSA. They also wanted to know if there is additional evidence of the relevance of OSA symptom subtypes, particularly with respect to cardiovascular disease .

Participant-reported symptoms, such as difficulty falling and staying asleep, snoring, fatigue, drowsy driving and daytime sleepiness, and responses to the Epworth Sleepiness Scale were used to determine the patient’s subtype. Assessments including questionnaires and in-home polysomnography were conducted at baseline (between 1995 and 1998) and follow-up (between 2001 and 2003), while CV outcomes were assessed until the end of follow-up (between 2008 and 2011).

In all, 1,207 patients from the Sleep Heart Health Study met criteria for moderate to severe OSA (apnea-hypopnea index, or AHI, of 15 or greater) and were included in the final analysis. They were followed for a mean of 12 years. Based on the clustering of symptoms, the researchers identified four OSA symptom subtypes: disturbed sleep (12%), minimally symptomatic (33%), excessively sleepy (17%), and moderately sleepy (38%) – proportions that were similar to those observed in prior studies.

The disturbed sleep subtype presented with increased prevalence of “insomnialike” symptoms, such as difficulty initiating or maintaining sleep, according to Dr. Mazzotti. “On the other hand, the excessively sleepy subtype presented with a very high prevalence of several symptoms related to excessive daytime sleepiness, while the moderately sleepy showed a moderately high prevalence of such symptoms, but not as much when compared to the excessively sleepy subtype,” he explained. “Finally, the minimally symptomatic subtype was found to have the lowest prevalence of all investigated symptoms, suggesting that these patients have low symptom burden. They do not complain as much, even though they have moderate-to-severe OSA.”

Next, Dr. Mazzotti and colleagues used Kaplan-Meier survival analysis and Cox proportional hazards models to evaluate whether subtypes were associated with incident coronary heart disease (CHD), heart failure, and CV disease, including CV mortality. Similar analyses were performed comparing each symptom subtype with 2,830 individuals without OSA (AHI less than 5).

Compared with other subtypes, the excessively sleepy group had a more than threefold increased odds of prevalent heart failure, after adjustment for other CV risk factors. They also had a 1.7- to 2.3-fold increased risk for incident CV disease (P less than .001), CHD (P = .015) and heart failure (P = 0.018), after adjustment for other CV risk factors.

“Compared to individuals without OSA, the excessively sleepy subtype is the only subtype with increased risk of incident CV disease and CHD,” Dr. Mazzotti said. “It is possible that excessively sleepy OSA patients are more likely to benefit from CPAP therapy in preventing CV disease.” These results were published online earlier this year (Am J Respir Crit Care Med. 2019 Feb 15. doi: 10.1164/rccm.201808-1509OC).

Dr. Mazzotti reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Mazzotti D et al. SLEEP 2019, Abstract 0586.

SAN ANTONIO – Patients with obstructive sleep apnea who complain of feeling tired when they wake up, being sleepy during the day, and have a high score on the Epworth Sleepiness Scale face an increased risk for cardiovascular disease, results from a population-based analysis suggest.

Doug Brunk/MDedge News

“OSA is a highly heterogeneous disease, with multiple clinical presentations and consequences,” the study’s first author, Diego R. Mazzotti, PhD, said at the annual meeting of the Associated Professional Sleep Societies. “These patients also have diverse comorbidities, and there are arbitrary severity definitions and variable therapeutic responses. It’s difficult to lump these patients together.”

Symptom subtypes of OSA were originally described in the Icelandic Sleep Apnea Cohort, and defined as excessively sleepy, minimally symptomatic, and disturbed sleep (Eur Respir J. 2014; 44[6]:1600-7). These distinct clusters were identified based on symptom experiences and the existence of major comorbidities. “This concept is more popular today, trying to identify symptom clusters, or groups of individuals, that share similar polysomnographic data, and then compare differences in prevalence or incidence of cardiovascular disease,” said Dr. Mazzotti, a research associate at the University of Pennsylvania, Philadelphia. “That’s a concept that needs to be moving forward.”

Dr. Mazzotti and colleagues set out to determine if OSA symptom subtypes are present in the Sleep Heart Health Study, a multicenter, prospective, community-based cohort of individuals aged 40 years and older designed to assess the cardiovascular (CV) consequences of OSA. They also wanted to know if there is additional evidence of the relevance of OSA symptom subtypes, particularly with respect to cardiovascular disease .

Participant-reported symptoms, such as difficulty falling and staying asleep, snoring, fatigue, drowsy driving and daytime sleepiness, and responses to the Epworth Sleepiness Scale were used to determine the patient’s subtype. Assessments including questionnaires and in-home polysomnography were conducted at baseline (between 1995 and 1998) and follow-up (between 2001 and 2003), while CV outcomes were assessed until the end of follow-up (between 2008 and 2011).

In all, 1,207 patients from the Sleep Heart Health Study met criteria for moderate to severe OSA (apnea-hypopnea index, or AHI, of 15 or greater) and were included in the final analysis. They were followed for a mean of 12 years. Based on the clustering of symptoms, the researchers identified four OSA symptom subtypes: disturbed sleep (12%), minimally symptomatic (33%), excessively sleepy (17%), and moderately sleepy (38%) – proportions that were similar to those observed in prior studies.

The disturbed sleep subtype presented with increased prevalence of “insomnialike” symptoms, such as difficulty initiating or maintaining sleep, according to Dr. Mazzotti. “On the other hand, the excessively sleepy subtype presented with a very high prevalence of several symptoms related to excessive daytime sleepiness, while the moderately sleepy showed a moderately high prevalence of such symptoms, but not as much when compared to the excessively sleepy subtype,” he explained. “Finally, the minimally symptomatic subtype was found to have the lowest prevalence of all investigated symptoms, suggesting that these patients have low symptom burden. They do not complain as much, even though they have moderate-to-severe OSA.”

Next, Dr. Mazzotti and colleagues used Kaplan-Meier survival analysis and Cox proportional hazards models to evaluate whether subtypes were associated with incident coronary heart disease (CHD), heart failure, and CV disease, including CV mortality. Similar analyses were performed comparing each symptom subtype with 2,830 individuals without OSA (AHI less than 5).

Compared with other subtypes, the excessively sleepy group had a more than threefold increased odds of prevalent heart failure, after adjustment for other CV risk factors. They also had a 1.7- to 2.3-fold increased risk for incident CV disease (P less than .001), CHD (P = .015) and heart failure (P = 0.018), after adjustment for other CV risk factors.

“Compared to individuals without OSA, the excessively sleepy subtype is the only subtype with increased risk of incident CV disease and CHD,” Dr. Mazzotti said. “It is possible that excessively sleepy OSA patients are more likely to benefit from CPAP therapy in preventing CV disease.” These results were published online earlier this year (Am J Respir Crit Care Med. 2019 Feb 15. doi: 10.1164/rccm.201808-1509OC).

Dr. Mazzotti reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Mazzotti D et al. SLEEP 2019, Abstract 0586.

SAN ANTONIO – Patients with obstructive sleep apnea who complain of feeling tired when they wake up, being sleepy during the day, and have a high score on the Epworth Sleepiness Scale face an increased risk for cardiovascular disease, results from a population-based analysis suggest.

Doug Brunk/MDedge News

“OSA is a highly heterogeneous disease, with multiple clinical presentations and consequences,” the study’s first author, Diego R. Mazzotti, PhD, said at the annual meeting of the Associated Professional Sleep Societies. “These patients also have diverse comorbidities, and there are arbitrary severity definitions and variable therapeutic responses. It’s difficult to lump these patients together.”

Symptom subtypes of OSA were originally described in the Icelandic Sleep Apnea Cohort, and defined as excessively sleepy, minimally symptomatic, and disturbed sleep (Eur Respir J. 2014; 44[6]:1600-7). These distinct clusters were identified based on symptom experiences and the existence of major comorbidities. “This concept is more popular today, trying to identify symptom clusters, or groups of individuals, that share similar polysomnographic data, and then compare differences in prevalence or incidence of cardiovascular disease,” said Dr. Mazzotti, a research associate at the University of Pennsylvania, Philadelphia. “That’s a concept that needs to be moving forward.”

Dr. Mazzotti and colleagues set out to determine if OSA symptom subtypes are present in the Sleep Heart Health Study, a multicenter, prospective, community-based cohort of individuals aged 40 years and older designed to assess the cardiovascular (CV) consequences of OSA. They also wanted to know if there is additional evidence of the relevance of OSA symptom subtypes, particularly with respect to cardiovascular disease .

Participant-reported symptoms, such as difficulty falling and staying asleep, snoring, fatigue, drowsy driving and daytime sleepiness, and responses to the Epworth Sleepiness Scale were used to determine the patient’s subtype. Assessments including questionnaires and in-home polysomnography were conducted at baseline (between 1995 and 1998) and follow-up (between 2001 and 2003), while CV outcomes were assessed until the end of follow-up (between 2008 and 2011).

In all, 1,207 patients from the Sleep Heart Health Study met criteria for moderate to severe OSA (apnea-hypopnea index, or AHI, of 15 or greater) and were included in the final analysis. They were followed for a mean of 12 years. Based on the clustering of symptoms, the researchers identified four OSA symptom subtypes: disturbed sleep (12%), minimally symptomatic (33%), excessively sleepy (17%), and moderately sleepy (38%) – proportions that were similar to those observed in prior studies.

