Pulmonology

BALTIMORE – In children with pharyngitis, it’s safe to skip group A Streptococcus testing if there are no exudates, children are 11 years or older, and there is either no cervical adenopathy or adenopathy without fever, according to a Boston Children’s Hospital investigation.

LightFieldStudios/iStock/Getty Images Plus

The prevalence of group A Streptococcus among children who meet those criteria is 13%, less than the estimated asymptomatic carriage rate of about 15%. Among 67,127 children tested for strep and treated for sore throats in a network of retail health clinics across the United States, 35% fit the profile.

Investigators led by Daniel Shapiro, MD, a pediatrics fellow at Boston Children’s, concluded that “laboratory testing for GAS [group A Streptococcus] might be safely avoided in a large proportion of patients with sore throats. In doing so, we may avoid some of the downstream effects of unnecessary antibiotic use.” Incorporating the rules into EHRs “might help physicians identify patients who are at low risk of GAS pharyngitis.”

The study team tackled a long-standing and vexing problem in general pediatrics: how to distinguish viral from GAS pharyngitis. They often present the same way, so it’s difficult to tell them apart, but important to do so to prevent misuse of antibiotics. Health care providers generally rely on rapid strep tests and other assays to make the call, but they have to be used cautiously, because asymptomatic carriers also will test positive and be at risk for unnecessary treatment, Dr. Shapiro said at the Pediatric Academic Societies annual meeting.

To try to prevent that, the Infectious Disease Society of America (IDSA) recommends against strep testing in children who present with overt viral signs, including cough, rhinorrhea, oral ulcers, and hoarseness (Clin Infect Dis. 2012 Nov 15;55[10]:1279-82).

In a previous study at Boston Children’s ED, however, Dr. Shapiro and his colleagues found that 29% of children with overt viral features were positive for GAS, suggesting that the IDSA guidelines probably go too far (Pediatrics. 2017 May;139[5]. pii: e20163403).

“One might conclude that while it’s a good rule of thumb to avoid testing patients with viral features, some of the patients with viral features really do have GAS pharyngitis, so the recommendation to forgo testing in all these kids needs a little bit of refinement,” he said.

That was the goal of the new study; the team sought to identify viral features that signaled a low risk of GAS pharyngitis and, therefore, no need for testing. Low risk was defined as less than 15%, in keeping with the asymptomatic carriage rate.

The 67,127 patients were aged 3-21 years. Their signs and symptoms were collected at the retail clinics in a standardized form. The subjects had rapid strep tests, with negative results confirmed by DNA probe or culture.

Fifty-four percent had viral features, defined in the study as cough, runny nose, or hoarseness (oral ulcers weren’t collected on the form). The overall prevalence of GAS was 35%, similar to previous studies; 39% of children with no viral features tested positive for GAS versus 26% of children with all three. Exudates and age below 11 years were strongly associated with GAS among patients with viral features.

It turned out that just 23% of children without exudates were GAS positive; the number fell to 15% when limited to children 11 years or older, and to 13% when either no cervical adenopathy or adenopathy without fever were added to the mix. So skip the strep test in pharyngitis when there are no exudates in children 11 years or older lacking cervical adenopathy or who have adenopathy without fever.

There was no industry funding, and Dr. Shapiro didn’t have any disclosures.

aotto@mdedge.com

BALTIMORE – In children with pharyngitis, it’s safe to skip group A Streptococcus testing if there are no exudates, children are 11 years or older, and there is either no cervical adenopathy or adenopathy without fever, according to a Boston Children’s Hospital investigation.

LightFieldStudios/iStock/Getty Images Plus

The prevalence of group A Streptococcus among children who meet those criteria is 13%, less than the estimated asymptomatic carriage rate of about 15%. Among 67,127 children tested for strep and treated for sore throats in a network of retail health clinics across the United States, 35% fit the profile.

Investigators led by Daniel Shapiro, MD, a pediatrics fellow at Boston Children’s, concluded that “laboratory testing for GAS [group A Streptococcus] might be safely avoided in a large proportion of patients with sore throats. In doing so, we may avoid some of the downstream effects of unnecessary antibiotic use.” Incorporating the rules into EHRs “might help physicians identify patients who are at low risk of GAS pharyngitis.”

The study team tackled a long-standing and vexing problem in general pediatrics: how to distinguish viral from GAS pharyngitis. They often present the same way, so it’s difficult to tell them apart, but important to do so to prevent misuse of antibiotics. Health care providers generally rely on rapid strep tests and other assays to make the call, but they have to be used cautiously, because asymptomatic carriers also will test positive and be at risk for unnecessary treatment, Dr. Shapiro said at the Pediatric Academic Societies annual meeting.

To try to prevent that, the Infectious Disease Society of America (IDSA) recommends against strep testing in children who present with overt viral signs, including cough, rhinorrhea, oral ulcers, and hoarseness (Clin Infect Dis. 2012 Nov 15;55[10]:1279-82).

In a previous study at Boston Children’s ED, however, Dr. Shapiro and his colleagues found that 29% of children with overt viral features were positive for GAS, suggesting that the IDSA guidelines probably go too far (Pediatrics. 2017 May;139[5]. pii: e20163403).

“One might conclude that while it’s a good rule of thumb to avoid testing patients with viral features, some of the patients with viral features really do have GAS pharyngitis, so the recommendation to forgo testing in all these kids needs a little bit of refinement,” he said.

That was the goal of the new study; the team sought to identify viral features that signaled a low risk of GAS pharyngitis and, therefore, no need for testing. Low risk was defined as less than 15%, in keeping with the asymptomatic carriage rate.

The 67,127 patients were aged 3-21 years. Their signs and symptoms were collected at the retail clinics in a standardized form. The subjects had rapid strep tests, with negative results confirmed by DNA probe or culture.

Fifty-four percent had viral features, defined in the study as cough, runny nose, or hoarseness (oral ulcers weren’t collected on the form). The overall prevalence of GAS was 35%, similar to previous studies; 39% of children with no viral features tested positive for GAS versus 26% of children with all three. Exudates and age below 11 years were strongly associated with GAS among patients with viral features.

It turned out that just 23% of children without exudates were GAS positive; the number fell to 15% when limited to children 11 years or older, and to 13% when either no cervical adenopathy or adenopathy without fever were added to the mix. So skip the strep test in pharyngitis when there are no exudates in children 11 years or older lacking cervical adenopathy or who have adenopathy without fever.

There was no industry funding, and Dr. Shapiro didn’t have any disclosures.

aotto@mdedge.com

BALTIMORE – In children with pharyngitis, it’s safe to skip group A Streptococcus testing if there are no exudates, children are 11 years or older, and there is either no cervical adenopathy or adenopathy without fever, according to a Boston Children’s Hospital investigation.

LightFieldStudios/iStock/Getty Images Plus

The prevalence of group A Streptococcus among children who meet those criteria is 13%, less than the estimated asymptomatic carriage rate of about 15%. Among 67,127 children tested for strep and treated for sore throats in a network of retail health clinics across the United States, 35% fit the profile.

Investigators led by Daniel Shapiro, MD, a pediatrics fellow at Boston Children’s, concluded that “laboratory testing for GAS [group A Streptococcus] might be safely avoided in a large proportion of patients with sore throats. In doing so, we may avoid some of the downstream effects of unnecessary antibiotic use.” Incorporating the rules into EHRs “might help physicians identify patients who are at low risk of GAS pharyngitis.”

The study team tackled a long-standing and vexing problem in general pediatrics: how to distinguish viral from GAS pharyngitis. They often present the same way, so it’s difficult to tell them apart, but important to do so to prevent misuse of antibiotics. Health care providers generally rely on rapid strep tests and other assays to make the call, but they have to be used cautiously, because asymptomatic carriers also will test positive and be at risk for unnecessary treatment, Dr. Shapiro said at the Pediatric Academic Societies annual meeting.

To try to prevent that, the Infectious Disease Society of America (IDSA) recommends against strep testing in children who present with overt viral signs, including cough, rhinorrhea, oral ulcers, and hoarseness (Clin Infect Dis. 2012 Nov 15;55[10]:1279-82).

In a previous study at Boston Children’s ED, however, Dr. Shapiro and his colleagues found that 29% of children with overt viral features were positive for GAS, suggesting that the IDSA guidelines probably go too far (Pediatrics. 2017 May;139[5]. pii: e20163403).

“One might conclude that while it’s a good rule of thumb to avoid testing patients with viral features, some of the patients with viral features really do have GAS pharyngitis, so the recommendation to forgo testing in all these kids needs a little bit of refinement,” he said.

That was the goal of the new study; the team sought to identify viral features that signaled a low risk of GAS pharyngitis and, therefore, no need for testing. Low risk was defined as less than 15%, in keeping with the asymptomatic carriage rate.

The 67,127 patients were aged 3-21 years. Their signs and symptoms were collected at the retail clinics in a standardized form. The subjects had rapid strep tests, with negative results confirmed by DNA probe or culture.

Fifty-four percent had viral features, defined in the study as cough, runny nose, or hoarseness (oral ulcers weren’t collected on the form). The overall prevalence of GAS was 35%, similar to previous studies; 39% of children with no viral features tested positive for GAS versus 26% of children with all three. Exudates and age below 11 years were strongly associated with GAS among patients with viral features.

It turned out that just 23% of children without exudates were GAS positive; the number fell to 15% when limited to children 11 years or older, and to 13% when either no cervical adenopathy or adenopathy without fever were added to the mix. So skip the strep test in pharyngitis when there are no exudates in children 11 years or older lacking cervical adenopathy or who have adenopathy without fever.

There was no industry funding, and Dr. Shapiro didn’t have any disclosures.

aotto@mdedge.com

Interventional Chest/Diagnostic Procedures

Complications and economic burden of diagnostic procedures for lung abnormalities in the community setting

The influential National Lung Screening Trial (NLST) reported a 20% reduction in lung cancer-related deaths using low dose CT scan when compared with plain chest radiography (Aberle et al. N Engl J Med. 2011;365[5]:395). Many medical societies responded by recommending screening individuals at high-risk for lung cancer, and community-based lung cancer screening programs were developed across the US. A concerning feature of the study was the rate (23.3%) of false-positive findings after three rounds of screening and the potential for complications secondary to diagnostic invasive procedures.

Pediatric Chest Medicine

microRNAs: A New Biomarker

Biomarkers are essential tools in a clinician’s armamentarium. Biomarkers have multiple uses being indicators of a pathologic or physiologic process. One promising biomarker, now studied across multiple disorders, is microRNA (miRNA).

miRNAs are short (18–22 nucleotide) regulatory RNAs that bind mRNAs and decrease protein translation. miRNAs are generally co-transcribed with neighboring genes or co-transcribed within a cluster of miRNAs (a polycistronic cluster). Over 2,000 miRNAs are listed on miRBase (http://www.mirbase.org/), considered the central repository.

Function and biomarker utility of miRNAs are specific to the cells in which they are expressed. miRNAs isolated from circulating plasma exosomes have been shown to be stable over time, which is key in establishing their utility (Sanz-Rubio, et al. Sci Rep. 2018;8[1]:10306).

miRNAs have been credited with the function of micromanaging the circadian clock and sleep homeostasis in virtually all living organisms (Goodwin, et al. Cell Rep. 2018;23[13]:3776; Mehta, et al. J Mol Biol. 2013;425[19]:3609).

Preliminary work has identified dysregulated miRNAs in patients with obstructive sleep apnea (Li, et al. Medicine (Baltimore). 2017;96[34]:e7917). Exosomal miRNA has been shown to predict and protect against severe bronchopulmonary dysplasia (Lal, et al. JCI Insight. 2018;3[5]. pii: 93994).

Circadian miRNAs in salivary samples were found to have “altered” expression in autistic children with disordered sleep relative to peers with typical sleep (Hicks, et al. PLoS One. 2018;13[7]:e0198288). Collection from salivary samples facilitates multiple timed collection feasible at home and has multiple benefits.

Work on miRNAs, though preliminary, appears promising in providing a much-needed new perspective on pathophysiology and treatment in many disease processes.

Harish Rao, MD

Steering Committee Member

Pulmonary Physiology, Function, and Rehabilitation

Using impulse oscillometry in clinical practice

Impulse oscillometry (iOS) is an effort-independent test that requires minimal cooperation from the patient. It provides measures of respiratory mechanics during normal tidal breathing, including resistance (R), reactance (X), and impedance (Z) (Oostveen E, et al. Eur Respir J. 2003;22[6]:1026).

Airway R is largely, but not entirely, determined by cross-sectional area (Poiseuille’s Law). X is a surrogate for lung elastance, which is the inverse of compliance. Z is the combination of R and X and isn’t used clinically.