The disturbed sleep subtype presented with increased prevalence of “insomnialike” symptoms, such as difficulty initiating or maintaining sleep, according to Dr. Mazzotti. “On the other hand, the excessively sleepy subtype presented with a very high prevalence of several symptoms related to excessive daytime sleepiness, while the moderately sleepy showed a moderately high prevalence of such symptoms, but not as much when compared to the excessively sleepy subtype,” he explained. “Finally, the minimally symptomatic subtype was found to have the lowest prevalence of all investigated symptoms, suggesting that these patients have low symptom burden. They do not complain as much, even though they have moderate-to-severe OSA.”

Next, Dr. Mazzotti and colleagues used Kaplan-Meier survival analysis and Cox proportional hazards models to evaluate whether subtypes were associated with incident coronary heart disease (CHD), heart failure, and CV disease, including CV mortality. Similar analyses were performed comparing each symptom subtype with 2,830 individuals without OSA (AHI less than 5).

Compared with other subtypes, the excessively sleepy group had a more than threefold increased odds of prevalent heart failure, after adjustment for other CV risk factors. They also had a 1.7- to 2.3-fold increased risk for incident CV disease (P less than .001), CHD (P = .015) and heart failure (P = 0.018), after adjustment for other CV risk factors.

“Compared to individuals without OSA, the excessively sleepy subtype is the only subtype with increased risk of incident CV disease and CHD,” Dr. Mazzotti said. “It is possible that excessively sleepy OSA patients are more likely to benefit from CPAP therapy in preventing CV disease.” These results were published online earlier this year (Am J Respir Crit Care Med. 2019 Feb 15. doi: 10.1164/rccm.201808-1509OC).

Dr. Mazzotti reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Mazzotti D et al. SLEEP 2019, Abstract 0586.

Acute exacerbations in chronic obstructive pulmonary disease could also trigger a cardiac event such as MI or stroke, particularly in older individuals, new research has found.

In Respirology, researchers report the outcomes of a nationwide, register-based study involving 118,807 patients with chronic obstructive pulmonary disease (COPD) who experienced a major adverse cardiac event after an exacerbation.

They found that the risk of any major cardiac adverse event increased 270% in the 4 weeks after the onset of an exacerbation (95% confidence interval, 3.60-3.80). The strongest association was seen for cardiovascular death, for which there was a 333% increase in risk, but there was also a 257% increase in the risk of acute MI and 178% increase in the risk of stroke.

The risk of major adverse cardiac events was even higher among individuals who were hospitalized because of their COPD exacerbation (odds ratio, 5.92), compared with a 150% increase in risk among those who weren’t hospitalized but were treated with oral corticosteroids and 108% increase among those treated with amoxicillin with enzyme inhibitors.

The risk of a major cardiac event after a COPD exacerbation also increased with age. Among individuals younger than 55 years, there was a 131% increase in risk, but among those aged 55-69 years there was a 234% increase, among those aged 70-79 years the risk increased 282%, and among those aged 80 years and older it increased 318%.

Mette Reilev, from the department of public health at the University of Southern Denmark, Odense, and coauthors suggested that acute exacerbations were associated with elevated levels of systemic inflammatory markers such as fibrinogen and interleukin-6, which were potently prothrombotic and could potentially trigger cardiovascular events.

“Additionally, exacerbations may trigger type II myocardial infarctions secondary to an imbalance in oxygen supply and demand,” they wrote.

The authors raised the question of whether cardiovascular prevention strategies should be part of treatment recommendations for people with COPD, and suggested that prevention of COPD exacerbations could be justified even on cardiovascular grounds alone.

“Studies investigating the effect of cardiovascular treatment on the course of disease among COPD exacerbators are extremely scarce,” they wrote. “Thus, it is currently unknown how to optimize treatment and mitigate the increased risk of [major adverse cardiovascular events] following the onset of exacerbations.”

However, they noted that prednisolone treatment for more severe exacerbations may have a confounding effect, as oral corticosteroids could induce dyslipidemia, hypertension, and hyperglycemia, and increase long-term cardiovascular risk.

Six authors declared funding from the pharmaceutical industry – three of which were institutional support – unrelated to the study.

SOURCE: Reilev M et al. Respirology. 2019 Jun 21. doi: 10.1111/resp.13620.

Acute exacerbations in chronic obstructive pulmonary disease could also trigger a cardiac event such as MI or stroke, particularly in older individuals, new research has found.

In Respirology, researchers report the outcomes of a nationwide, register-based study involving 118,807 patients with chronic obstructive pulmonary disease (COPD) who experienced a major adverse cardiac event after an exacerbation.

They found that the risk of any major cardiac adverse event increased 270% in the 4 weeks after the onset of an exacerbation (95% confidence interval, 3.60-3.80). The strongest association was seen for cardiovascular death, for which there was a 333% increase in risk, but there was also a 257% increase in the risk of acute MI and 178% increase in the risk of stroke.

The risk of major adverse cardiac events was even higher among individuals who were hospitalized because of their COPD exacerbation (odds ratio, 5.92), compared with a 150% increase in risk among those who weren’t hospitalized but were treated with oral corticosteroids and 108% increase among those treated with amoxicillin with enzyme inhibitors.

The risk of a major cardiac event after a COPD exacerbation also increased with age. Among individuals younger than 55 years, there was a 131% increase in risk, but among those aged 55-69 years there was a 234% increase, among those aged 70-79 years the risk increased 282%, and among those aged 80 years and older it increased 318%.

Mette Reilev, from the department of public health at the University of Southern Denmark, Odense, and coauthors suggested that acute exacerbations were associated with elevated levels of systemic inflammatory markers such as fibrinogen and interleukin-6, which were potently prothrombotic and could potentially trigger cardiovascular events.

“Additionally, exacerbations may trigger type II myocardial infarctions secondary to an imbalance in oxygen supply and demand,” they wrote.

The authors raised the question of whether cardiovascular prevention strategies should be part of treatment recommendations for people with COPD, and suggested that prevention of COPD exacerbations could be justified even on cardiovascular grounds alone.

“Studies investigating the effect of cardiovascular treatment on the course of disease among COPD exacerbators are extremely scarce,” they wrote. “Thus, it is currently unknown how to optimize treatment and mitigate the increased risk of [major adverse cardiovascular events] following the onset of exacerbations.”

However, they noted that prednisolone treatment for more severe exacerbations may have a confounding effect, as oral corticosteroids could induce dyslipidemia, hypertension, and hyperglycemia, and increase long-term cardiovascular risk.

Six authors declared funding from the pharmaceutical industry – three of which were institutional support – unrelated to the study.

SOURCE: Reilev M et al. Respirology. 2019 Jun 21. doi: 10.1111/resp.13620.

Acute exacerbations in chronic obstructive pulmonary disease could also trigger a cardiac event such as MI or stroke, particularly in older individuals, new research has found.

In Respirology, researchers report the outcomes of a nationwide, register-based study involving 118,807 patients with chronic obstructive pulmonary disease (COPD) who experienced a major adverse cardiac event after an exacerbation.

They found that the risk of any major cardiac adverse event increased 270% in the 4 weeks after the onset of an exacerbation (95% confidence interval, 3.60-3.80). The strongest association was seen for cardiovascular death, for which there was a 333% increase in risk, but there was also a 257% increase in the risk of acute MI and 178% increase in the risk of stroke.

The risk of major adverse cardiac events was even higher among individuals who were hospitalized because of their COPD exacerbation (odds ratio, 5.92), compared with a 150% increase in risk among those who weren’t hospitalized but were treated with oral corticosteroids and 108% increase among those treated with amoxicillin with enzyme inhibitors.

The risk of a major cardiac event after a COPD exacerbation also increased with age. Among individuals younger than 55 years, there was a 131% increase in risk, but among those aged 55-69 years there was a 234% increase, among those aged 70-79 years the risk increased 282%, and among those aged 80 years and older it increased 318%.

Mette Reilev, from the department of public health at the University of Southern Denmark, Odense, and coauthors suggested that acute exacerbations were associated with elevated levels of systemic inflammatory markers such as fibrinogen and interleukin-6, which were potently prothrombotic and could potentially trigger cardiovascular events.

“Additionally, exacerbations may trigger type II myocardial infarctions secondary to an imbalance in oxygen supply and demand,” they wrote.

The authors raised the question of whether cardiovascular prevention strategies should be part of treatment recommendations for people with COPD, and suggested that prevention of COPD exacerbations could be justified even on cardiovascular grounds alone.

“Studies investigating the effect of cardiovascular treatment on the course of disease among COPD exacerbators are extremely scarce,” they wrote. “Thus, it is currently unknown how to optimize treatment and mitigate the increased risk of [major adverse cardiovascular events] following the onset of exacerbations.”

However, they noted that prednisolone treatment for more severe exacerbations may have a confounding effect, as oral corticosteroids could induce dyslipidemia, hypertension, and hyperglycemia, and increase long-term cardiovascular risk.

Six authors declared funding from the pharmaceutical industry – three of which were institutional support – unrelated to the study.

SOURCE: Reilev M et al. Respirology. 2019 Jun 21. doi: 10.1111/resp.13620.

The ratio of the forced expiratory volume in 1 second to the forced vital capacity (FEV₁:FVC) at the recommended threshold of 0.70 effectively diagnosed individuals at risk for clinically significant COPD, a longitudinal study of more than 24,000 individuals has found.

Guidelines from respiratory societies have long recommended a diagnosis of airflow obstruction when the FEV₁:FVC is less than 0.70, but no rigorous, population-based studies have been conducted to support this recommendation, wrote Surya P. Bhatt, MD, of the University of Alabama at Birmingham, and colleagues.

“The selection of a threshold for defining airflow obstruction has major implications for patient care and public health as the prevalence of airflow obstruction can vary by as much as 33% depending on which threshold is selected,” they said.

In a study published in JAMA, the researchers reviewed data from 24,207 participants in the National Heart, Lung, and Blood Institute Pooled Cohorts Study to assess the accuracy of different thresholds in predicting COPD events in a large, multiethnic, U.S. population. All participants underwent spirometry; the average age at spirometry was 63 years, and 54% of the patients were women. Patients were enrolled during 1987-2000 and received follow-up longitudinally through 2016.

Overall, 3,925 participants experienced COPD-related events during an average of 15 years of follow-up (more than 340,757 person-years). These events included 3,563 hospitalizations and 447 deaths related to COPD.

The researchers compared three thresholds for FEV₁:FVC ratios: a fixed optimal threshold of 0.71, a lower limit of normal (LLN) defined as 0.034, and the currently recommended 0.70.

The optimal 0.71 was not significantly different from the recommended 0.70 but was significantly more accurate than the LLN of 0.034. In addition, the 0.70 value was the optimal predictor in a subgroup analysis of ever-smokers and in multivariate analysis.

The findings were limited by several factors including the use of prebronchodilator spirometry, lack of adjustment for medication use, and limitation of outcomes to COPD mortality or clinical events mainly caused by COPD, which might exclude patients with mild to moderate disease, the researchers noted.

However, the study “provides population-based evidence to support 0.70 as the optimal FEV₁:FVC threshold for defining clinically significant airflow obstruction,” to help clinicians identify patients at increased risk for significant COPD, they said.

Lead author Dr. Bhatt disclosed a National Institutes of Health grant, consulting fees from Sunovion and research funds from Proterix Bio. The study was supported by grants from multiple agencies of the National Institutes of Health, including the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging.

SOURCE: Bhatt SP et al. JAMA. 2019. 321:2438-47.

The ratio of the forced expiratory volume in 1 second to the forced vital capacity (FEV₁:FVC) at the recommended threshold of 0.70 effectively diagnosed individuals at risk for clinically significant COPD, a longitudinal study of more than 24,000 individuals has found.

Guidelines from respiratory societies have long recommended a diagnosis of airflow obstruction when the FEV₁:FVC is less than 0.70, but no rigorous, population-based studies have been conducted to support this recommendation, wrote Surya P. Bhatt, MD, of the University of Alabama at Birmingham, and colleagues.

“The selection of a threshold for defining airflow obstruction has major implications for patient care and public health as the prevalence of airflow obstruction can vary by as much as 33% depending on which threshold is selected,” they said.

In a study published in JAMA, the researchers reviewed data from 24,207 participants in the National Heart, Lung, and Blood Institute Pooled Cohorts Study to assess the accuracy of different thresholds in predicting COPD events in a large, multiethnic, U.S. population. All participants underwent spirometry; the average age at spirometry was 63 years, and 54% of the patients were women. Patients were enrolled during 1987-2000 and received follow-up longitudinally through 2016.

Overall, 3,925 participants experienced COPD-related events during an average of 15 years of follow-up (more than 340,757 person-years). These events included 3,563 hospitalizations and 447 deaths related to COPD.

The researchers compared three thresholds for FEV₁:FVC ratios: a fixed optimal threshold of 0.71, a lower limit of normal (LLN) defined as 0.034, and the currently recommended 0.70.

The optimal 0.71 was not significantly different from the recommended 0.70 but was significantly more accurate than the LLN of 0.034. In addition, the 0.70 value was the optimal predictor in a subgroup analysis of ever-smokers and in multivariate analysis.

The findings were limited by several factors including the use of prebronchodilator spirometry, lack of adjustment for medication use, and limitation of outcomes to COPD mortality or clinical events mainly caused by COPD, which might exclude patients with mild to moderate disease, the researchers noted.

However, the study “provides population-based evidence to support 0.70 as the optimal FEV₁:FVC threshold for defining clinically significant airflow obstruction,” to help clinicians identify patients at increased risk for significant COPD, they said.

Lead author Dr. Bhatt disclosed a National Institutes of Health grant, consulting fees from Sunovion and research funds from Proterix Bio. The study was supported by grants from multiple agencies of the National Institutes of Health, including the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging.

SOURCE: Bhatt SP et al. JAMA. 2019. 321:2438-47.

The ratio of the forced expiratory volume in 1 second to the forced vital capacity (FEV₁:FVC) at the recommended threshold of 0.70 effectively diagnosed individuals at risk for clinically significant COPD, a longitudinal study of more than 24,000 individuals has found.

Guidelines from respiratory societies have long recommended a diagnosis of airflow obstruction when the FEV₁:FVC is less than 0.70, but no rigorous, population-based studies have been conducted to support this recommendation, wrote Surya P. Bhatt, MD, of the University of Alabama at Birmingham, and colleagues.

“The selection of a threshold for defining airflow obstruction has major implications for patient care and public health as the prevalence of airflow obstruction can vary by as much as 33% depending on which threshold is selected,” they said.

In a study published in JAMA, the researchers reviewed data from 24,207 participants in the National Heart, Lung, and Blood Institute Pooled Cohorts Study to assess the accuracy of different thresholds in predicting COPD events in a large, multiethnic, U.S. population. All participants underwent spirometry; the average age at spirometry was 63 years, and 54% of the patients were women. Patients were enrolled during 1987-2000 and received follow-up longitudinally through 2016.

Overall, 3,925 participants experienced COPD-related events during an average of 15 years of follow-up (more than 340,757 person-years). These events included 3,563 hospitalizations and 447 deaths related to COPD.

The researchers compared three thresholds for FEV₁:FVC ratios: a fixed optimal threshold of 0.71, a lower limit of normal (LLN) defined as 0.034, and the currently recommended 0.70.

The optimal 0.71 was not significantly different from the recommended 0.70 but was significantly more accurate than the LLN of 0.034. In addition, the 0.70 value was the optimal predictor in a subgroup analysis of ever-smokers and in multivariate analysis.

The findings were limited by several factors including the use of prebronchodilator spirometry, lack of adjustment for medication use, and limitation of outcomes to COPD mortality or clinical events mainly caused by COPD, which might exclude patients with mild to moderate disease, the researchers noted.

However, the study “provides population-based evidence to support 0.70 as the optimal FEV₁:FVC threshold for defining clinically significant airflow obstruction,” to help clinicians identify patients at increased risk for significant COPD, they said.

Lead author Dr. Bhatt disclosed a National Institutes of Health grant, consulting fees from Sunovion and research funds from Proterix Bio. The study was supported by grants from multiple agencies of the National Institutes of Health, including the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging.

SOURCE: Bhatt SP et al. JAMA. 2019. 321:2438-47.

When making prescribing decisions, health care professionals should assume that apps for depression and smoking cessation will share user data with third parties despite claims made in privacy policy statements, recent research shows.

“Mechanisms that potentially enable a small number of dominant online service providers to link information about the use of mental health apps, without either user consent or awareness, appear to be prevalent,” Kit Huckvale, MB ChB, MSc, PhD, of Black Dog Institute at the University of New South Wales Sydney in Randwick, New South Wales, Australia, and colleagues wrote in their study. “Mismatches between declared privacy policies and observed behavior highlight the continuing need for innovation around trust and transparency for health apps.” The study was published in JAMA Network Open.

Dr. Huckvale and colleagues examined the top 36 depression and smoking cessation apps for Android and iOS in the United States accessed in January 2018; Of the apps downloaded, 15 apps were Android-only, 14 apps were iOS-only, and 7 apps were available on both platforms. The apps were assessed over a series of two sessions while network traffic was captured during use, which allowed researchers to determine what personal information was in each data transmission and where the information was going.

There were 25 apps with a privacy policy (69%), 22 of 25 apps (88%) described how that app primarily collected data, and only 16 of 25 apps (64%) provided information on secondary uses of data. Despite 23 of 25 apps (92%) addressing “the possibility of transmission of data to any third party,” 33 of 36 apps overall (92%) transmitted data to third parties. The two most common entities that received third-party data for marketing, advertising, or analytic purposes were Google and Facebook (29 of 36 apps; 81%). However, 12 of 28 apps (43%) that sent data to Google and 6 of 12 apps (50%) that sent data to Facebook disclosed that they would share data with those companies.

The type of data sent to Google and Facebook consisted of a strong identifier to the device or a username (9 of 33 apps; 27%), or a weak identifier in the form of an advertising identifier or a pseudonymous profile that can link users to their behavior on the app and on other products and platforms (26 of 33 apps; 79%).