There are several benefits to using iOS, as opposed to or in conjunction with standard spirometry. First, iOS yields respiratory function measurements for patients, like the elderly and young children, who cannot provide acceptable and reproducible spirometry (Pezzoli L, et al. Age Ageing. 2003;32[1]:43). Second, it provides a real-world assessment of lung function because R and X values are obtained during tidal breathing. Humans don’t use the forced maneuvers needed for spirometry during normal daily activities, which weakens the correlation of FEV₁ with respiratory symptoms. Forced maneuvers also create artifacts from gas compression and cause small airway closure, which limits inferences made from standard spirometry (Brusasco V, et al. Eur Respir J. 2005;26[5]:948). Lastly, R and X provide information not available from spirometry, and iOS is particularly sensitive for detecting small airway dysfunction (Berger K, et al. Chest. 2015;148[5]:1131).

Clinical and disease-specific indications for iOS are still being established. As discussed above, iOS is appropriate for any patient unable to perform spirometry. As new inhalers designed to deliver medication to the distal airways become available, subtle abnormalities detected via iOS will provide a target for specific therapies (Lipworth B. Ann Allergy Asthma Immunol. 2013;110[4]:233). iOS shows significant promise as a noninvasive assessment for supraglottic diseases, like vocal cord dysfunction, and can quantify changes over time following invasive intervention to relieve upper airway obstruction (Bikov A, et al. Chest. 2015;148[3]:731; Horan T, et al. Chest. 2001:120[1]:69). As their comfort level with interpretation improves, pulmonologists will find iOS is an important tool for disease diagnosis and treatment.

Aaron Holley, MD, FCCP

Steering Committee Member

Pulmonary Vascular Disease

Hemodynamic definition of pulmonary hypertension changed

Many patients worldwide went to bed February 26, 2018, with normal pulmonary pressures and woke up the next morning with pulmonary hypertension (PH). That day, experts met at the World Symposium on PH in Nice, France, and changed the definition of resting PH from a mean pulmonary artery pressure (mPAP) of greater than or equal to 25 mm Hg to a mPAP greater 20 mm Hg (Simmoneau, et al. Eur Respir J. 2019;53:1801913). The First World Health Organization symposium on PH in 1973 established the 25 mm Hg cutoff to distinguish primary PH from what was then considered less severe forms of PH. This definition, acknowledged as arbitrary and conservative at the time, has persisted due to a paucity of data establishing a definitively abnormal mPAP threshold.

Two contemporary findings provide justification for the definition change: (1)Normal mPAP is 14 ± 3.3 mm Hg in healthy subjects (Kovacs, et al. Eur Respir J. 2009;34[4]:888). (2) Patients with mPAP greater than 20 mm Hg suffer worse outcomes compared with control subjects (Maron, et al. Circulation. 2016;133[13]:1240).

Preserving the other hemodynamic criteria for group 1 PH, pulmonary artery wedge pressure less than or equal to 15 mm Hg and pulmonary vascular resistance greater than or equal to 3 Wood units, experts also recommend applying the new definition to all pre-capillary PH, including groups 3, 4, and applicable group 5 diagnoses.

Importantly, new guidelines do not recommend treating PH patients with mPAP 21-24 mm Hg: “A change in the hemodynamic definition of PH due to [pulmonary vascular diseases] does not imply treating these additional patients, but highlights the importance of close monitoring in this population.”

John Kingrey, MD

Steering Committee Member

Thoracic Oncology

Lung Cancer and Women

While the overall incidence of lung cancer (LC) has decreased among both men and women, the decline among men has been steeper compared with women. Further, in women born in the 1950s to 1960s, the incidence has actually increased and cannot be fully explained by sex differences in smoking behavior (Jemal, et al. N Engl J Med. 2018;378:1999). Data suggest that women may be more susceptible to the harmful effects of tobacco and that the biology of LC may be different in women. In addition, LC in nonsmokers is more likely to occur in women.

LC is the leading cause of cancer death in both women and men worldwide, but the dramatic rise in the mortality rate from LC in women was qualified as a “full blown epidemic” in the Surgeon General’s 2001 Women and Smoking report.

The benefits of lung cancer screening (LCS) in the National Lung Screening Trial (NLST) were higher in women than in men and significantly greater in the subset of women (16%) that entered the Nelson trial – reduction in 10-year LC mortality of 61% vs. 26% in men (De Koning, et al. J Thorac Oncol. 2018;13[10]: suppl S185. Abstract PL02.05). A retrospective review of patients diagnosed with LC between 2005 and 2011 showed that only 37% of women vs. 50% of men met LCS criteria (Wang, et al. JAMA 2015;313[8]:853).

Lung cancer needs to be recognized as an important women’s health issue, and there is need for continued attention to sex differences in LC risk, LCS criteria, and outcomes.

Anne Gonzalez, MD, FCCP

Steering Committee Member

Interventional Chest/Diagnostic Procedures

Complications and economic burden of diagnostic procedures for lung abnormalities in the community setting

The influential National Lung Screening Trial (NLST) reported a 20% reduction in lung cancer-related deaths using low dose CT scan when compared with plain chest radiography (Aberle et al. N Engl J Med. 2011;365[5]:395). Many medical societies responded by recommending screening individuals at high-risk for lung cancer, and community-based lung cancer screening programs were developed across the US. A concerning feature of the study was the rate (23.3%) of false-positive findings after three rounds of screening and the potential for complications secondary to diagnostic invasive procedures.

Pediatric Chest Medicine

microRNAs: A New Biomarker

Biomarkers are essential tools in a clinician’s armamentarium. Biomarkers have multiple uses being indicators of a pathologic or physiologic process. One promising biomarker, now studied across multiple disorders, is microRNA (miRNA).

miRNAs are short (18–22 nucleotide) regulatory RNAs that bind mRNAs and decrease protein translation. miRNAs are generally co-transcribed with neighboring genes or co-transcribed within a cluster of miRNAs (a polycistronic cluster). Over 2,000 miRNAs are listed on miRBase (http://www.mirbase.org/), considered the central repository.

Function and biomarker utility of miRNAs are specific to the cells in which they are expressed. miRNAs isolated from circulating plasma exosomes have been shown to be stable over time, which is key in establishing their utility (Sanz-Rubio, et al. Sci Rep. 2018;8[1]:10306).

miRNAs have been credited with the function of micromanaging the circadian clock and sleep homeostasis in virtually all living organisms (Goodwin, et al. Cell Rep. 2018;23[13]:3776; Mehta, et al. J Mol Biol. 2013;425[19]:3609).

Preliminary work has identified dysregulated miRNAs in patients with obstructive sleep apnea (Li, et al. Medicine (Baltimore). 2017;96[34]:e7917). Exosomal miRNA has been shown to predict and protect against severe bronchopulmonary dysplasia (Lal, et al. JCI Insight. 2018;3[5]. pii: 93994).

Circadian miRNAs in salivary samples were found to have “altered” expression in autistic children with disordered sleep relative to peers with typical sleep (Hicks, et al. PLoS One. 2018;13[7]:e0198288). Collection from salivary samples facilitates multiple timed collection feasible at home and has multiple benefits.

Work on miRNAs, though preliminary, appears promising in providing a much-needed new perspective on pathophysiology and treatment in many disease processes.

Harish Rao, MD

Steering Committee Member

Pulmonary Physiology, Function, and Rehabilitation

Using impulse oscillometry in clinical practice

Impulse oscillometry (iOS) is an effort-independent test that requires minimal cooperation from the patient. It provides measures of respiratory mechanics during normal tidal breathing, including resistance (R), reactance (X), and impedance (Z) (Oostveen E, et al. Eur Respir J. 2003;22[6]:1026).

Airway R is largely, but not entirely, determined by cross-sectional area (Poiseuille’s Law). X is a surrogate for lung elastance, which is the inverse of compliance. Z is the combination of R and X and isn’t used clinically.

There are several benefits to using iOS, as opposed to or in conjunction with standard spirometry. First, iOS yields respiratory function measurements for patients, like the elderly and young children, who cannot provide acceptable and reproducible spirometry (Pezzoli L, et al. Age Ageing. 2003;32[1]:43). Second, it provides a real-world assessment of lung function because R and X values are obtained during tidal breathing. Humans don’t use the forced maneuvers needed for spirometry during normal daily activities, which weakens the correlation of FEV₁ with respiratory symptoms. Forced maneuvers also create artifacts from gas compression and cause small airway closure, which limits inferences made from standard spirometry (Brusasco V, et al. Eur Respir J. 2005;26[5]:948). Lastly, R and X provide information not available from spirometry, and iOS is particularly sensitive for detecting small airway dysfunction (Berger K, et al. Chest. 2015;148[5]:1131).

Clinical and disease-specific indications for iOS are still being established. As discussed above, iOS is appropriate for any patient unable to perform spirometry. As new inhalers designed to deliver medication to the distal airways become available, subtle abnormalities detected via iOS will provide a target for specific therapies (Lipworth B. Ann Allergy Asthma Immunol. 2013;110[4]:233). iOS shows significant promise as a noninvasive assessment for supraglottic diseases, like vocal cord dysfunction, and can quantify changes over time following invasive intervention to relieve upper airway obstruction (Bikov A, et al. Chest. 2015;148[3]:731; Horan T, et al. Chest. 2001:120[1]:69). As their comfort level with interpretation improves, pulmonologists will find iOS is an important tool for disease diagnosis and treatment.

Aaron Holley, MD, FCCP

Steering Committee Member

Pulmonary Vascular Disease

Hemodynamic definition of pulmonary hypertension changed

Many patients worldwide went to bed February 26, 2018, with normal pulmonary pressures and woke up the next morning with pulmonary hypertension (PH). That day, experts met at the World Symposium on PH in Nice, France, and changed the definition of resting PH from a mean pulmonary artery pressure (mPAP) of greater than or equal to 25 mm Hg to a mPAP greater 20 mm Hg (Simmoneau, et al. Eur Respir J. 2019;53:1801913). The First World Health Organization symposium on PH in 1973 established the 25 mm Hg cutoff to distinguish primary PH from what was then considered less severe forms of PH. This definition, acknowledged as arbitrary and conservative at the time, has persisted due to a paucity of data establishing a definitively abnormal mPAP threshold.

Two contemporary findings provide justification for the definition change: (1)Normal mPAP is 14 ± 3.3 mm Hg in healthy subjects (Kovacs, et al. Eur Respir J. 2009;34[4]:888). (2) Patients with mPAP greater than 20 mm Hg suffer worse outcomes compared with control subjects (Maron, et al. Circulation. 2016;133[13]:1240).

Preserving the other hemodynamic criteria for group 1 PH, pulmonary artery wedge pressure less than or equal to 15 mm Hg and pulmonary vascular resistance greater than or equal to 3 Wood units, experts also recommend applying the new definition to all pre-capillary PH, including groups 3, 4, and applicable group 5 diagnoses.

Importantly, new guidelines do not recommend treating PH patients with mPAP 21-24 mm Hg: “A change in the hemodynamic definition of PH due to [pulmonary vascular diseases] does not imply treating these additional patients, but highlights the importance of close monitoring in this population.”

John Kingrey, MD

Steering Committee Member

Thoracic Oncology

Lung Cancer and Women

While the overall incidence of lung cancer (LC) has decreased among both men and women, the decline among men has been steeper compared with women. Further, in women born in the 1950s to 1960s, the incidence has actually increased and cannot be fully explained by sex differences in smoking behavior (Jemal, et al. N Engl J Med. 2018;378:1999). Data suggest that women may be more susceptible to the harmful effects of tobacco and that the biology of LC may be different in women. In addition, LC in nonsmokers is more likely to occur in women.

LC is the leading cause of cancer death in both women and men worldwide, but the dramatic rise in the mortality rate from LC in women was qualified as a “full blown epidemic” in the Surgeon General’s 2001 Women and Smoking report.

The benefits of lung cancer screening (LCS) in the National Lung Screening Trial (NLST) were higher in women than in men and significantly greater in the subset of women (16%) that entered the Nelson trial – reduction in 10-year LC mortality of 61% vs. 26% in men (De Koning, et al. J Thorac Oncol. 2018;13[10]: suppl S185. Abstract PL02.05). A retrospective review of patients diagnosed with LC between 2005 and 2011 showed that only 37% of women vs. 50% of men met LCS criteria (Wang, et al. JAMA 2015;313[8]:853).

Lung cancer needs to be recognized as an important women’s health issue, and there is need for continued attention to sex differences in LC risk, LCS criteria, and outcomes.