“As smartphones continue to gain capabilities to collect new forms of personal, biometric, and health information, it is imperative for the health care community to respond with new methods and processes to review apps and ensure they remain safe and protect personal health information,” the researchers concluded.

One of the investigators, Mark E. Larsen, DPhil, reported receiving grants from National Health and Medical Research Council. The other authors reported no relevant conflicts of interest.

SOURCE: Huckvale K et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.2542.

When making prescribing decisions, health care professionals should assume that apps for depression and smoking cessation will share user data with third parties despite claims made in privacy policy statements, recent research shows.

“Mechanisms that potentially enable a small number of dominant online service providers to link information about the use of mental health apps, without either user consent or awareness, appear to be prevalent,” Kit Huckvale, MB ChB, MSc, PhD, of Black Dog Institute at the University of New South Wales Sydney in Randwick, New South Wales, Australia, and colleagues wrote in their study. “Mismatches between declared privacy policies and observed behavior highlight the continuing need for innovation around trust and transparency for health apps.” The study was published in JAMA Network Open.

Dr. Huckvale and colleagues examined the top 36 depression and smoking cessation apps for Android and iOS in the United States accessed in January 2018; Of the apps downloaded, 15 apps were Android-only, 14 apps were iOS-only, and 7 apps were available on both platforms. The apps were assessed over a series of two sessions while network traffic was captured during use, which allowed researchers to determine what personal information was in each data transmission and where the information was going.

There were 25 apps with a privacy policy (69%), 22 of 25 apps (88%) described how that app primarily collected data, and only 16 of 25 apps (64%) provided information on secondary uses of data. Despite 23 of 25 apps (92%) addressing “the possibility of transmission of data to any third party,” 33 of 36 apps overall (92%) transmitted data to third parties. The two most common entities that received third-party data for marketing, advertising, or analytic purposes were Google and Facebook (29 of 36 apps; 81%). However, 12 of 28 apps (43%) that sent data to Google and 6 of 12 apps (50%) that sent data to Facebook disclosed that they would share data with those companies.

The type of data sent to Google and Facebook consisted of a strong identifier to the device or a username (9 of 33 apps; 27%), or a weak identifier in the form of an advertising identifier or a pseudonymous profile that can link users to their behavior on the app and on other products and platforms (26 of 33 apps; 79%).

“As smartphones continue to gain capabilities to collect new forms of personal, biometric, and health information, it is imperative for the health care community to respond with new methods and processes to review apps and ensure they remain safe and protect personal health information,” the researchers concluded.

One of the investigators, Mark E. Larsen, DPhil, reported receiving grants from National Health and Medical Research Council. The other authors reported no relevant conflicts of interest.

SOURCE: Huckvale K et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.2542.

When making prescribing decisions, health care professionals should assume that apps for depression and smoking cessation will share user data with third parties despite claims made in privacy policy statements, recent research shows.

“Mechanisms that potentially enable a small number of dominant online service providers to link information about the use of mental health apps, without either user consent or awareness, appear to be prevalent,” Kit Huckvale, MB ChB, MSc, PhD, of Black Dog Institute at the University of New South Wales Sydney in Randwick, New South Wales, Australia, and colleagues wrote in their study. “Mismatches between declared privacy policies and observed behavior highlight the continuing need for innovation around trust and transparency for health apps.” The study was published in JAMA Network Open.

Dr. Huckvale and colleagues examined the top 36 depression and smoking cessation apps for Android and iOS in the United States accessed in January 2018; Of the apps downloaded, 15 apps were Android-only, 14 apps were iOS-only, and 7 apps were available on both platforms. The apps were assessed over a series of two sessions while network traffic was captured during use, which allowed researchers to determine what personal information was in each data transmission and where the information was going.

There were 25 apps with a privacy policy (69%), 22 of 25 apps (88%) described how that app primarily collected data, and only 16 of 25 apps (64%) provided information on secondary uses of data. Despite 23 of 25 apps (92%) addressing “the possibility of transmission of data to any third party,” 33 of 36 apps overall (92%) transmitted data to third parties. The two most common entities that received third-party data for marketing, advertising, or analytic purposes were Google and Facebook (29 of 36 apps; 81%). However, 12 of 28 apps (43%) that sent data to Google and 6 of 12 apps (50%) that sent data to Facebook disclosed that they would share data with those companies.

The type of data sent to Google and Facebook consisted of a strong identifier to the device or a username (9 of 33 apps; 27%), or a weak identifier in the form of an advertising identifier or a pseudonymous profile that can link users to their behavior on the app and on other products and platforms (26 of 33 apps; 79%).

“As smartphones continue to gain capabilities to collect new forms of personal, biometric, and health information, it is imperative for the health care community to respond with new methods and processes to review apps and ensure they remain safe and protect personal health information,” the researchers concluded.

One of the investigators, Mark E. Larsen, DPhil, reported receiving grants from National Health and Medical Research Council. The other authors reported no relevant conflicts of interest.

SOURCE: Huckvale K et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.2542.

See Mangione and Aronowitz editorials

Mechanical pressure induced by friction of the elbows on the thighs may result in proliferation of the stratum corneum and the release of hemosiderin from erythrocytes, resulting in the skin changes seen in this patient, which because of the tripod positioning are known as “thinker’s sign,” a term coined in 1963 by Rothenberg¹ to describe findings in patients with chronic pulmonary disease and advanced respiratory insufficiency. It is also referred to as the Dahl sign, based on a report by Dahl of similar findings in patients with emphysema.²

See Mangione and Aronowitz editorials

Mechanical pressure induced by friction of the elbows on the thighs may result in proliferation of the stratum corneum and the release of hemosiderin from erythrocytes, resulting in the skin changes seen in this patient, which because of the tripod positioning are known as “thinker’s sign,” a term coined in 1963 by Rothenberg¹ to describe findings in patients with chronic pulmonary disease and advanced respiratory insufficiency. It is also referred to as the Dahl sign, based on a report by Dahl of similar findings in patients with emphysema.²

See Mangione and Aronowitz editorials

Mechanical pressure induced by friction of the elbows on the thighs may result in proliferation of the stratum corneum and the release of hemosiderin from erythrocytes, resulting in the skin changes seen in this patient, which because of the tripod positioning are known as “thinker’s sign,” a term coined in 1963 by Rothenberg¹ to describe findings in patients with chronic pulmonary disease and advanced respiratory insufficiency. It is also referred to as the Dahl sign, based on a report by Dahl of similar findings in patients with emphysema.²

Pneumocystis jirovecii (previously carinii) pneumonia (PCP) is rare in patients taking biologic response modifiers for rheumatic disease.^1–10 However, prophylaxis should be considered in patients who have granulomatosis with polyangiitis or underlying pulmonary disease, or who are concomitantly receiving glucocorticoids in high doses. There is some risk of adverse reactions to the prophylactic medicine.^1,11–21 Until clear guidelines are available, the decision to initiate PCP prophylaxis and the choice of agent should be individualized.

THE BURDEN OF PCP

In a meta-analysis²³ of 867 patients who developed PCP and did not have HIV infection, 20.1% had autoimmune or chronic inflammatory disease and the rest were transplant recipients or had malignancies. The mortality rate was 30.6%.

PHARMACOLOGIC RISK FACTORS FOR PCP

Treatment with glucocorticoids

Treatment with glucocorticoids is an important risk factor for PCP, independent of biologic therapy.

Calero-Bernal et al¹¹ reported on 128 patients with non-HIV PCP, of whom 114 (89%) had received a glucocorticoid for more than 4 weeks, and 98 (76%) were currently receiving one. The mean daily dose was equivalent to 27.73 mg of prednisone per day in those on glucocorticoids only, and 21.34 mg in those receiving glucocorticoids in combination with other immunosuppressants.

Park et al,¹² in a retrospective study of Korean patients treated for rheumatic disease with high-dose glucocorticoids (≥ 30 mg/day of prednisone or equivalent for more than 4 weeks), reported an incidence rate of PCP of 2.37 per 100 patient-years in those not on prophylaxis.

Other studies^13,14 have also found a prednisone dose greater than 15 to 20 mg per day for more than 4 weeks or concomitant use of 2 or more disease-modifying antirheumatic drugs to be a significant risk factor.^13,14

Tumor necrosis factor alpha antagonists

A US Food and Drug Administration review¹ of voluntary reports of adverse drug events estimated the incidence of PCP to be 2.3 per 100,000 patient-years with infliximab and 1.6 per 100,000 patient-years with etanercept. In most cases, other immunosuppressants were used concomitantly.¹

Postmarketing surveillance² of 5,000 patients with rheumatoid arthritis showed an incidence of suspected PCP of 0.4% within the first 6 months of starting infliximab therapy.

Komano et al,¹⁵ in a case-control study of patients with rheumatoid arthritis treated with infliximab, reported that all 21 patients with PCP were also on methotrexate (median dosage 8 mg per week) and prednisolone (median dosage 7.5 mg per day).

PCP has also been reported after adalimumab use in combination with prednisone, azathioprine, and methotrexate, as well as with certolizumab, golimumab, tocilizumab, abatacept, and rituximab.^{3–6,24–26}

Rituximab

Calero-Bernal et al¹¹ reported that 23% of patients with non-HIV PCP who were receiving immunosuppressant drugs were on rituximab.

Alexandre et al¹⁶ performed a retrospective review of 11 cases of PCP complicating rituximab therapy for autoimmune disease, in which 10 (91%) of the patients were also on corticosteroids, with a median dosage of 30 mg of prednisone daily. A literature review of an additional 18 cases revealed similar findings.

 

 

PATIENT RISK FACTORS FOR PCP

Pulmonary disease, age, other factors

Komano et al,¹⁵ in their study of patients with rheumatoid arthritis treated with infliximab, found that 10 (48%) of 21 patients with PCP had preexisting pulmonary disease, compared with 11 (10.8%) of 102 patients without PCP (P < .001). Patients with PCP were older (mean age 64 vs 54, P < .001), were on higher median doses of prednisolone per day (7.5 vs 5 mg, P = .001), and had lower median serum immunoglobulin G (IgG) levels (944 vs 1,394 mg/dL, P < .001).¹⁵ 

Tadros et al¹³ performed a case-control study that also showed that patients with autoimmune disease who developed PCP had lower lymphocyte counts than controls on admission. Other risk factors included low CD4 counts and age older than 50.

Li et al¹⁷ found that patients with autoimmune or inflammatory disease with PCP were more likely to have low CD3, CD4, and CD8 cell counts, as well as albumin levels less than 28 g/L. They therefore suggested that lymphocyte subtyping may be a useful tool to guide PCP prophylaxis.

Granulomatosis with polyangiitis

Patients with granulomatosis with polyangiitis have a significantly higher incidence of PCP than patients with other connective tissue diseases.

Ward and Donald¹⁸ reviewed 223 cases of PCP in patients with connective tissue disease. The highest frequency (89 cases per 10,000 hospitalizations per year) was in patients with granulomatosis with polyangiitis, followed by 65 per 10,000 hospitalizations per year for patients with polyarteritis nodosa. The lowest frequency was in rheumatoid arthritis patients, at 2 per 10,000 hospitalizations per year. In decreasing order, diseases with significant associations with PCP were:

• Polyarteritis nodosa (odds ratio [OR] 10.20, 95% confidence interval [CI] 5.69–18.29)
• Granulomatosis with polyangiitis (OR 7.81, 95% CI 4.71–13.05)
• Inflammatory myopathy (OR 4.44, 95% CI 2.67–7.38)
• Systemic lupus erythematosus (OR 2.52, 95% CI 1.66–3.82).

Vallabhaneni and Chiller,²⁶ in a meta-analysis including rheumatoid arthritis patients on biologics, did not find an increased risk of PCP (OR 1.77, 95% CI 0.42–7.47).

Park et al¹² found that the highest incidences of PCP were in patients with granulomatosis with polyangiitis, microscopic polyangiitis, and systemic sclerosis. For systemic sclerosis, the main reason for giving high-dose glucocorticoids was interstitial lung disease.

Other studies^19,20,28 also found an association with coexisting pulmonary disease in patients with rheumatoid arthritis.

CURRENT GUIDELINES

There are guidelines for primary and secondary prophylaxis of PCP in HIV-positive patients with CD4 counts less than 200/mm³ or a history of acquired immunodeficiency syndrome (AIDS)-defining illness.²⁷ Additionally, patients with a CD4 cell percentage less than 14% should be considered for prophylaxis.²⁷

Unfortunately, there are no guidelines for prophylaxis in patients taking immunosuppressants for rheumatic disease.

The recommended regimen for PCP prophylaxis in HIV-infected patients is trimethoprim-sulfamethoxazole, 1 double-strength or 1 single-strength tablet daily. Alternative regimens include 1 double-strength tablet 3 times per week, dapsone, aerosolized pentamidine, and atovaquone.²⁷

There are also guidelines for prophylaxis in kidney transplant recipients, as well as for patients with hematologic malignancies and solid-organ malignancies, particularly those on chemotherapeutic agents and the T-cell-depleting agent alemtuzumab.^29–31

Italian clinical practice guidelines for the use of tumor necrosis factor antagonists in inflammatory bowel disease recommend consideration of PCP prophylaxis in patients who are also on other immunosuppressants, particularly high-dose glucocorticoids.³²

Prophylaxis has been shown to increase life expectancy and quality-adjusted life-years and to reduce cost for patients on immunosuppressive therapy for granulomatosis with polyangiitis.²¹ The European Society of Clinical Microbiology and Infectious Diseases recently produced consensus statements recommending PCP prophylaxis for patients on rituximab with other concomitant immunosuppressants such as the equivalent of prednisone 20 mg daily for more than 4 weeks.³³ Prophylaxis was not recommended for other biologic therapies.^34,35

THE RISKS OF PROPHYLAXIS

The risk of PCP should be weighed against the risk of prophylaxis in patients with rheumatic disease. Adverse reactions to sulfonamide antibiotics including disease flares have been reported in patients with systemic lupus erythematosus.^36,37 Other studies have found no increased risk of flares in patients taking trimethoprim-sulfamethoxazole for PCP prophylaxis.^12,38 A retrospective analysis of patients with vasculitis found no increased risk of combining methotrexate and trimethoprim-sulfamethoxazole.³⁹

KEY POINTS

• PCP is an opportunistic infection with a high risk of death.
• PCP has been reported with biologics used as immunomodulators in rheumatic disease.
• PCP prophylaxis should be considered in patients at high risk of PCP, such as those who have granulomatosis with polyangiitis, underlying pulmonary disease or who are concomitantly taking glucocorticoids.

Pneumocystis jirovecii (previously carinii) pneumonia (PCP) is rare in patients taking biologic response modifiers for rheumatic disease.^1–10 However, prophylaxis should be considered in patients who have granulomatosis with polyangiitis or underlying pulmonary disease, or who are concomitantly receiving glucocorticoids in high doses. There is some risk of adverse reactions to the prophylactic medicine.^1,11–21 Until clear guidelines are available, the decision to initiate PCP prophylaxis and the choice of agent should be individualized.

THE BURDEN OF PCP

In a meta-analysis²³ of 867 patients who developed PCP and did not have HIV infection, 20.1% had autoimmune or chronic inflammatory disease and the rest were transplant recipients or had malignancies. The mortality rate was 30.6%.

PHARMACOLOGIC RISK FACTORS FOR PCP

Treatment with glucocorticoids

Treatment with glucocorticoids is an important risk factor for PCP, independent of biologic therapy.

Calero-Bernal et al¹¹ reported on 128 patients with non-HIV PCP, of whom 114 (89%) had received a glucocorticoid for more than 4 weeks, and 98 (76%) were currently receiving one. The mean daily dose was equivalent to 27.73 mg of prednisone per day in those on glucocorticoids only, and 21.34 mg in those receiving glucocorticoids in combination with other immunosuppressants.

Park et al,¹² in a retrospective study of Korean patients treated for rheumatic disease with high-dose glucocorticoids (≥ 30 mg/day of prednisone or equivalent for more than 4 weeks), reported an incidence rate of PCP of 2.37 per 100 patient-years in those not on prophylaxis.

Other studies^13,14 have also found a prednisone dose greater than 15 to 20 mg per day for more than 4 weeks or concomitant use of 2 or more disease-modifying antirheumatic drugs to be a significant risk factor.^13,14

Tumor necrosis factor alpha antagonists

A US Food and Drug Administration review¹ of voluntary reports of adverse drug events estimated the incidence of PCP to be 2.3 per 100,000 patient-years with infliximab and 1.6 per 100,000 patient-years with etanercept. In most cases, other immunosuppressants were used concomitantly.¹

Postmarketing surveillance² of 5,000 patients with rheumatoid arthritis showed an incidence of suspected PCP of 0.4% within the first 6 months of starting infliximab therapy.

Komano et al,¹⁵ in a case-control study of patients with rheumatoid arthritis treated with infliximab, reported that all 21 patients with PCP were also on methotrexate (median dosage 8 mg per week) and prednisolone (median dosage 7.5 mg per day).

PCP has also been reported after adalimumab use in combination with prednisone, azathioprine, and methotrexate, as well as with certolizumab, golimumab, tocilizumab, abatacept, and rituximab.^{3–6,24–26}

Rituximab

Calero-Bernal et al¹¹ reported that 23% of patients with non-HIV PCP who were receiving immunosuppressant drugs were on rituximab.

Alexandre et al¹⁶ performed a retrospective review of 11 cases of PCP complicating rituximab therapy for autoimmune disease, in which 10 (91%) of the patients were also on corticosteroids, with a median dosage of 30 mg of prednisone daily. A literature review of an additional 18 cases revealed similar findings.

 

 

PATIENT RISK FACTORS FOR PCP

Pulmonary disease, age, other factors

Komano et al,¹⁵ in their study of patients with rheumatoid arthritis treated with infliximab, found that 10 (48%) of 21 patients with PCP had preexisting pulmonary disease, compared with 11 (10.8%) of 102 patients without PCP (P < .001). Patients with PCP were older (mean age 64 vs 54, P < .001), were on higher median doses of prednisolone per day (7.5 vs 5 mg, P = .001), and had lower median serum immunoglobulin G (IgG) levels (944 vs 1,394 mg/dL, P < .001).¹⁵ 

Tadros et al¹³ performed a case-control study that also showed that patients with autoimmune disease who developed PCP had lower lymphocyte counts than controls on admission. Other risk factors included low CD4 counts and age older than 50.