Anne Gonzalez, MD, FCCP

Steering Committee Member

Interventional Chest/Diagnostic Procedures

Complications and economic burden of diagnostic procedures for lung abnormalities in the community setting

The influential National Lung Screening Trial (NLST) reported a 20% reduction in lung cancer-related deaths using low dose CT scan when compared with plain chest radiography (Aberle et al. N Engl J Med. 2011;365[5]:395). Many medical societies responded by recommending screening individuals at high-risk for lung cancer, and community-based lung cancer screening programs were developed across the US. A concerning feature of the study was the rate (23.3%) of false-positive findings after three rounds of screening and the potential for complications secondary to diagnostic invasive procedures.

Pediatric Chest Medicine

microRNAs: A New Biomarker

Biomarkers are essential tools in a clinician’s armamentarium. Biomarkers have multiple uses being indicators of a pathologic or physiologic process. One promising biomarker, now studied across multiple disorders, is microRNA (miRNA).

miRNAs are short (18–22 nucleotide) regulatory RNAs that bind mRNAs and decrease protein translation. miRNAs are generally co-transcribed with neighboring genes or co-transcribed within a cluster of miRNAs (a polycistronic cluster). Over 2,000 miRNAs are listed on miRBase (http://www.mirbase.org/), considered the central repository.

Function and biomarker utility of miRNAs are specific to the cells in which they are expressed. miRNAs isolated from circulating plasma exosomes have been shown to be stable over time, which is key in establishing their utility (Sanz-Rubio, et al. Sci Rep. 2018;8[1]:10306).

miRNAs have been credited with the function of micromanaging the circadian clock and sleep homeostasis in virtually all living organisms (Goodwin, et al. Cell Rep. 2018;23[13]:3776; Mehta, et al. J Mol Biol. 2013;425[19]:3609).

Preliminary work has identified dysregulated miRNAs in patients with obstructive sleep apnea (Li, et al. Medicine (Baltimore). 2017;96[34]:e7917). Exosomal miRNA has been shown to predict and protect against severe bronchopulmonary dysplasia (Lal, et al. JCI Insight. 2018;3[5]. pii: 93994).

Circadian miRNAs in salivary samples were found to have “altered” expression in autistic children with disordered sleep relative to peers with typical sleep (Hicks, et al. PLoS One. 2018;13[7]:e0198288). Collection from salivary samples facilitates multiple timed collection feasible at home and has multiple benefits.

Work on miRNAs, though preliminary, appears promising in providing a much-needed new perspective on pathophysiology and treatment in many disease processes.

Harish Rao, MD

Steering Committee Member

Pulmonary Physiology, Function, and Rehabilitation

Using impulse oscillometry in clinical practice

Impulse oscillometry (iOS) is an effort-independent test that requires minimal cooperation from the patient. It provides measures of respiratory mechanics during normal tidal breathing, including resistance (R), reactance (X), and impedance (Z) (Oostveen E, et al. Eur Respir J. 2003;22[6]:1026).

Airway R is largely, but not entirely, determined by cross-sectional area (Poiseuille’s Law). X is a surrogate for lung elastance, which is the inverse of compliance. Z is the combination of R and X and isn’t used clinically.

There are several benefits to using iOS, as opposed to or in conjunction with standard spirometry. First, iOS yields respiratory function measurements for patients, like the elderly and young children, who cannot provide acceptable and reproducible spirometry (Pezzoli L, et al. Age Ageing. 2003;32[1]:43). Second, it provides a real-world assessment of lung function because R and X values are obtained during tidal breathing. Humans don’t use the forced maneuvers needed for spirometry during normal daily activities, which weakens the correlation of FEV₁ with respiratory symptoms. Forced maneuvers also create artifacts from gas compression and cause small airway closure, which limits inferences made from standard spirometry (Brusasco V, et al. Eur Respir J. 2005;26[5]:948). Lastly, R and X provide information not available from spirometry, and iOS is particularly sensitive for detecting small airway dysfunction (Berger K, et al. Chest. 2015;148[5]:1131).

Clinical and disease-specific indications for iOS are still being established. As discussed above, iOS is appropriate for any patient unable to perform spirometry. As new inhalers designed to deliver medication to the distal airways become available, subtle abnormalities detected via iOS will provide a target for specific therapies (Lipworth B. Ann Allergy Asthma Immunol. 2013;110[4]:233). iOS shows significant promise as a noninvasive assessment for supraglottic diseases, like vocal cord dysfunction, and can quantify changes over time following invasive intervention to relieve upper airway obstruction (Bikov A, et al. Chest. 2015;148[3]:731; Horan T, et al. Chest. 2001:120[1]:69). As their comfort level with interpretation improves, pulmonologists will find iOS is an important tool for disease diagnosis and treatment.

Aaron Holley, MD, FCCP

Steering Committee Member

Pulmonary Vascular Disease

Hemodynamic definition of pulmonary hypertension changed

Many patients worldwide went to bed February 26, 2018, with normal pulmonary pressures and woke up the next morning with pulmonary hypertension (PH). That day, experts met at the World Symposium on PH in Nice, France, and changed the definition of resting PH from a mean pulmonary artery pressure (mPAP) of greater than or equal to 25 mm Hg to a mPAP greater 20 mm Hg (Simmoneau, et al. Eur Respir J. 2019;53:1801913). The First World Health Organization symposium on PH in 1973 established the 25 mm Hg cutoff to distinguish primary PH from what was then considered less severe forms of PH. This definition, acknowledged as arbitrary and conservative at the time, has persisted due to a paucity of data establishing a definitively abnormal mPAP threshold.

Two contemporary findings provide justification for the definition change: (1)Normal mPAP is 14 ± 3.3 mm Hg in healthy subjects (Kovacs, et al. Eur Respir J. 2009;34[4]:888). (2) Patients with mPAP greater than 20 mm Hg suffer worse outcomes compared with control subjects (Maron, et al. Circulation. 2016;133[13]:1240).

Preserving the other hemodynamic criteria for group 1 PH, pulmonary artery wedge pressure less than or equal to 15 mm Hg and pulmonary vascular resistance greater than or equal to 3 Wood units, experts also recommend applying the new definition to all pre-capillary PH, including groups 3, 4, and applicable group 5 diagnoses.

Importantly, new guidelines do not recommend treating PH patients with mPAP 21-24 mm Hg: “A change in the hemodynamic definition of PH due to [pulmonary vascular diseases] does not imply treating these additional patients, but highlights the importance of close monitoring in this population.”

John Kingrey, MD

Steering Committee Member

Thoracic Oncology

Lung Cancer and Women

While the overall incidence of lung cancer (LC) has decreased among both men and women, the decline among men has been steeper compared with women. Further, in women born in the 1950s to 1960s, the incidence has actually increased and cannot be fully explained by sex differences in smoking behavior (Jemal, et al. N Engl J Med. 2018;378:1999). Data suggest that women may be more susceptible to the harmful effects of tobacco and that the biology of LC may be different in women. In addition, LC in nonsmokers is more likely to occur in women.

LC is the leading cause of cancer death in both women and men worldwide, but the dramatic rise in the mortality rate from LC in women was qualified as a “full blown epidemic” in the Surgeon General’s 2001 Women and Smoking report.

The benefits of lung cancer screening (LCS) in the National Lung Screening Trial (NLST) were higher in women than in men and significantly greater in the subset of women (16%) that entered the Nelson trial – reduction in 10-year LC mortality of 61% vs. 26% in men (De Koning, et al. J Thorac Oncol. 2018;13[10]: suppl S185. Abstract PL02.05). A retrospective review of patients diagnosed with LC between 2005 and 2011 showed that only 37% of women vs. 50% of men met LCS criteria (Wang, et al. JAMA 2015;313[8]:853).

Lung cancer needs to be recognized as an important women’s health issue, and there is need for continued attention to sex differences in LC risk, LCS criteria, and outcomes.

Anne Gonzalez, MD, FCCP

Steering Committee Member

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (ARTIs) include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common cause of ambulatory care visits, accounting for almost 120 million, or about 10% of all visits, per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D protects against ARTIs, but only in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N=10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI, and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR] = 0.88; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25-hydroxyvitamin D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or vitamin D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (ARTIs) include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common cause of ambulatory care visits, accounting for almost 120 million, or about 10% of all visits, per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D protects against ARTIs, but only in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N=10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI, and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR] = 0.88; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25-hydroxyvitamin D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or vitamin D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (ARTIs) include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common cause of ambulatory care visits, accounting for almost 120 million, or about 10% of all visits, per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D protects against ARTIs, but only in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N=10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI, and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR] = 0.88; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25-hydroxyvitamin D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or vitamin D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

The mean number of office visits for otitis media in children younger than 5 years dropped significantly after the introduction of the 13-valent pneumococcal conjugate vaccine, according to findings published in the International Journal of Pediatric Otorhinolaryngology.

KatarzynaBialasiewicz/Thinkstock

Previous studies have shown that more than half of children with otitis media (OM) have serotypes included in the PCV7 vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F), wrote Xiaofeng Zhou, MD, of Pfizer, New York, and colleagues.

To assess the impact of PCV13, with the additional serotypes 1, 3, 5, 6A, 7F, and 19A, the researchers analyzed data from the U.S. National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey for three time periods: pre-PCV7 (1997-1999), after the introduction of PCV7 (2001-2009), and after the introduction of PCV13 (2011-2013).

Between the pre-PCV7 and PCV13 time periods, the researchers found significant reductions in the mean rates of OM visits of 48% and 41% among children younger than 2 years and younger than 5 years, respectively; reductions were 24% and 22%, respectively, when comparing PCV13 and PCV7. Ambulatory care visits for skin rash and trauma were not significantly different among the study periods.

Comparing the PCV7 and PCV13 time periods, the mean number of OM visits per 100 children declined from 84 to 64 per 100 children younger than 2 years, 41 to 34 per 100 children between ages 2 and 5 years, and from 59 to 46 per 100 children younger than 5 years.

The study findings were limited by several factors including the use of an ecologic study design, which was chosen to help reduce selection bias, but that did not show evidence of the field effectiveness of the PCV13 vaccine. Another limitation was the potential misclassification of patients with OM given clinician variability in diagnostic criteria, the researchers noted.

“Our results in this study, while not providing direct evidence of causality, nonetheless suggest a significant and positive impact of the PCV13 vaccination program on otitis media for children less than 5 years of age in the U.S., with further reductions in OM visits observed in PCV13 period following a decade of PCV7 use,” Dr. Zhou and associates said.

The investigators are employed by Pfizer, which funded the study.

SOURCE: Zhou X et al. Int J Pediatr Otorhinolaryngol. 2019 Apr. 119:96-102.

The mean number of office visits for otitis media in children younger than 5 years dropped significantly after the introduction of the 13-valent pneumococcal conjugate vaccine, according to findings published in the International Journal of Pediatric Otorhinolaryngology.

KatarzynaBialasiewicz/Thinkstock

Previous studies have shown that more than half of children with otitis media (OM) have serotypes included in the PCV7 vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F), wrote Xiaofeng Zhou, MD, of Pfizer, New York, and colleagues.

To assess the impact of PCV13, with the additional serotypes 1, 3, 5, 6A, 7F, and 19A, the researchers analyzed data from the U.S. National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey for three time periods: pre-PCV7 (1997-1999), after the introduction of PCV7 (2001-2009), and after the introduction of PCV13 (2011-2013).

Between the pre-PCV7 and PCV13 time periods, the researchers found significant reductions in the mean rates of OM visits of 48% and 41% among children younger than 2 years and younger than 5 years, respectively; reductions were 24% and 22%, respectively, when comparing PCV13 and PCV7. Ambulatory care visits for skin rash and trauma were not significantly different among the study periods.

Comparing the PCV7 and PCV13 time periods, the mean number of OM visits per 100 children declined from 84 to 64 per 100 children younger than 2 years, 41 to 34 per 100 children between ages 2 and 5 years, and from 59 to 46 per 100 children younger than 5 years.

The study findings were limited by several factors including the use of an ecologic study design, which was chosen to help reduce selection bias, but that did not show evidence of the field effectiveness of the PCV13 vaccine. Another limitation was the potential misclassification of patients with OM given clinician variability in diagnostic criteria, the researchers noted.

“Our results in this study, while not providing direct evidence of causality, nonetheless suggest a significant and positive impact of the PCV13 vaccination program on otitis media for children less than 5 years of age in the U.S., with further reductions in OM visits observed in PCV13 period following a decade of PCV7 use,” Dr. Zhou and associates said.

The investigators are employed by Pfizer, which funded the study.

SOURCE: Zhou X et al. Int J Pediatr Otorhinolaryngol. 2019 Apr. 119:96-102.