Li et al¹⁷ found that patients with autoimmune or inflammatory disease with PCP were more likely to have low CD3, CD4, and CD8 cell counts, as well as albumin levels less than 28 g/L. They therefore suggested that lymphocyte subtyping may be a useful tool to guide PCP prophylaxis.

Granulomatosis with polyangiitis

Patients with granulomatosis with polyangiitis have a significantly higher incidence of PCP than patients with other connective tissue diseases.

Ward and Donald¹⁸ reviewed 223 cases of PCP in patients with connective tissue disease. The highest frequency (89 cases per 10,000 hospitalizations per year) was in patients with granulomatosis with polyangiitis, followed by 65 per 10,000 hospitalizations per year for patients with polyarteritis nodosa. The lowest frequency was in rheumatoid arthritis patients, at 2 per 10,000 hospitalizations per year. In decreasing order, diseases with significant associations with PCP were:

• Polyarteritis nodosa (odds ratio [OR] 10.20, 95% confidence interval [CI] 5.69–18.29)
• Granulomatosis with polyangiitis (OR 7.81, 95% CI 4.71–13.05)
• Inflammatory myopathy (OR 4.44, 95% CI 2.67–7.38)
• Systemic lupus erythematosus (OR 2.52, 95% CI 1.66–3.82).

Vallabhaneni and Chiller,²⁶ in a meta-analysis including rheumatoid arthritis patients on biologics, did not find an increased risk of PCP (OR 1.77, 95% CI 0.42–7.47).

Park et al¹² found that the highest incidences of PCP were in patients with granulomatosis with polyangiitis, microscopic polyangiitis, and systemic sclerosis. For systemic sclerosis, the main reason for giving high-dose glucocorticoids was interstitial lung disease.

Other studies^19,20,28 also found an association with coexisting pulmonary disease in patients with rheumatoid arthritis.

CURRENT GUIDELINES

There are guidelines for primary and secondary prophylaxis of PCP in HIV-positive patients with CD4 counts less than 200/mm³ or a history of acquired immunodeficiency syndrome (AIDS)-defining illness.²⁷ Additionally, patients with a CD4 cell percentage less than 14% should be considered for prophylaxis.²⁷

Unfortunately, there are no guidelines for prophylaxis in patients taking immunosuppressants for rheumatic disease.

The recommended regimen for PCP prophylaxis in HIV-infected patients is trimethoprim-sulfamethoxazole, 1 double-strength or 1 single-strength tablet daily. Alternative regimens include 1 double-strength tablet 3 times per week, dapsone, aerosolized pentamidine, and atovaquone.²⁷

There are also guidelines for prophylaxis in kidney transplant recipients, as well as for patients with hematologic malignancies and solid-organ malignancies, particularly those on chemotherapeutic agents and the T-cell-depleting agent alemtuzumab.^29–31

Italian clinical practice guidelines for the use of tumor necrosis factor antagonists in inflammatory bowel disease recommend consideration of PCP prophylaxis in patients who are also on other immunosuppressants, particularly high-dose glucocorticoids.³²

Prophylaxis has been shown to increase life expectancy and quality-adjusted life-years and to reduce cost for patients on immunosuppressive therapy for granulomatosis with polyangiitis.²¹ The European Society of Clinical Microbiology and Infectious Diseases recently produced consensus statements recommending PCP prophylaxis for patients on rituximab with other concomitant immunosuppressants such as the equivalent of prednisone 20 mg daily for more than 4 weeks.³³ Prophylaxis was not recommended for other biologic therapies.^34,35

THE RISKS OF PROPHYLAXIS

The risk of PCP should be weighed against the risk of prophylaxis in patients with rheumatic disease. Adverse reactions to sulfonamide antibiotics including disease flares have been reported in patients with systemic lupus erythematosus.^36,37 Other studies have found no increased risk of flares in patients taking trimethoprim-sulfamethoxazole for PCP prophylaxis.^12,38 A retrospective analysis of patients with vasculitis found no increased risk of combining methotrexate and trimethoprim-sulfamethoxazole.³⁹

KEY POINTS

• PCP is an opportunistic infection with a high risk of death.
• PCP has been reported with biologics used as immunomodulators in rheumatic disease.
• PCP prophylaxis should be considered in patients at high risk of PCP, such as those who have granulomatosis with polyangiitis, underlying pulmonary disease or who are concomitantly taking glucocorticoids.

Pneumocystis jirovecii (previously carinii) pneumonia (PCP) is rare in patients taking biologic response modifiers for rheumatic disease.^1–10 However, prophylaxis should be considered in patients who have granulomatosis with polyangiitis or underlying pulmonary disease, or who are concomitantly receiving glucocorticoids in high doses. There is some risk of adverse reactions to the prophylactic medicine.^1,11–21 Until clear guidelines are available, the decision to initiate PCP prophylaxis and the choice of agent should be individualized.

THE BURDEN OF PCP

In a meta-analysis²³ of 867 patients who developed PCP and did not have HIV infection, 20.1% had autoimmune or chronic inflammatory disease and the rest were transplant recipients or had malignancies. The mortality rate was 30.6%.

PHARMACOLOGIC RISK FACTORS FOR PCP

Treatment with glucocorticoids

Treatment with glucocorticoids is an important risk factor for PCP, independent of biologic therapy.

Calero-Bernal et al¹¹ reported on 128 patients with non-HIV PCP, of whom 114 (89%) had received a glucocorticoid for more than 4 weeks, and 98 (76%) were currently receiving one. The mean daily dose was equivalent to 27.73 mg of prednisone per day in those on glucocorticoids only, and 21.34 mg in those receiving glucocorticoids in combination with other immunosuppressants.

Park et al,¹² in a retrospective study of Korean patients treated for rheumatic disease with high-dose glucocorticoids (≥ 30 mg/day of prednisone or equivalent for more than 4 weeks), reported an incidence rate of PCP of 2.37 per 100 patient-years in those not on prophylaxis.

Other studies^13,14 have also found a prednisone dose greater than 15 to 20 mg per day for more than 4 weeks or concomitant use of 2 or more disease-modifying antirheumatic drugs to be a significant risk factor.^13,14

Tumor necrosis factor alpha antagonists

A US Food and Drug Administration review¹ of voluntary reports of adverse drug events estimated the incidence of PCP to be 2.3 per 100,000 patient-years with infliximab and 1.6 per 100,000 patient-years with etanercept. In most cases, other immunosuppressants were used concomitantly.¹

Postmarketing surveillance² of 5,000 patients with rheumatoid arthritis showed an incidence of suspected PCP of 0.4% within the first 6 months of starting infliximab therapy.

Komano et al,¹⁵ in a case-control study of patients with rheumatoid arthritis treated with infliximab, reported that all 21 patients with PCP were also on methotrexate (median dosage 8 mg per week) and prednisolone (median dosage 7.5 mg per day).

PCP has also been reported after adalimumab use in combination with prednisone, azathioprine, and methotrexate, as well as with certolizumab, golimumab, tocilizumab, abatacept, and rituximab.^{3–6,24–26}

Rituximab

Calero-Bernal et al¹¹ reported that 23% of patients with non-HIV PCP who were receiving immunosuppressant drugs were on rituximab.

Alexandre et al¹⁶ performed a retrospective review of 11 cases of PCP complicating rituximab therapy for autoimmune disease, in which 10 (91%) of the patients were also on corticosteroids, with a median dosage of 30 mg of prednisone daily. A literature review of an additional 18 cases revealed similar findings.

 

 

PATIENT RISK FACTORS FOR PCP

Pulmonary disease, age, other factors

Komano et al,¹⁵ in their study of patients with rheumatoid arthritis treated with infliximab, found that 10 (48%) of 21 patients with PCP had preexisting pulmonary disease, compared with 11 (10.8%) of 102 patients without PCP (P < .001). Patients with PCP were older (mean age 64 vs 54, P < .001), were on higher median doses of prednisolone per day (7.5 vs 5 mg, P = .001), and had lower median serum immunoglobulin G (IgG) levels (944 vs 1,394 mg/dL, P < .001).¹⁵ 

Tadros et al¹³ performed a case-control study that also showed that patients with autoimmune disease who developed PCP had lower lymphocyte counts than controls on admission. Other risk factors included low CD4 counts and age older than 50.

Li et al¹⁷ found that patients with autoimmune or inflammatory disease with PCP were more likely to have low CD3, CD4, and CD8 cell counts, as well as albumin levels less than 28 g/L. They therefore suggested that lymphocyte subtyping may be a useful tool to guide PCP prophylaxis.

Granulomatosis with polyangiitis

Patients with granulomatosis with polyangiitis have a significantly higher incidence of PCP than patients with other connective tissue diseases.

Ward and Donald¹⁸ reviewed 223 cases of PCP in patients with connective tissue disease. The highest frequency (89 cases per 10,000 hospitalizations per year) was in patients with granulomatosis with polyangiitis, followed by 65 per 10,000 hospitalizations per year for patients with polyarteritis nodosa. The lowest frequency was in rheumatoid arthritis patients, at 2 per 10,000 hospitalizations per year. In decreasing order, diseases with significant associations with PCP were:

• Polyarteritis nodosa (odds ratio [OR] 10.20, 95% confidence interval [CI] 5.69–18.29)
• Granulomatosis with polyangiitis (OR 7.81, 95% CI 4.71–13.05)
• Inflammatory myopathy (OR 4.44, 95% CI 2.67–7.38)
• Systemic lupus erythematosus (OR 2.52, 95% CI 1.66–3.82).

Vallabhaneni and Chiller,²⁶ in a meta-analysis including rheumatoid arthritis patients on biologics, did not find an increased risk of PCP (OR 1.77, 95% CI 0.42–7.47).

Park et al¹² found that the highest incidences of PCP were in patients with granulomatosis with polyangiitis, microscopic polyangiitis, and systemic sclerosis. For systemic sclerosis, the main reason for giving high-dose glucocorticoids was interstitial lung disease.

Other studies^19,20,28 also found an association with coexisting pulmonary disease in patients with rheumatoid arthritis.

CURRENT GUIDELINES

There are guidelines for primary and secondary prophylaxis of PCP in HIV-positive patients with CD4 counts less than 200/mm³ or a history of acquired immunodeficiency syndrome (AIDS)-defining illness.²⁷ Additionally, patients with a CD4 cell percentage less than 14% should be considered for prophylaxis.²⁷

Unfortunately, there are no guidelines for prophylaxis in patients taking immunosuppressants for rheumatic disease.

The recommended regimen for PCP prophylaxis in HIV-infected patients is trimethoprim-sulfamethoxazole, 1 double-strength or 1 single-strength tablet daily. Alternative regimens include 1 double-strength tablet 3 times per week, dapsone, aerosolized pentamidine, and atovaquone.²⁷

There are also guidelines for prophylaxis in kidney transplant recipients, as well as for patients with hematologic malignancies and solid-organ malignancies, particularly those on chemotherapeutic agents and the T-cell-depleting agent alemtuzumab.^29–31

Italian clinical practice guidelines for the use of tumor necrosis factor antagonists in inflammatory bowel disease recommend consideration of PCP prophylaxis in patients who are also on other immunosuppressants, particularly high-dose glucocorticoids.³²

Prophylaxis has been shown to increase life expectancy and quality-adjusted life-years and to reduce cost for patients on immunosuppressive therapy for granulomatosis with polyangiitis.²¹ The European Society of Clinical Microbiology and Infectious Diseases recently produced consensus statements recommending PCP prophylaxis for patients on rituximab with other concomitant immunosuppressants such as the equivalent of prednisone 20 mg daily for more than 4 weeks.³³ Prophylaxis was not recommended for other biologic therapies.^34,35

THE RISKS OF PROPHYLAXIS

The risk of PCP should be weighed against the risk of prophylaxis in patients with rheumatic disease. Adverse reactions to sulfonamide antibiotics including disease flares have been reported in patients with systemic lupus erythematosus.^36,37 Other studies have found no increased risk of flares in patients taking trimethoprim-sulfamethoxazole for PCP prophylaxis.^12,38 A retrospective analysis of patients with vasculitis found no increased risk of combining methotrexate and trimethoprim-sulfamethoxazole.³⁹

KEY POINTS

• PCP is an opportunistic infection with a high risk of death.
• PCP has been reported with biologics used as immunomodulators in rheumatic disease.
• PCP prophylaxis should be considered in patients at high risk of PCP, such as those who have granulomatosis with polyangiitis, underlying pulmonary disease or who are concomitantly taking glucocorticoids.

"I have trained myself to see what others overlook."
—Sherlock Holmes¹

The article by Grandjean and Huber in this issue² is a timely reminder of the importance of skilled observation in medical care. Osler³ considered observation to represent “the whole art of medicine,” but warned that “for some men it is quite as difficult to record an observation in brief and plain language.” This insight captures not only the never-ending feud between written and visual communication, but also the higher efficiency of images. Leonardo da Vinci, a visual thinker with a touch of dyslexia,⁴ often boasted in colorful terms about the superiority of the visual. Next to his amazing rendition of a bovine heart he scribbled, “[Writer] how could you describe this heart in words without filling a whole book? So, don’t bother with words unless you are speaking to the blind…you will always be overruled by the painter.”⁵

See related article and editorial

Ironically, physicians have often preferred the written over the visual. Oliver Wendell Holmes Sr., professor of anatomy at Harvard Medical School and renowned essayist, once wrote a scathing review of a new anatomy textbook that, according to him, had just too many pictures. “Let a student have illustrations,” he thundered “and just so surely will he use them at the expense of the text.”⁶ The book was Gray’s Anatomy, but Holmes’ tirade exemplifies the conundrum of our profession: to become physicians we must read (and memorize) lots of written text, with little emphasis on how much more efficiently information might be conveyed through a single picture.

This trend is probably worsening. When I first came to the United States 43 years ago, I was amazed at how many of my professors immediately grabbed a sheet of paper and started drawing their explanations to my questions. But I have not seen much of this lately, and that is a pity, since pictures are undoubtedly a better way of communicating.

OBSERVING A PATIENT WITH COPD

Netter’s patient is also exhaling through pursed lips. This reduces the respiratory rate and carbon dioxide level, while improving distribution of ventilation,^9,10 oxygen saturation, tidal volume, inspiratory muscle strength, and diaphragmatic efficiency.^11,12 Since less inspiratory force is required for each breath, dyspnea is also improved.^13,14 Diagnostically, pursed‑lip breathing increases the probability of chronic obstructive pulmonary disease (COPD), with a likelihood ratio of 5.05.¹⁵

The man in The Pink Puffer is using accessory respiratory muscles, which not only represents one of the earliest signs of airway obstruction, but also reflects severe disease. In fact, use of accessory respiratory muscles occurs in more than 90% of COPD patients admitted for acute exacerbations.⁷

Lastly, Netter’s patient exhibits inspiratory retraction of supraclavicular fossae and interspaces (tirage), which indicates increased airway resistance and reduced forced expiratory volume in 1 second (FEV₁).^16,17 A clavicular “lift” of more than 5 mm correlates with an FEV₁ of 0.6 L.¹⁸

But what is odd about this patient is what Netter did not portray: clubbing. This goes against the conventional wisdom of the time but is actually correct, since we now know that clubbing is more a feature of chronic bronchitis than emphysema.¹⁹ In fact, if present in a “pink puffer,” it should suggest an underlying malignancy. Hence, Netter reminds us that we should never convince ourselves that we see something simply because we know it should be there. Instead, we should always rely on what we see. This is, after all, how Vesalius debunked Galen’s anatomic errors: by seeing for himself. Tom McCrae, Osler’s right-hand man at Johns Hopkins, used to warn his students that one misses more by not seeing than by not knowing. Leonardo put it simply: “Wisdom is the daughter of [visual] experience.”²⁰ In the end, Netter’s drawing reminds us that a picture is truly worth a thousand words.

 

 

TEACHING STUDENTS TO OBSERVE

Unfortunately, detecting detail is difficult. It is also very difficult to teach. For the past few months I’ve been asking astute clinicians how they observe, and most of them seem befuddled, as if I had asked which muscles they contract in order to walk. They just walk. And they just observe.

So, how can we rekindle this important but underappreciated component of the physician’s skill set? First of all, by becoming cognizant of its fundamental role in medicine. Second, by accepting that this is something that cannot be easily tested by single-best- answer, black-and-white, multiple-choice exams. Recognizing the complexity of clinical skills reminds us that not all that counts in medicine can be counted, and not all that can be counted counts. Yet it also provides a hurdle, since testing typically drives curriculum. If we cannot assess observation, how can we reincorporate it in the curriculum? Lastly, we need to regain ownership of the teaching of this skill. No art instructor can properly identify and interpret clinical findings. Hence, physicians ought to teach it. In the end, learning how to properly observe is a personal and lifelong effort. As Osler put it, “There is no more difficult art to acquire than the art of observation.”²¹

Leonardo used to quip that “There are three classes of people: those who see, those who see when they are shown, and those who do not see.”²² Yet this time Leonardo might have been wrong. There are really only two kinds of people: those who have been taught how to observe and those who have not. Leonardo was lucky enough to have been apprenticed to an artist whose nickname was Verrocchio, which resembles the Italian words vero occhio, a “fine eye.” Without Verrocchio, even Leonardo might not have become such a skilled observer. How many Verrocchios are around today?