The mean number of office visits for otitis media in children younger than 5 years dropped significantly after the introduction of the 13-valent pneumococcal conjugate vaccine, according to findings published in the International Journal of Pediatric Otorhinolaryngology.

KatarzynaBialasiewicz/Thinkstock

Previous studies have shown that more than half of children with otitis media (OM) have serotypes included in the PCV7 vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F), wrote Xiaofeng Zhou, MD, of Pfizer, New York, and colleagues.

To assess the impact of PCV13, with the additional serotypes 1, 3, 5, 6A, 7F, and 19A, the researchers analyzed data from the U.S. National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey for three time periods: pre-PCV7 (1997-1999), after the introduction of PCV7 (2001-2009), and after the introduction of PCV13 (2011-2013).

Between the pre-PCV7 and PCV13 time periods, the researchers found significant reductions in the mean rates of OM visits of 48% and 41% among children younger than 2 years and younger than 5 years, respectively; reductions were 24% and 22%, respectively, when comparing PCV13 and PCV7. Ambulatory care visits for skin rash and trauma were not significantly different among the study periods.

Comparing the PCV7 and PCV13 time periods, the mean number of OM visits per 100 children declined from 84 to 64 per 100 children younger than 2 years, 41 to 34 per 100 children between ages 2 and 5 years, and from 59 to 46 per 100 children younger than 5 years.

The study findings were limited by several factors including the use of an ecologic study design, which was chosen to help reduce selection bias, but that did not show evidence of the field effectiveness of the PCV13 vaccine. Another limitation was the potential misclassification of patients with OM given clinician variability in diagnostic criteria, the researchers noted.

“Our results in this study, while not providing direct evidence of causality, nonetheless suggest a significant and positive impact of the PCV13 vaccination program on otitis media for children less than 5 years of age in the U.S., with further reductions in OM visits observed in PCV13 period following a decade of PCV7 use,” Dr. Zhou and associates said.

The investigators are employed by Pfizer, which funded the study.

SOURCE: Zhou X et al. Int J Pediatr Otorhinolaryngol. 2019 Apr. 119:96-102.

A 63-year-old woman with a history of hypertension presents to the emergency department (ED) with acute-onset shortness of breath and pleuritic chest pain after traveling across the country for a work conference. She has no history of cancer, liver disease, or renal disease. Her blood pressure is 140/80 mm Hg, and her heart rate, 90 beats/min. You diagnose an acute PE in this patient and start anticoagulation. Should you admit her to the hospital to decrease morbidity and mortality?

According to the CDC, venous thromboembolism (VTE) affects about 900,000 people each year, and about 60,000 to 100,000 of these patients die annually.² Pulmonary embolism is the third leading cause of death from cardiovascular disease, following heart attack and stroke.³ Prompt diagnosis and treatment with systemic anticoagulation improves patient outcomes and decreases the risk for long-term complications.

The 2016 American College of Chest Physicians (CHEST) guideline on antithrombotic therapy for VTE recommends home treatment or early discharge over standard discharge (after the first 5 days of treatment) for patients who meet the following clinical criteria: “clinically stable with good cardiopulmonary reserve; no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (ie, < 70,000/mm³); expected to be compliant with treatment; and feels well enough to be treated at home.”³

The guideline states that various clinical decision tools, such as the Pulmonary Embolism Severity Index (PESI), can aid in identifying low-risk patients to be considered for treatment at home. The PESI uses age, gender, vital signs, mental status, and a history of cancer, lung, and cardiac disease to stratify patients by risk.⁴

A systematic review of 1 randomized controlled trial (RCT) and 7 observational studies found that in low-risk patients, outpatient treatment was as safe as inpatient treatment.⁵ This more recent study determines the net clinical benefit of hospitalized versus outpatient management in a wider range of patients with acute PE, regardless of initial risk.¹

STUDY SUMMARY

Hospitalization confers no benefit to stable PE patients

This retrospective, propensity-matched cohort study compared rates of adverse events in 1127 patients with acute PE managed in the hospital versus outpatient setting.¹ Patients were classified as outpatients if they were discharged from the ED or discharged from the hospital within 48 hours of admission. Patients were included if a symptomatic acute PE was diagnosed via CT or high-probability ventilation-perfusion scan and excluded if they were younger than 19, were diagnosed with a PE during hospitalization, had chronic PE, or were hemodynamically unstable, among other factors. The investigators calculated PESI scores for all patients.

Propensity scores matched patients on 28 characteristics and known risk factors for adverse events to ensure the groups were similar. The primary outcome was rate of adverse events, including recurrent VTE, major bleeding, or death at 14 days. The secondary outcome included rates of the above during the 3-month follow-up period.

Continue to: Of the 1127 eligible patients...

Of the 1127 eligible patients, 1081 were included in the matched cohort, with 576 (53%) treated as hospitalized patients and 505 (47%) treated as outpatients. The mean age of the matched cohorts was 63.2 years for the inpatient group and 63.6 years for the outpatient group. Overall, the cohorts were well matched.

The 14-day rate of adverse events was higher in hospitalized patients than in outpatients (13% vs 3.3%; odds ratio [OR], 5.07), with each of the adverse events that made up the primary outcome occurring more frequently in the hospitalized group (see Table). The rate of adverse events at 3 months was also greater for hospitalized patients compared with outpatients (21.7% vs 6.9%; OR, 4.9). The results remained similar for high-risk patients (Class III-V) based on their PESI score.

WHAT’S NEW

Higher rate of adverse events in inpatients

This trial supports the CHEST guideline recommendations to manage hemodynamically stable patients with acute PE as outpatients.³ It adds to the conversation by demonstrating higher rates of adverse events with hospitalization, even in high-risk subgroups (PESI Class III-V).

CAVEATS

Good study, but it wasn’t an RCT

While this is a well-designed cohort study, it is not an RCT. This study defined outpatient management as patients discharged from the ED or hospitalized for < 48 hours. However, only 59 of the 544 patients in the outpatient group were early hospital discharges; the rest were never admitted. Finally, a specialized thrombosis clinic followed up with the patients within 24 hours of discharge, and patients had telephone access to specialized health care professionals; such organization of care contributed to the safe outpatient management of these PE patients.

CHALLENGES TO IMPLEMENTATION

Insurance coverage may present an issue

Medication coverage of direct oral anticoagulants and low-molecular-weight heparin may present a barrier to patients treated in the outpatient setting who have no insurance or are insured by certain carriers.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[12]:777-779).

A 63-year-old woman with a history of hypertension presents to the emergency department (ED) with acute-onset shortness of breath and pleuritic chest pain after traveling across the country for a work conference. She has no history of cancer, liver disease, or renal disease. Her blood pressure is 140/80 mm Hg, and her heart rate, 90 beats/min. You diagnose an acute PE in this patient and start anticoagulation. Should you admit her to the hospital to decrease morbidity and mortality?

According to the CDC, venous thromboembolism (VTE) affects about 900,000 people each year, and about 60,000 to 100,000 of these patients die annually.² Pulmonary embolism is the third leading cause of death from cardiovascular disease, following heart attack and stroke.³ Prompt diagnosis and treatment with systemic anticoagulation improves patient outcomes and decreases the risk for long-term complications.

The 2016 American College of Chest Physicians (CHEST) guideline on antithrombotic therapy for VTE recommends home treatment or early discharge over standard discharge (after the first 5 days of treatment) for patients who meet the following clinical criteria: “clinically stable with good cardiopulmonary reserve; no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (ie, < 70,000/mm³); expected to be compliant with treatment; and feels well enough to be treated at home.”³

The guideline states that various clinical decision tools, such as the Pulmonary Embolism Severity Index (PESI), can aid in identifying low-risk patients to be considered for treatment at home. The PESI uses age, gender, vital signs, mental status, and a history of cancer, lung, and cardiac disease to stratify patients by risk.⁴

A systematic review of 1 randomized controlled trial (RCT) and 7 observational studies found that in low-risk patients, outpatient treatment was as safe as inpatient treatment.⁵ This more recent study determines the net clinical benefit of hospitalized versus outpatient management in a wider range of patients with acute PE, regardless of initial risk.¹

STUDY SUMMARY

Hospitalization confers no benefit to stable PE patients

This retrospective, propensity-matched cohort study compared rates of adverse events in 1127 patients with acute PE managed in the hospital versus outpatient setting.¹ Patients were classified as outpatients if they were discharged from the ED or discharged from the hospital within 48 hours of admission. Patients were included if a symptomatic acute PE was diagnosed via CT or high-probability ventilation-perfusion scan and excluded if they were younger than 19, were diagnosed with a PE during hospitalization, had chronic PE, or were hemodynamically unstable, among other factors. The investigators calculated PESI scores for all patients.

Propensity scores matched patients on 28 characteristics and known risk factors for adverse events to ensure the groups were similar. The primary outcome was rate of adverse events, including recurrent VTE, major bleeding, or death at 14 days. The secondary outcome included rates of the above during the 3-month follow-up period.

Continue to: Of the 1127 eligible patients...

Of the 1127 eligible patients, 1081 were included in the matched cohort, with 576 (53%) treated as hospitalized patients and 505 (47%) treated as outpatients. The mean age of the matched cohorts was 63.2 years for the inpatient group and 63.6 years for the outpatient group. Overall, the cohorts were well matched.

The 14-day rate of adverse events was higher in hospitalized patients than in outpatients (13% vs 3.3%; odds ratio [OR], 5.07), with each of the adverse events that made up the primary outcome occurring more frequently in the hospitalized group (see Table). The rate of adverse events at 3 months was also greater for hospitalized patients compared with outpatients (21.7% vs 6.9%; OR, 4.9). The results remained similar for high-risk patients (Class III-V) based on their PESI score.

WHAT’S NEW

Higher rate of adverse events in inpatients

This trial supports the CHEST guideline recommendations to manage hemodynamically stable patients with acute PE as outpatients.³ It adds to the conversation by demonstrating higher rates of adverse events with hospitalization, even in high-risk subgroups (PESI Class III-V).

CAVEATS

Good study, but it wasn’t an RCT

While this is a well-designed cohort study, it is not an RCT. This study defined outpatient management as patients discharged from the ED or hospitalized for < 48 hours. However, only 59 of the 544 patients in the outpatient group were early hospital discharges; the rest were never admitted. Finally, a specialized thrombosis clinic followed up with the patients within 24 hours of discharge, and patients had telephone access to specialized health care professionals; such organization of care contributed to the safe outpatient management of these PE patients.

CHALLENGES TO IMPLEMENTATION

Insurance coverage may present an issue

Medication coverage of direct oral anticoagulants and low-molecular-weight heparin may present a barrier to patients treated in the outpatient setting who have no insurance or are insured by certain carriers.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[12]:777-779).

A 63-year-old woman with a history of hypertension presents to the emergency department (ED) with acute-onset shortness of breath and pleuritic chest pain after traveling across the country for a work conference. She has no history of cancer, liver disease, or renal disease. Her blood pressure is 140/80 mm Hg, and her heart rate, 90 beats/min. You diagnose an acute PE in this patient and start anticoagulation. Should you admit her to the hospital to decrease morbidity and mortality?

According to the CDC, venous thromboembolism (VTE) affects about 900,000 people each year, and about 60,000 to 100,000 of these patients die annually.² Pulmonary embolism is the third leading cause of death from cardiovascular disease, following heart attack and stroke.³ Prompt diagnosis and treatment with systemic anticoagulation improves patient outcomes and decreases the risk for long-term complications.

The 2016 American College of Chest Physicians (CHEST) guideline on antithrombotic therapy for VTE recommends home treatment or early discharge over standard discharge (after the first 5 days of treatment) for patients who meet the following clinical criteria: “clinically stable with good cardiopulmonary reserve; no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (ie, < 70,000/mm³); expected to be compliant with treatment; and feels well enough to be treated at home.”³

The guideline states that various clinical decision tools, such as the Pulmonary Embolism Severity Index (PESI), can aid in identifying low-risk patients to be considered for treatment at home. The PESI uses age, gender, vital signs, mental status, and a history of cancer, lung, and cardiac disease to stratify patients by risk.⁴

A systematic review of 1 randomized controlled trial (RCT) and 7 observational studies found that in low-risk patients, outpatient treatment was as safe as inpatient treatment.⁵ This more recent study determines the net clinical benefit of hospitalized versus outpatient management in a wider range of patients with acute PE, regardless of initial risk.¹

STUDY SUMMARY

Hospitalization confers no benefit to stable PE patients

This retrospective, propensity-matched cohort study compared rates of adverse events in 1127 patients with acute PE managed in the hospital versus outpatient setting.¹ Patients were classified as outpatients if they were discharged from the ED or discharged from the hospital within 48 hours of admission. Patients were included if a symptomatic acute PE was diagnosed via CT or high-probability ventilation-perfusion scan and excluded if they were younger than 19, were diagnosed with a PE during hospitalization, had chronic PE, or were hemodynamically unstable, among other factors. The investigators calculated PESI scores for all patients.

Propensity scores matched patients on 28 characteristics and known risk factors for adverse events to ensure the groups were similar. The primary outcome was rate of adverse events, including recurrent VTE, major bleeding, or death at 14 days. The secondary outcome included rates of the above during the 3-month follow-up period.

Continue to: Of the 1127 eligible patients...

Of the 1127 eligible patients, 1081 were included in the matched cohort, with 576 (53%) treated as hospitalized patients and 505 (47%) treated as outpatients. The mean age of the matched cohorts was 63.2 years for the inpatient group and 63.6 years for the outpatient group. Overall, the cohorts were well matched.

The 14-day rate of adverse events was higher in hospitalized patients than in outpatients (13% vs 3.3%; odds ratio [OR], 5.07), with each of the adverse events that made up the primary outcome occurring more frequently in the hospitalized group (see Table). The rate of adverse events at 3 months was also greater for hospitalized patients compared with outpatients (21.7% vs 6.9%; OR, 4.9). The results remained similar for high-risk patients (Class III-V) based on their PESI score.

WHAT’S NEW

Higher rate of adverse events in inpatients

This trial supports the CHEST guideline recommendations to manage hemodynamically stable patients with acute PE as outpatients.³ It adds to the conversation by demonstrating higher rates of adverse events with hospitalization, even in high-risk subgroups (PESI Class III-V).

CAVEATS

Good study, but it wasn’t an RCT

While this is a well-designed cohort study, it is not an RCT. This study defined outpatient management as patients discharged from the ED or hospitalized for < 48 hours. However, only 59 of the 544 patients in the outpatient group were early hospital discharges; the rest were never admitted. Finally, a specialized thrombosis clinic followed up with the patients within 24 hours of discharge, and patients had telephone access to specialized health care professionals; such organization of care contributed to the safe outpatient management of these PE patients.

CHALLENGES TO IMPLEMENTATION

Insurance coverage may present an issue

Medication coverage of direct oral anticoagulants and low-molecular-weight heparin may present a barrier to patients treated in the outpatient setting who have no insurance or are insured by certain carriers.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[12]:777-779).

Yes, but with caution. Multiple randomized controlled trials showed that procalcitonin testing can help guide antibiotic management in a variety of clinical scenarios including sepsis, respiratory tract infection, and exacerbation of chronic obstructive pulmonary disease (COPD), and that procalcitonin guidance led to less antibiotic use with either unchanged or better outcomes. Moreover, observational studies have shown high negative predictive values for procalcitonin testing in other clinical situations such as bacteremia and bacterial meningitis, allowing clinicians to rule out these diagnoses if the clinical probability is low or moderate.

Nonetheless, clinical judgment must be exercised to consider the possibility of false- positive and false-negative results, especially if clinical suspicion for bacterial infection is high.

A RESPONSE TO BACTERIAL TOXIN

Procalcitonin is a peptide precursor of calcitonin that is produced by C cells of the thyroid and by neuroendocrine cells of the lung and intestine in response to bacterial toxin. In contrast, procalcitonin levels are down-regulated in viral infection.

Levels of procalcitonin increase 6 to 12 hours after stimulation, and the half-life is roughly 24 hours.¹ This suggests levels should decrease by one-half daily if an infection is controlled and is responding to therapy (assuming normal clearance).

The test costs about $25, with a turnaround time of 20 to 60 minutes, or longer at institutions that send the test out or run the tests in batches.

Point-of-care procalcitonin testing is emerging but not yet commercially available in the United States. Despite extensive observational studies and randomized controlled trials over the past 20 years, procalcitonin’s physiologic role remains unclear. The large body of evidence of the clinical utility of procalcitonin measurement has been summarized in several meta-analyses in different diseases.

PROCALCITONIN TESTING IN SEPSIS

Trials of procalcitonin testing have had slightly different inclusion criteria that commonly overlap with similar diagnoses. Sepsis is the broadest cohort studied.

The Procalcitonin to Reduce Antibiotic Treatments in Acutely Ill Patients (PRORATA) trial² randomized 621 patients admitted to the intensive care unit (ICU) with suspected bacterial infections to antibiotic therapy guided by procalcitonin concentrations or to antibiotic therapy based on current guidelines. The source of infection varied, but 73% of patients had pulmonary infections.The procalcitonin algorithm was as follows:

• Starting antibiotics was discouraged if the procalcitonin concentration was less than 0.5 ng/mL, and strongly discouraged if less than 0.25 ng/mL
• Starting antibiotics was encouraged if the concentration was 0.5 ng/mL or higher, and strongly encouraged if 1 ng/mL or higher
• Stopping antibiotics was encouraged if the concentration dropped by at least 80% from the peak level or to a level greater than or equal to 0.25 ng/mL; stopping was strongly encouraged if the concentration fell below 0.25 ng/mL.

There was also guidance to change antibiotics if procalcitonin increased on therapy and was above 0.5 ng/mL.

Although the study physicians generally followed the algorithm, they were allowed to override it based on clinical judgment. The main results were that the number of days without antibiotics was higher in the procalcitonin group than in the controls (14.3 vs 11.6 days), with no other statistically significant difference between groups. These findings supported the idea that procalcitonin can guide clinicians to safely “deprescribe” antibiotics.

The Stop Antibiotics on Guidance of Procalcitonin Study (SAPS),³ published in 2016, was a larger trial with similar design, in 1,575 patients admitted to the ICU with suspected infection. Antibiotic use was less and the 28-day mortality rate was lower with procalcitonin guidance: 20% vs 25% in the intention-to-treat analysis.

 

 

ACUTE RESPIRATORY TRACT INFECTION

The Procalcitonin Guided Antibiotic Therapy and Hospitalisation in Patients With Lower Respiratory Tract Infections (ProHOSP) trial⁴ randomized 1,381 patients to antibiotic therapy guided by procalcitonin levels or standard guidelines. Most patients had community-acquired pneumonia, while the rest had exacerbations of COPD, acute bronchitis, or other lower respiratory tract infections.

In the study algorithm, starting or continuing antibiotics was discouraged if procalcitonin levels were 0.25 ng/mL or less, and strongly discouraged if less than 0.1 ng/mL. Starting or continuing antibiotics was encouraged if levels were greater than 0.25 ng/mL, and strongly encouraged if greater than 0.5 ng/mL.

The algorithm recommended stopping antibiotics if procalcitonin levels fell below 0.25 ng/mL or decreased by 80%, and strongly recommended stopping them if procalcitonin fell below 0.1 ng/mL or decreased by 90%.

The treating physician could override the algorithm if the patient was unstable, was in an ICU, or had Legionella infection.

Antibiotic use was less in the procalcitonin-guided arm (75.4% vs 87.7%; mean duration 5.7 days vs 8.7 days), as was the rate of adverse effects from antibiotics (19.8% vs 28.1%). Rates of recurrence or rehospitalization were also lower with procalcitonin guidance (3.7% vs 6.5%), presumably because of fewer antibiotic-related side effects or better diagnostic accuracy. Rates of death and ICU admission were similar in the 2 groups. These findings were similar to those of PRORATA and SAPS, demonstrating that guidance with procalcitonin levels decreased antibiotic utilization, with other outcomes either improved or unchanged.

Schuetz et al,⁵ in a 2018 meta-analysis, collected data on 6,708 patients from 26 trials in 12 countries and found that procalcitonin guidance decreased antibiotic exposure by 2.4 days and reduced the rate of antibiotic-related side effects (16% vs 22%). Although there was skepticism about the mortality benefit reported in the SAPS trial, a similar mortality benefit was found in this meta-analysis (30-day mortality rates were 9% vs 10%), suggesting that measuring procalcitonin not only reduces unnecessary antibiotic exposure, but also saves lives.

Although decreasing antibiotic exposure may not confer a survival benefit, procalcitonin guidance likely clarifies the diagnosis and thus expedites proper treatment in patients with sepsis-like syndromes that are actually due to a noninfectious pathology (eg, pulmonary embolism, myocardial infarction, adrenal insufficiency).

Negative findings in ProACT

The Procalcitonin Antibiotic Consensus Trial (ProACT)⁶ subsequently reported findings discordant with those above but was flawed in that adherence to the procalcitonin guideline by physicians was only 62% in the subgroup of patients with low procalcitonin results, which accounted for almost 90% of patients. Overall adherence by physicians to the procalcitonin guideline was 65%, much lower than in other trials (ProHOSP had over 90% adherence).⁴ Further, ProACT was done in American centers unfamiliar with procalcitonin, and it seems they did not trust low procalcitonin values as a reason to stop or avoid antibiotics.

ACUTE EXACERBATIONS OF COPD

Multiple small randomized controlled trials and subgroups of larger studies like ProHOSP have studied the use of procalcitonin in acute exacerbations of COPD. Most studies used a design similar to the algorithm in ProHOSP.

Mathioudakis et al,⁷ in a meta-analysis of 8 trials with a total of 1,062 patients with acute exacerbation of COPD, found that with procalcitonin guidance, prescription of antibiotics on admission decreased by almost one-half, and courses of antibiotics were approximately 4 days shorter without any statistically significant difference in rates of treatment failure, length of hospital stay, recurrence, rehospitalization, or overall mortality.

However, the quality of the studies included in the meta-analysis was deemed only low to moderate, and thus the authors concluded, “Procalcitonin-based protocols appear to be clinically effective; however, confirmatory trials with rigorous methodology are required.”⁷ Nonetheless, given the lack of data supporting current practices for patient selection for antibiotics in COPD exacerbations, a strategy involving procalcitonin seems to be reasonable.

 

 

BACTEREMIA

Observational studies from as far as back as 1999 have examined the association of procalcitonin levels with bacteremia. The study designs were generally similar, with procalcitonin levels checked at time of blood culture, mostly in emergency rooms, and the procalcitonin value correlated with blood culture results. The general conclusion has been that procalcitonin has diagnostic value in ruling out bacteremia but should be used in the context of pretest probability rather than in isolation.

Hattori et al⁸ performed one of the largest studies, in 1,331 patients, using a procalcitonin level cutoff of 0.9 ng/mL. The sensitivity was 72% and specificity was 69%, which are not impressive; however, the negative predictive value was 95%, and even higher at lower cutoff values. Further, procalcitonin was significantly better at predicting bacteremia than either the white blood cell count or C-reactive protein level, with the latter two being hardly better than random chance.

Hoeboer et al⁹ performed a meta-analysis of various studies with a total of 16,514 patients. Using a cutoff of 0.5 ng/mL, they reported a sensitivity of 76% and a specificity of 69% with a negative predictive value of 97% in emergency rooms, 95% on regular wards, and 98% in ICUs. The high negative predictive value of procalcitonin can allow clinicians to stratify bacteremia risk to determine which patients need blood cultures, which in turn may help clinicians order blood cultures more appropriately and avoid unnecessary costs, delays, and harms associated with false-positive results, such as additional visits, additional testing, and unnecessary use of antibiotics.

MENINGITIS

As with bacteremia, observational studies have reported fairly high negative predictive values for procalcitonin in bacterial meningitis. The correlation is not surprising, given that most cases of bacterial meningitis occur due to hematogenous dissemination.

A 2015 meta-analysis of 9 studies and 725 patients reported a pooled sensitivity of 90%, specificity 90%, positive likelihood ratio 27.3, and negative likelihood ratio 0.13.¹⁰ Cutoffs for procalcitonin levels varied, but the most common value was 0.5 ng/mL. The authors also noted that the diagnostic utility of procalcitonin was far superior to C-reactive protein in this scenario, concluding that serum procalcitonin is a highly accurate test to distinguish between bacterial and viral causes in suspected meningitis.¹⁰

OTHER CLINICAL APPLICATIONS

Postoperative infection

Small studies have assessed procalcitonin as a marker to rule out postoperative infections,^11,12 but the heterogeneity of study designs and populations makes it difficult to combine the studies for meta-analysis. Nevertheless, the general trend is that there may be a role for procalcitonin, and that procalcitonin has better diagnostic yield than the white blood cell count or C-reactive protein level. The optimal cutoff depends on the surgery, since a small elevation in procalcitonin can be expected with the stress of surgery; and since the degree of elevation varies with type of surgery, the result must be interpreted with caution.