"I have trained myself to see what others overlook."
—Sherlock Holmes¹

The article by Grandjean and Huber in this issue² is a timely reminder of the importance of skilled observation in medical care. Osler³ considered observation to represent “the whole art of medicine,” but warned that “for some men it is quite as difficult to record an observation in brief and plain language.” This insight captures not only the never-ending feud between written and visual communication, but also the higher efficiency of images. Leonardo da Vinci, a visual thinker with a touch of dyslexia,⁴ often boasted in colorful terms about the superiority of the visual. Next to his amazing rendition of a bovine heart he scribbled, “[Writer] how could you describe this heart in words without filling a whole book? So, don’t bother with words unless you are speaking to the blind…you will always be overruled by the painter.”⁵

See related article and editorial

Ironically, physicians have often preferred the written over the visual. Oliver Wendell Holmes Sr., professor of anatomy at Harvard Medical School and renowned essayist, once wrote a scathing review of a new anatomy textbook that, according to him, had just too many pictures. “Let a student have illustrations,” he thundered “and just so surely will he use them at the expense of the text.”⁶ The book was Gray’s Anatomy, but Holmes’ tirade exemplifies the conundrum of our profession: to become physicians we must read (and memorize) lots of written text, with little emphasis on how much more efficiently information might be conveyed through a single picture.

This trend is probably worsening. When I first came to the United States 43 years ago, I was amazed at how many of my professors immediately grabbed a sheet of paper and started drawing their explanations to my questions. But I have not seen much of this lately, and that is a pity, since pictures are undoubtedly a better way of communicating.

OBSERVING A PATIENT WITH COPD

Netter’s patient is also exhaling through pursed lips. This reduces the respiratory rate and carbon dioxide level, while improving distribution of ventilation,^9,10 oxygen saturation, tidal volume, inspiratory muscle strength, and diaphragmatic efficiency.^11,12 Since less inspiratory force is required for each breath, dyspnea is also improved.^13,14 Diagnostically, pursed‑lip breathing increases the probability of chronic obstructive pulmonary disease (COPD), with a likelihood ratio of 5.05.¹⁵

The man in The Pink Puffer is using accessory respiratory muscles, which not only represents one of the earliest signs of airway obstruction, but also reflects severe disease. In fact, use of accessory respiratory muscles occurs in more than 90% of COPD patients admitted for acute exacerbations.⁷

Lastly, Netter’s patient exhibits inspiratory retraction of supraclavicular fossae and interspaces (tirage), which indicates increased airway resistance and reduced forced expiratory volume in 1 second (FEV₁).^16,17 A clavicular “lift” of more than 5 mm correlates with an FEV₁ of 0.6 L.¹⁸

But what is odd about this patient is what Netter did not portray: clubbing. This goes against the conventional wisdom of the time but is actually correct, since we now know that clubbing is more a feature of chronic bronchitis than emphysema.¹⁹ In fact, if present in a “pink puffer,” it should suggest an underlying malignancy. Hence, Netter reminds us that we should never convince ourselves that we see something simply because we know it should be there. Instead, we should always rely on what we see. This is, after all, how Vesalius debunked Galen’s anatomic errors: by seeing for himself. Tom McCrae, Osler’s right-hand man at Johns Hopkins, used to warn his students that one misses more by not seeing than by not knowing. Leonardo put it simply: “Wisdom is the daughter of [visual] experience.”²⁰ In the end, Netter’s drawing reminds us that a picture is truly worth a thousand words.

 

 

TEACHING STUDENTS TO OBSERVE

Unfortunately, detecting detail is difficult. It is also very difficult to teach. For the past few months I’ve been asking astute clinicians how they observe, and most of them seem befuddled, as if I had asked which muscles they contract in order to walk. They just walk. And they just observe.

So, how can we rekindle this important but underappreciated component of the physician’s skill set? First of all, by becoming cognizant of its fundamental role in medicine. Second, by accepting that this is something that cannot be easily tested by single-best- answer, black-and-white, multiple-choice exams. Recognizing the complexity of clinical skills reminds us that not all that counts in medicine can be counted, and not all that can be counted counts. Yet it also provides a hurdle, since testing typically drives curriculum. If we cannot assess observation, how can we reincorporate it in the curriculum? Lastly, we need to regain ownership of the teaching of this skill. No art instructor can properly identify and interpret clinical findings. Hence, physicians ought to teach it. In the end, learning how to properly observe is a personal and lifelong effort. As Osler put it, “There is no more difficult art to acquire than the art of observation.”²¹

Leonardo used to quip that “There are three classes of people: those who see, those who see when they are shown, and those who do not see.”²² Yet this time Leonardo might have been wrong. There are really only two kinds of people: those who have been taught how to observe and those who have not. Leonardo was lucky enough to have been apprenticed to an artist whose nickname was Verrocchio, which resembles the Italian words vero occhio, a “fine eye.” Without Verrocchio, even Leonardo might not have become such a skilled observer. How many Verrocchios are around today?

"I have trained myself to see what others overlook."
—Sherlock Holmes¹

The article by Grandjean and Huber in this issue² is a timely reminder of the importance of skilled observation in medical care. Osler³ considered observation to represent “the whole art of medicine,” but warned that “for some men it is quite as difficult to record an observation in brief and plain language.” This insight captures not only the never-ending feud between written and visual communication, but also the higher efficiency of images. Leonardo da Vinci, a visual thinker with a touch of dyslexia,⁴ often boasted in colorful terms about the superiority of the visual. Next to his amazing rendition of a bovine heart he scribbled, “[Writer] how could you describe this heart in words without filling a whole book? So, don’t bother with words unless you are speaking to the blind…you will always be overruled by the painter.”⁵

See related article and editorial

Ironically, physicians have often preferred the written over the visual. Oliver Wendell Holmes Sr., professor of anatomy at Harvard Medical School and renowned essayist, once wrote a scathing review of a new anatomy textbook that, according to him, had just too many pictures. “Let a student have illustrations,” he thundered “and just so surely will he use them at the expense of the text.”⁶ The book was Gray’s Anatomy, but Holmes’ tirade exemplifies the conundrum of our profession: to become physicians we must read (and memorize) lots of written text, with little emphasis on how much more efficiently information might be conveyed through a single picture.

This trend is probably worsening. When I first came to the United States 43 years ago, I was amazed at how many of my professors immediately grabbed a sheet of paper and started drawing their explanations to my questions. But I have not seen much of this lately, and that is a pity, since pictures are undoubtedly a better way of communicating.

OBSERVING A PATIENT WITH COPD

Netter’s patient is also exhaling through pursed lips. This reduces the respiratory rate and carbon dioxide level, while improving distribution of ventilation,^9,10 oxygen saturation, tidal volume, inspiratory muscle strength, and diaphragmatic efficiency.^11,12 Since less inspiratory force is required for each breath, dyspnea is also improved.^13,14 Diagnostically, pursed‑lip breathing increases the probability of chronic obstructive pulmonary disease (COPD), with a likelihood ratio of 5.05.¹⁵

The man in The Pink Puffer is using accessory respiratory muscles, which not only represents one of the earliest signs of airway obstruction, but also reflects severe disease. In fact, use of accessory respiratory muscles occurs in more than 90% of COPD patients admitted for acute exacerbations.⁷

Lastly, Netter’s patient exhibits inspiratory retraction of supraclavicular fossae and interspaces (tirage), which indicates increased airway resistance and reduced forced expiratory volume in 1 second (FEV₁).^16,17 A clavicular “lift” of more than 5 mm correlates with an FEV₁ of 0.6 L.¹⁸

But what is odd about this patient is what Netter did not portray: clubbing. This goes against the conventional wisdom of the time but is actually correct, since we now know that clubbing is more a feature of chronic bronchitis than emphysema.¹⁹ In fact, if present in a “pink puffer,” it should suggest an underlying malignancy. Hence, Netter reminds us that we should never convince ourselves that we see something simply because we know it should be there. Instead, we should always rely on what we see. This is, after all, how Vesalius debunked Galen’s anatomic errors: by seeing for himself. Tom McCrae, Osler’s right-hand man at Johns Hopkins, used to warn his students that one misses more by not seeing than by not knowing. Leonardo put it simply: “Wisdom is the daughter of [visual] experience.”²⁰ In the end, Netter’s drawing reminds us that a picture is truly worth a thousand words.

 

 

TEACHING STUDENTS TO OBSERVE

Unfortunately, detecting detail is difficult. It is also very difficult to teach. For the past few months I’ve been asking astute clinicians how they observe, and most of them seem befuddled, as if I had asked which muscles they contract in order to walk. They just walk. And they just observe.

So, how can we rekindle this important but underappreciated component of the physician’s skill set? First of all, by becoming cognizant of its fundamental role in medicine. Second, by accepting that this is something that cannot be easily tested by single-best- answer, black-and-white, multiple-choice exams. Recognizing the complexity of clinical skills reminds us that not all that counts in medicine can be counted, and not all that can be counted counts. Yet it also provides a hurdle, since testing typically drives curriculum. If we cannot assess observation, how can we reincorporate it in the curriculum? Lastly, we need to regain ownership of the teaching of this skill. No art instructor can properly identify and interpret clinical findings. Hence, physicians ought to teach it. In the end, learning how to properly observe is a personal and lifelong effort. As Osler put it, “There is no more difficult art to acquire than the art of observation.”²¹

Leonardo used to quip that “There are three classes of people: those who see, those who see when they are shown, and those who do not see.”²² Yet this time Leonardo might have been wrong. There are really only two kinds of people: those who have been taught how to observe and those who have not. Leonardo was lucky enough to have been apprenticed to an artist whose nickname was Verrocchio, which resembles the Italian words vero occhio, a “fine eye.” Without Verrocchio, even Leonardo might not have become such a skilled observer. How many Verrocchios are around today?