Malignancy

In malignancy-associated conditions such as neutropenic fever and tumor fever, the clinical utility of procalcitonin is somewhat diminished, as malignancy can cause elevated procalcitonin levels (especially in metastatic disease), but a low concentration still has a fair negative predictive value (approximately 90%) for bloodstream infections.¹³

A retrospective study suggested that the ratio of procalcitonin to C-reactive protein could improve diagnostic accuracy in patients with malignancies, presumably because an elevation of procalcitonin out of proportion to elevation in C-reactive protein favored a bacterial infection rather than nonspecific inflammation related to malignancy.¹⁴

Cardiac syndromes

In cardiac syndromes, dyspnea and abnormal chest imaging may make it difficult to exclude respiratory infections. Schuetz et al¹⁵ reviewed the potential value of procalcitonin testing in a variety of cardiac disorders, especially in acute cardiovascular conditions whose presentation resembles that of sepsis or acute respiratory tract infection. They concluded it may have a role in diagnosis and prognosis in these settings, as well as guiding drug therapy.

Localized infections

Though localized infections such as cystitis, cellulitis, and osteomyelitis often do not affect procalcitonin levels, the test may help assess illness severity and rule out associated bacteremia.

One study found that a low procalcitonin level was insufficient to rule out urinary tract infection, but procalcitonin levels predicted bacteremia better than any other variable or combination of variables; moreover, procalcitonin had a negative predictive value as high as 97% for ruling out bacteremia associated with urinary tract infection.¹⁶

 

 

ROLE IN PROGNOSIS

In addition to being a useful marker for diagnosis of bacterial infections, the procalcitonin level has significant prognostic implications, as a high or persistently elevated level correlates with a higher rate of all-cause mortality.¹⁷ The prognostic capability may enhance triage decisions.

Because the procalcitonin level lacks specificity, clinicians need to be aware of noninfectious causes of elevations such as malignancy, surgery, impaired renal function,⁸ and myocardial infarction.¹⁸ In these scenarios, it is important to think critically about the procalcitonin result and consider an adjusted cutoff.

A study of procalcitonin to predict a positive blood culture in patients with renal disease suggested an optimal cutoff value of 1.06 ng/mL for patients with an estimated glomerular filtration rate of 30 to 60 mL/min/1.73m², and a value of 2.50 ng/mL for a rate less than 30 mL/min/1.73m².⁸

In a chronic process like malignancy, the procalcitonin level is usually not markedly elevated. But it can also remain persistently elevated, with no improvement associated with effective antibiotic treatment and no clinical deterioration associated with treatment failure.

Use of procalcitonin and troponin

For some patients, there may be diagnostic uncertainty about interpreting procalcitonin and troponin results, as both plaque-rupture myocardial infarction and demand ischemia from sepsis can cause elevation in both values. In a study of patients with acute myocardial infarction, the procalcitonin level peaked at 3.57 ng/mL and troponin peaked at 60 ng/mL at about 24 hours after admission.¹⁸ This suggests that a troponin-to-procalcitonin ratio may help distinguish acute myocardial infarction from demand ischemia, though the optimal cutoff is unknown.

Both troponin and procalcitonin levels can help rule out acute severe illness (eg, bloodstream infection, acute myocardial infarction). But both can be falsely negative in early presentation or in less severe disease (eg, localized infection, unstable angina), as well as in noninfectious inflammation and nonobstructive myocardial injury.

Both are important prognostic markers. Furthermore, both can be chronically elevated in patients with renal disease, but both still have a characteristic rise and fall in acute disease states. But neither should be used in isolation without information from electrocardiography, other tests, and the clinical context.

CAVEATS AND CHALLENGES

Based on clinical experience and reported studies, procalcitonin testing has proven valuable in the diagnosis, prognosis, and management of a range of diseases, particularly certain infections.

However, procalcitonin testing must be applied cautiously and judiciously. There is a potential for early false-negative results, and false-positive results can occur in conditions such as kidney disease, myocardial infarction, postoperative stress response, and malignancy, though there may be ways to factor these conditions into interpretation of procalcitonin results.

Widespread procalcitonin testing may lead to excessive costs, though the cost for each test is reasonable and probably offset by benefits of diagnostic clarification and decreased use of antibiotics, if appropriately applied.

The primary roles for procalcitonin testing are to rule out infection in patients with low probability of infection and to allow safe early cessation of antibiotic therapy in patients with presumed bacterial infection. Procalcitonin testing can enable providers to stop antibiotics safely, with the general trend showing decreased antibiotic utilization without patient harm. This can result in healthcare cost savings and improved patient outcomes such as decreased length of hospital stay, decreased readmission rates, fewer adverse effects from antibiotics, and possibly improved mortality rates.

Despite the potential benefits from procalcitonin testing, results must be interpreted within the clinical context because a host of factors can affect the values. Extreme values are more useful than intermediate values, which are difficult to interpret and have poor predictive value.

Although all current biomarkers for infection are imperfect, procalcitonin appears to have better diagnostic accuracy than other markers such as the white blood cell count and C-reactive protein in multiple clinical scenarios, and its appropriate use appears to improve important outcomes such as survival.

Yes, but with caution. Multiple randomized controlled trials showed that procalcitonin testing can help guide antibiotic management in a variety of clinical scenarios including sepsis, respiratory tract infection, and exacerbation of chronic obstructive pulmonary disease (COPD), and that procalcitonin guidance led to less antibiotic use with either unchanged or better outcomes. Moreover, observational studies have shown high negative predictive values for procalcitonin testing in other clinical situations such as bacteremia and bacterial meningitis, allowing clinicians to rule out these diagnoses if the clinical probability is low or moderate.

Nonetheless, clinical judgment must be exercised to consider the possibility of false- positive and false-negative results, especially if clinical suspicion for bacterial infection is high.

A RESPONSE TO BACTERIAL TOXIN

Procalcitonin is a peptide precursor of calcitonin that is produced by C cells of the thyroid and by neuroendocrine cells of the lung and intestine in response to bacterial toxin. In contrast, procalcitonin levels are down-regulated in viral infection.

Levels of procalcitonin increase 6 to 12 hours after stimulation, and the half-life is roughly 24 hours.¹ This suggests levels should decrease by one-half daily if an infection is controlled and is responding to therapy (assuming normal clearance).

The test costs about $25, with a turnaround time of 20 to 60 minutes, or longer at institutions that send the test out or run the tests in batches.

Point-of-care procalcitonin testing is emerging but not yet commercially available in the United States. Despite extensive observational studies and randomized controlled trials over the past 20 years, procalcitonin’s physiologic role remains unclear. The large body of evidence of the clinical utility of procalcitonin measurement has been summarized in several meta-analyses in different diseases.

PROCALCITONIN TESTING IN SEPSIS

Trials of procalcitonin testing have had slightly different inclusion criteria that commonly overlap with similar diagnoses. Sepsis is the broadest cohort studied.

The Procalcitonin to Reduce Antibiotic Treatments in Acutely Ill Patients (PRORATA) trial² randomized 621 patients admitted to the intensive care unit (ICU) with suspected bacterial infections to antibiotic therapy guided by procalcitonin concentrations or to antibiotic therapy based on current guidelines. The source of infection varied, but 73% of patients had pulmonary infections.The procalcitonin algorithm was as follows:

• Starting antibiotics was discouraged if the procalcitonin concentration was less than 0.5 ng/mL, and strongly discouraged if less than 0.25 ng/mL
• Starting antibiotics was encouraged if the concentration was 0.5 ng/mL or higher, and strongly encouraged if 1 ng/mL or higher
• Stopping antibiotics was encouraged if the concentration dropped by at least 80% from the peak level or to a level greater than or equal to 0.25 ng/mL; stopping was strongly encouraged if the concentration fell below 0.25 ng/mL.

There was also guidance to change antibiotics if procalcitonin increased on therapy and was above 0.5 ng/mL.

Although the study physicians generally followed the algorithm, they were allowed to override it based on clinical judgment. The main results were that the number of days without antibiotics was higher in the procalcitonin group than in the controls (14.3 vs 11.6 days), with no other statistically significant difference between groups. These findings supported the idea that procalcitonin can guide clinicians to safely “deprescribe” antibiotics.

The Stop Antibiotics on Guidance of Procalcitonin Study (SAPS),³ published in 2016, was a larger trial with similar design, in 1,575 patients admitted to the ICU with suspected infection. Antibiotic use was less and the 28-day mortality rate was lower with procalcitonin guidance: 20% vs 25% in the intention-to-treat analysis.

 

 

ACUTE RESPIRATORY TRACT INFECTION

The Procalcitonin Guided Antibiotic Therapy and Hospitalisation in Patients With Lower Respiratory Tract Infections (ProHOSP) trial⁴ randomized 1,381 patients to antibiotic therapy guided by procalcitonin levels or standard guidelines. Most patients had community-acquired pneumonia, while the rest had exacerbations of COPD, acute bronchitis, or other lower respiratory tract infections.

In the study algorithm, starting or continuing antibiotics was discouraged if procalcitonin levels were 0.25 ng/mL or less, and strongly discouraged if less than 0.1 ng/mL. Starting or continuing antibiotics was encouraged if levels were greater than 0.25 ng/mL, and strongly encouraged if greater than 0.5 ng/mL.

The algorithm recommended stopping antibiotics if procalcitonin levels fell below 0.25 ng/mL or decreased by 80%, and strongly recommended stopping them if procalcitonin fell below 0.1 ng/mL or decreased by 90%.

The treating physician could override the algorithm if the patient was unstable, was in an ICU, or had Legionella infection.

Antibiotic use was less in the procalcitonin-guided arm (75.4% vs 87.7%; mean duration 5.7 days vs 8.7 days), as was the rate of adverse effects from antibiotics (19.8% vs 28.1%). Rates of recurrence or rehospitalization were also lower with procalcitonin guidance (3.7% vs 6.5%), presumably because of fewer antibiotic-related side effects or better diagnostic accuracy. Rates of death and ICU admission were similar in the 2 groups. These findings were similar to those of PRORATA and SAPS, demonstrating that guidance with procalcitonin levels decreased antibiotic utilization, with other outcomes either improved or unchanged.

Schuetz et al,⁵ in a 2018 meta-analysis, collected data on 6,708 patients from 26 trials in 12 countries and found that procalcitonin guidance decreased antibiotic exposure by 2.4 days and reduced the rate of antibiotic-related side effects (16% vs 22%). Although there was skepticism about the mortality benefit reported in the SAPS trial, a similar mortality benefit was found in this meta-analysis (30-day mortality rates were 9% vs 10%), suggesting that measuring procalcitonin not only reduces unnecessary antibiotic exposure, but also saves lives.

Although decreasing antibiotic exposure may not confer a survival benefit, procalcitonin guidance likely clarifies the diagnosis and thus expedites proper treatment in patients with sepsis-like syndromes that are actually due to a noninfectious pathology (eg, pulmonary embolism, myocardial infarction, adrenal insufficiency).

Negative findings in ProACT

The Procalcitonin Antibiotic Consensus Trial (ProACT)⁶ subsequently reported findings discordant with those above but was flawed in that adherence to the procalcitonin guideline by physicians was only 62% in the subgroup of patients with low procalcitonin results, which accounted for almost 90% of patients. Overall adherence by physicians to the procalcitonin guideline was 65%, much lower than in other trials (ProHOSP had over 90% adherence).⁴ Further, ProACT was done in American centers unfamiliar with procalcitonin, and it seems they did not trust low procalcitonin values as a reason to stop or avoid antibiotics.

ACUTE EXACERBATIONS OF COPD

Multiple small randomized controlled trials and subgroups of larger studies like ProHOSP have studied the use of procalcitonin in acute exacerbations of COPD. Most studies used a design similar to the algorithm in ProHOSP.

Mathioudakis et al,⁷ in a meta-analysis of 8 trials with a total of 1,062 patients with acute exacerbation of COPD, found that with procalcitonin guidance, prescription of antibiotics on admission decreased by almost one-half, and courses of antibiotics were approximately 4 days shorter without any statistically significant difference in rates of treatment failure, length of hospital stay, recurrence, rehospitalization, or overall mortality.

However, the quality of the studies included in the meta-analysis was deemed only low to moderate, and thus the authors concluded, “Procalcitonin-based protocols appear to be clinically effective; however, confirmatory trials with rigorous methodology are required.”⁷ Nonetheless, given the lack of data supporting current practices for patient selection for antibiotics in COPD exacerbations, a strategy involving procalcitonin seems to be reasonable.

 

 

BACTEREMIA

Observational studies from as far as back as 1999 have examined the association of procalcitonin levels with bacteremia. The study designs were generally similar, with procalcitonin levels checked at time of blood culture, mostly in emergency rooms, and the procalcitonin value correlated with blood culture results. The general conclusion has been that procalcitonin has diagnostic value in ruling out bacteremia but should be used in the context of pretest probability rather than in isolation.

Hattori et al⁸ performed one of the largest studies, in 1,331 patients, using a procalcitonin level cutoff of 0.9 ng/mL. The sensitivity was 72% and specificity was 69%, which are not impressive; however, the negative predictive value was 95%, and even higher at lower cutoff values. Further, procalcitonin was significantly better at predicting bacteremia than either the white blood cell count or C-reactive protein level, with the latter two being hardly better than random chance.

Hoeboer et al⁹ performed a meta-analysis of various studies with a total of 16,514 patients. Using a cutoff of 0.5 ng/mL, they reported a sensitivity of 76% and a specificity of 69% with a negative predictive value of 97% in emergency rooms, 95% on regular wards, and 98% in ICUs. The high negative predictive value of procalcitonin can allow clinicians to stratify bacteremia risk to determine which patients need blood cultures, which in turn may help clinicians order blood cultures more appropriately and avoid unnecessary costs, delays, and harms associated with false-positive results, such as additional visits, additional testing, and unnecessary use of antibiotics.

MENINGITIS

As with bacteremia, observational studies have reported fairly high negative predictive values for procalcitonin in bacterial meningitis. The correlation is not surprising, given that most cases of bacterial meningitis occur due to hematogenous dissemination.

A 2015 meta-analysis of 9 studies and 725 patients reported a pooled sensitivity of 90%, specificity 90%, positive likelihood ratio 27.3, and negative likelihood ratio 0.13.¹⁰ Cutoffs for procalcitonin levels varied, but the most common value was 0.5 ng/mL. The authors also noted that the diagnostic utility of procalcitonin was far superior to C-reactive protein in this scenario, concluding that serum procalcitonin is a highly accurate test to distinguish between bacterial and viral causes in suspected meningitis.¹⁰

OTHER CLINICAL APPLICATIONS

Postoperative infection

Small studies have assessed procalcitonin as a marker to rule out postoperative infections,^11,12 but the heterogeneity of study designs and populations makes it difficult to combine the studies for meta-analysis. Nevertheless, the general trend is that there may be a role for procalcitonin, and that procalcitonin has better diagnostic yield than the white blood cell count or C-reactive protein level. The optimal cutoff depends on the surgery, since a small elevation in procalcitonin can be expected with the stress of surgery; and since the degree of elevation varies with type of surgery, the result must be interpreted with caution.

Malignancy

In malignancy-associated conditions such as neutropenic fever and tumor fever, the clinical utility of procalcitonin is somewhat diminished, as malignancy can cause elevated procalcitonin levels (especially in metastatic disease), but a low concentration still has a fair negative predictive value (approximately 90%) for bloodstream infections.¹³

A retrospective study suggested that the ratio of procalcitonin to C-reactive protein could improve diagnostic accuracy in patients with malignancies, presumably because an elevation of procalcitonin out of proportion to elevation in C-reactive protein favored a bacterial infection rather than nonspecific inflammation related to malignancy.¹⁴

Cardiac syndromes

In cardiac syndromes, dyspnea and abnormal chest imaging may make it difficult to exclude respiratory infections. Schuetz et al¹⁵ reviewed the potential value of procalcitonin testing in a variety of cardiac disorders, especially in acute cardiovascular conditions whose presentation resembles that of sepsis or acute respiratory tract infection. They concluded it may have a role in diagnosis and prognosis in these settings, as well as guiding drug therapy.

Localized infections

Though localized infections such as cystitis, cellulitis, and osteomyelitis often do not affect procalcitonin levels, the test may help assess illness severity and rule out associated bacteremia.

One study found that a low procalcitonin level was insufficient to rule out urinary tract infection, but procalcitonin levels predicted bacteremia better than any other variable or combination of variables; moreover, procalcitonin had a negative predictive value as high as 97% for ruling out bacteremia associated with urinary tract infection.¹⁶

 

 

ROLE IN PROGNOSIS

In addition to being a useful marker for diagnosis of bacterial infections, the procalcitonin level has significant prognostic implications, as a high or persistently elevated level correlates with a higher rate of all-cause mortality.¹⁷ The prognostic capability may enhance triage decisions.

Because the procalcitonin level lacks specificity, clinicians need to be aware of noninfectious causes of elevations such as malignancy, surgery, impaired renal function,⁸ and myocardial infarction.¹⁸ In these scenarios, it is important to think critically about the procalcitonin result and consider an adjusted cutoff.

A study of procalcitonin to predict a positive blood culture in patients with renal disease suggested an optimal cutoff value of 1.06 ng/mL for patients with an estimated glomerular filtration rate of 30 to 60 mL/min/1.73m², and a value of 2.50 ng/mL for a rate less than 30 mL/min/1.73m².⁸

In a chronic process like malignancy, the procalcitonin level is usually not markedly elevated. But it can also remain persistently elevated, with no improvement associated with effective antibiotic treatment and no clinical deterioration associated with treatment failure.

Use of procalcitonin and troponin

For some patients, there may be diagnostic uncertainty about interpreting procalcitonin and troponin results, as both plaque-rupture myocardial infarction and demand ischemia from sepsis can cause elevation in both values. In a study of patients with acute myocardial infarction, the procalcitonin level peaked at 3.57 ng/mL and troponin peaked at 60 ng/mL at about 24 hours after admission.¹⁸ This suggests that a troponin-to-procalcitonin ratio may help distinguish acute myocardial infarction from demand ischemia, though the optimal cutoff is unknown.

Both troponin and procalcitonin levels can help rule out acute severe illness (eg, bloodstream infection, acute myocardial infarction). But both can be falsely negative in early presentation or in less severe disease (eg, localized infection, unstable angina), as well as in noninfectious inflammation and nonobstructive myocardial injury.

Both are important prognostic markers. Furthermore, both can be chronically elevated in patients with renal disease, but both still have a characteristic rise and fall in acute disease states. But neither should be used in isolation without information from electrocardiography, other tests, and the clinical context.

CAVEATS AND CHALLENGES

Based on clinical experience and reported studies, procalcitonin testing has proven valuable in the diagnosis, prognosis, and management of a range of diseases, particularly certain infections.

However, procalcitonin testing must be applied cautiously and judiciously. There is a potential for early false-negative results, and false-positive results can occur in conditions such as kidney disease, myocardial infarction, postoperative stress response, and malignancy, though there may be ways to factor these conditions into interpretation of procalcitonin results.

Widespread procalcitonin testing may lead to excessive costs, though the cost for each test is reasonable and probably offset by benefits of diagnostic clarification and decreased use of antibiotics, if appropriately applied.

The primary roles for procalcitonin testing are to rule out infection in patients with low probability of infection and to allow safe early cessation of antibiotic therapy in patients with presumed bacterial infection. Procalcitonin testing can enable providers to stop antibiotics safely, with the general trend showing decreased antibiotic utilization without patient harm. This can result in healthcare cost savings and improved patient outcomes such as decreased length of hospital stay, decreased readmission rates, fewer adverse effects from antibiotics, and possibly improved mortality rates.

Despite the potential benefits from procalcitonin testing, results must be interpreted within the clinical context because a host of factors can affect the values. Extreme values are more useful than intermediate values, which are difficult to interpret and have poor predictive value.

Although all current biomarkers for infection are imperfect, procalcitonin appears to have better diagnostic accuracy than other markers such as the white blood cell count and C-reactive protein in multiple clinical scenarios, and its appropriate use appears to improve important outcomes such as survival.

Yes, but with caution. Multiple randomized controlled trials showed that procalcitonin testing can help guide antibiotic management in a variety of clinical scenarios including sepsis, respiratory tract infection, and exacerbation of chronic obstructive pulmonary disease (COPD), and that procalcitonin guidance led to less antibiotic use with either unchanged or better outcomes. Moreover, observational studies have shown high negative predictive values for procalcitonin testing in other clinical situations such as bacteremia and bacterial meningitis, allowing clinicians to rule out these diagnoses if the clinical probability is low or moderate.

Nonetheless, clinical judgment must be exercised to consider the possibility of false- positive and false-negative results, especially if clinical suspicion for bacterial infection is high.

A RESPONSE TO BACTERIAL TOXIN

Procalcitonin is a peptide precursor of calcitonin that is produced by C cells of the thyroid and by neuroendocrine cells of the lung and intestine in response to bacterial toxin. In contrast, procalcitonin levels are down-regulated in viral infection.

Levels of procalcitonin increase 6 to 12 hours after stimulation, and the half-life is roughly 24 hours.¹ This suggests levels should decrease by one-half daily if an infection is controlled and is responding to therapy (assuming normal clearance).

The test costs about $25, with a turnaround time of 20 to 60 minutes, or longer at institutions that send the test out or run the tests in batches.

Point-of-care procalcitonin testing is emerging but not yet commercially available in the United States. Despite extensive observational studies and randomized controlled trials over the past 20 years, procalcitonin’s physiologic role remains unclear. The large body of evidence of the clinical utility of procalcitonin measurement has been summarized in several meta-analyses in different diseases.

PROCALCITONIN TESTING IN SEPSIS

Trials of procalcitonin testing have had slightly different inclusion criteria that commonly overlap with similar diagnoses. Sepsis is the broadest cohort studied.

The Procalcitonin to Reduce Antibiotic Treatments in Acutely Ill Patients (PRORATA) trial² randomized 621 patients admitted to the intensive care unit (ICU) with suspected bacterial infections to antibiotic therapy guided by procalcitonin concentrations or to antibiotic therapy based on current guidelines. The source of infection varied, but 73% of patients had pulmonary infections.The procalcitonin algorithm was as follows:

• Starting antibiotics was discouraged if the procalcitonin concentration was less than 0.5 ng/mL, and strongly discouraged if less than 0.25 ng/mL
• Starting antibiotics was encouraged if the concentration was 0.5 ng/mL or higher, and strongly encouraged if 1 ng/mL or higher
• Stopping antibiotics was encouraged if the concentration dropped by at least 80% from the peak level or to a level greater than or equal to 0.25 ng/mL; stopping was strongly encouraged if the concentration fell below 0.25 ng/mL.

There was also guidance to change antibiotics if procalcitonin increased on therapy and was above 0.5 ng/mL.

Although the study physicians generally followed the algorithm, they were allowed to override it based on clinical judgment. The main results were that the number of days without antibiotics was higher in the procalcitonin group than in the controls (14.3 vs 11.6 days), with no other statistically significant difference between groups. These findings supported the idea that procalcitonin can guide clinicians to safely “deprescribe” antibiotics.

The Stop Antibiotics on Guidance of Procalcitonin Study (SAPS),³ published in 2016, was a larger trial with similar design, in 1,575 patients admitted to the ICU with suspected infection. Antibiotic use was less and the 28-day mortality rate was lower with procalcitonin guidance: 20% vs 25% in the intention-to-treat analysis.

 

 

ACUTE RESPIRATORY TRACT INFECTION

The Procalcitonin Guided Antibiotic Therapy and Hospitalisation in Patients With Lower Respiratory Tract Infections (ProHOSP) trial⁴ randomized 1,381 patients to antibiotic therapy guided by procalcitonin levels or standard guidelines. Most patients had community-acquired pneumonia, while the rest had exacerbations of COPD, acute bronchitis, or other lower respiratory tract infections.

In the study algorithm, starting or continuing antibiotics was discouraged if procalcitonin levels were 0.25 ng/mL or less, and strongly discouraged if less than 0.1 ng/mL. Starting or continuing antibiotics was encouraged if levels were greater than 0.25 ng/mL, and strongly encouraged if greater than 0.5 ng/mL.

The algorithm recommended stopping antibiotics if procalcitonin levels fell below 0.25 ng/mL or decreased by 80%, and strongly recommended stopping them if procalcitonin fell below 0.1 ng/mL or decreased by 90%.

The treating physician could override the algorithm if the patient was unstable, was in an ICU, or had Legionella infection.

Antibiotic use was less in the procalcitonin-guided arm (75.4% vs 87.7%; mean duration 5.7 days vs 8.7 days), as was the rate of adverse effects from antibiotics (19.8% vs 28.1%). Rates of recurrence or rehospitalization were also lower with procalcitonin guidance (3.7% vs 6.5%), presumably because of fewer antibiotic-related side effects or better diagnostic accuracy. Rates of death and ICU admission were similar in the 2 groups. These findings were similar to those of PRORATA and SAPS, demonstrating that guidance with procalcitonin levels decreased antibiotic utilization, with other outcomes either improved or unchanged.

Schuetz et al,⁵ in a 2018 meta-analysis, collected data on 6,708 patients from 26 trials in 12 countries and found that procalcitonin guidance decreased antibiotic exposure by 2.4 days and reduced the rate of antibiotic-related side effects (16% vs 22%). Although there was skepticism about the mortality benefit reported in the SAPS trial, a similar mortality benefit was found in this meta-analysis (30-day mortality rates were 9% vs 10%), suggesting that measuring procalcitonin not only reduces unnecessary antibiotic exposure, but also saves lives.

Although decreasing antibiotic exposure may not confer a survival benefit, procalcitonin guidance likely clarifies the diagnosis and thus expedites proper treatment in patients with sepsis-like syndromes that are actually due to a noninfectious pathology (eg, pulmonary embolism, myocardial infarction, adrenal insufficiency).

Negative findings in ProACT

The Procalcitonin Antibiotic Consensus Trial (ProACT)⁶ subsequently reported findings discordant with those above but was flawed in that adherence to the procalcitonin guideline by physicians was only 62% in the subgroup of patients with low procalcitonin results, which accounted for almost 90% of patients. Overall adherence by physicians to the procalcitonin guideline was 65%, much lower than in other trials (ProHOSP had over 90% adherence).⁴ Further, ProACT was done in American centers unfamiliar with procalcitonin, and it seems they did not trust low procalcitonin values as a reason to stop or avoid antibiotics.

ACUTE EXACERBATIONS OF COPD

Multiple small randomized controlled trials and subgroups of larger studies like ProHOSP have studied the use of procalcitonin in acute exacerbations of COPD. Most studies used a design similar to the algorithm in ProHOSP.

Mathioudakis et al,⁷ in a meta-analysis of 8 trials with a total of 1,062 patients with acute exacerbation of COPD, found that with procalcitonin guidance, prescription of antibiotics on admission decreased by almost one-half, and courses of antibiotics were approximately 4 days shorter without any statistically significant difference in rates of treatment failure, length of hospital stay, recurrence, rehospitalization, or overall mortality.

However, the quality of the studies included in the meta-analysis was deemed only low to moderate, and thus the authors concluded, “Procalcitonin-based protocols appear to be clinically effective; however, confirmatory trials with rigorous methodology are required.”⁷ Nonetheless, given the lack of data supporting current practices for patient selection for antibiotics in COPD exacerbations, a strategy involving procalcitonin seems to be reasonable.

 

 

BACTEREMIA

Observational studies from as far as back as 1999 have examined the association of procalcitonin levels with bacteremia. The study designs were generally similar, with procalcitonin levels checked at time of blood culture, mostly in emergency rooms, and the procalcitonin value correlated with blood culture results. The general conclusion has been that procalcitonin has diagnostic value in ruling out bacteremia but should be used in the context of pretest probability rather than in isolation.

Hattori et al⁸ performed one of the largest studies, in 1,331 patients, using a procalcitonin level cutoff of 0.9 ng/mL. The sensitivity was 72% and specificity was 69%, which are not impressive; however, the negative predictive value was 95%, and even higher at lower cutoff values. Further, procalcitonin was significantly better at predicting bacteremia than either the white blood cell count or C-reactive protein level, with the latter two being hardly better than random chance.

Hoeboer et al⁹ performed a meta-analysis of various studies with a total of 16,514 patients. Using a cutoff of 0.5 ng/mL, they reported a sensitivity of 76% and a specificity of 69% with a negative predictive value of 97% in emergency rooms, 95% on regular wards, and 98% in ICUs. The high negative predictive value of procalcitonin can allow clinicians to stratify bacteremia risk to determine which patients need blood cultures, which in turn may help clinicians order blood cultures more appropriately and avoid unnecessary costs, delays, and harms associated with false-positive results, such as additional visits, additional testing, and unnecessary use of antibiotics.

MENINGITIS

As with bacteremia, observational studies have reported fairly high negative predictive values for procalcitonin in bacterial meningitis. The correlation is not surprising, given that most cases of bacterial meningitis occur due to hematogenous dissemination.

A 2015 meta-analysis of 9 studies and 725 patients reported a pooled sensitivity of 90%, specificity 90%, positive likelihood ratio 27.3, and negative likelihood ratio 0.13.¹⁰ Cutoffs for procalcitonin levels varied, but the most common value was 0.5 ng/mL. The authors also noted that the diagnostic utility of procalcitonin was far superior to C-reactive protein in this scenario, concluding that serum procalcitonin is a highly accurate test to distinguish between bacterial and viral causes in suspected meningitis.¹⁰

OTHER CLINICAL APPLICATIONS

Postoperative infection

Small studies have assessed procalcitonin as a marker to rule out postoperative infections,^11,12 but the heterogeneity of study designs and populations makes it difficult to combine the studies for meta-analysis. Nevertheless, the general trend is that there may be a role for procalcitonin, and that procalcitonin has better diagnostic yield than the white blood cell count or C-reactive protein level. The optimal cutoff depends on the surgery, since a small elevation in procalcitonin can be expected with the stress of surgery; and since the degree of elevation varies with type of surgery, the result must be interpreted with caution.

Malignancy

In malignancy-associated conditions such as neutropenic fever and tumor fever, the clinical utility of procalcitonin is somewhat diminished, as malignancy can cause elevated procalcitonin levels (especially in metastatic disease), but a low concentration still has a fair negative predictive value (approximately 90%) for bloodstream infections.¹³

A retrospective study suggested that the ratio of procalcitonin to C-reactive protein could improve diagnostic accuracy in patients with malignancies, presumably because an elevation of procalcitonin out of proportion to elevation in C-reactive protein favored a bacterial infection rather than nonspecific inflammation related to malignancy.¹⁴

Cardiac syndromes

In cardiac syndromes, dyspnea and abnormal chest imaging may make it difficult to exclude respiratory infections. Schuetz et al¹⁵ reviewed the potential value of procalcitonin testing in a variety of cardiac disorders, especially in acute cardiovascular conditions whose presentation resembles that of sepsis or acute respiratory tract infection. They concluded it may have a role in diagnosis and prognosis in these settings, as well as guiding drug therapy.

Localized infections

Though localized infections such as cystitis, cellulitis, and osteomyelitis often do not affect procalcitonin levels, the test may help assess illness severity and rule out associated bacteremia.

One study found that a low procalcitonin level was insufficient to rule out urinary tract infection, but procalcitonin levels predicted bacteremia better than any other variable or combination of variables; moreover, procalcitonin had a negative predictive value as high as 97% for ruling out bacteremia associated with urinary tract infection.¹⁶

 

 

ROLE IN PROGNOSIS

In addition to being a useful marker for diagnosis of bacterial infections, the procalcitonin level has significant prognostic implications, as a high or persistently elevated level correlates with a higher rate of all-cause mortality.¹⁷ The prognostic capability may enhance triage decisions.

Because the procalcitonin level lacks specificity, clinicians need to be aware of noninfectious causes of elevations such as malignancy, surgery, impaired renal function,⁸ and myocardial infarction.¹⁸ In these scenarios, it is important to think critically about the procalcitonin result and consider an adjusted cutoff.

A study of procalcitonin to predict a positive blood culture in patients with renal disease suggested an optimal cutoff value of 1.06 ng/mL for patients with an estimated glomerular filtration rate of 30 to 60 mL/min/1.73m², and a value of 2.50 ng/mL for a rate less than 30 mL/min/1.73m².⁸

In a chronic process like malignancy, the procalcitonin level is usually not markedly elevated. But it can also remain persistently elevated, with no improvement associated with effective antibiotic treatment and no clinical deterioration associated with treatment failure.

Use of procalcitonin and troponin

For some patients, there may be diagnostic uncertainty about interpreting procalcitonin and troponin results, as both plaque-rupture myocardial infarction and demand ischemia from sepsis can cause elevation in both values. In a study of patients with acute myocardial infarction, the procalcitonin level peaked at 3.57 ng/mL and troponin peaked at 60 ng/mL at about 24 hours after admission.¹⁸ This suggests that a troponin-to-procalcitonin ratio may help distinguish acute myocardial infarction from demand ischemia, though the optimal cutoff is unknown.

Both troponin and procalcitonin levels can help rule out acute severe illness (eg, bloodstream infection, acute myocardial infarction). But both can be falsely negative in early presentation or in less severe disease (eg, localized infection, unstable angina), as well as in noninfectious inflammation and nonobstructive myocardial injury.

Both are important prognostic markers. Furthermore, both can be chronically elevated in patients with renal disease, but both still have a characteristic rise and fall in acute disease states. But neither should be used in isolation without information from electrocardiography, other tests, and the clinical context.

CAVEATS AND CHALLENGES

Based on clinical experience and reported studies, procalcitonin testing has proven valuable in the diagnosis, prognosis, and management of a range of diseases, particularly certain infections.

However, procalcitonin testing must be applied cautiously and judiciously. There is a potential for early false-negative results, and false-positive results can occur in conditions such as kidney disease, myocardial infarction, postoperative stress response, and malignancy, though there may be ways to factor these conditions into interpretation of procalcitonin results.

Widespread procalcitonin testing may lead to excessive costs, though the cost for each test is reasonable and probably offset by benefits of diagnostic clarification and decreased use of antibiotics, if appropriately applied.

The primary roles for procalcitonin testing are to rule out infection in patients with low probability of infection and to allow safe early cessation of antibiotic therapy in patients with presumed bacterial infection. Procalcitonin testing can enable providers to stop antibiotics safely, with the general trend showing decreased antibiotic utilization without patient harm. This can result in healthcare cost savings and improved patient outcomes such as decreased length of hospital stay, decreased readmission rates, fewer adverse effects from antibiotics, and possibly improved mortality rates.

Despite the potential benefits from procalcitonin testing, results must be interpreted within the clinical context because a host of factors can affect the values. Extreme values are more useful than intermediate values, which are difficult to interpret and have poor predictive value.

Although all current biomarkers for infection are imperfect, procalcitonin appears to have better diagnostic accuracy than other markers such as the white blood cell count and C-reactive protein in multiple clinical scenarios, and its appropriate use appears to improve important outcomes such as survival.

MAUI, HAWAII – The incidence of methotrexate pneumonitis has been reported as ranging from 3.5% to 7.6% among patients taking the disease-modifying antirheumatic drug. It’s an estimate that Aryeh Fischer, MD, counters with a one-word response: “Nonsense!”

Bruce Jancin/MDedge News

“There’s just no way that methotrexate is causing that much lung disease,” he declared at the 2019 Rheumatology Winter Clinical Symposium.

Dr. Fischer, a rheumatologist with joint appointments to the divisions of rheumatology and pulmonary sciences and critical care medicine at the University of Colorado at Denver, Aurora, noted that his opinion is considered controversial in the pulmonology world.

“I’m not allowed to talk about methotrexate at lung conferences. They stop you at the gate. They’re convinced in lung circles that methotrexate is the worst drug known to mankind,” he said.

Methotrexate pneumonitis is greatly overdiagnosed, Dr. Fischer explained, because it can be extremely difficult to distinguish from an acute flare of interstitial lung disease.

“My take home on methotrexate lung toxicity is this: I would just say, yes, it can occur, but it’s super rare and most often we’re not really sure that it was methotrexate pneumonitis. The diagnosis is not definitive, it’s exclusionary. We know that patients with interstitial lung disease of all types get acute exacerbations, and in idiopathic pulmonary fibrosis it’s actually the leading cause of mortality,” the rheumatologist said.

He highlighted a meta-analysis of 22 randomized, double-blind clinical trials published in 1990-2013 of methotrexate versus placebo or active comparators in 8,584 RA patients. The Irish investigators of that meta-analysis found that methotrexate was associated with a small albeit statistically significant 10% increase in the risk of all adverse respiratory events and an 11% increase in the risk of respiratory infection. However, patients on methotrexate were not at increased risk of mortality because of lung disease. And not a single case of methotrexate pneumonitis was reported after 2002 (Arthritis Rheumatol. 2014 Apr;66[4]:803-12).

Methotrexate pneumonitis is not dose dependent, nor is it related to treatment duration.

“Just because your patient has been on methotrexate for years does not mean they won’t get methotrexate lung toxicity,” he cautioned. “But this is not a chronic fibrotic interstitial lung disease, this is an acute onset of peripheral infiltrates and ground glass opacifications on chest imaging.”

Bronchoalveolar lavage classically shows a hypersensitivity pneumonitis with lymphocytosis. Transbronchial or surgical lung biopsy may show an organizing pneumonia or airway-based nonnecrotizing granulomas, again indicative of a hypersensitivity reaction.

Because the diagnostic picture is so often cloudy, Dr. Fischer generally tries to avoid methotrexate in patients with moderate or severe interstitial lung disease. “I have the luxury of avoiding it because we have so many great arthritis drugs these days,” he noted.

“That being said, the notion that we’re going to stop methotrexate in an 80-year-old who’s been on it for years and has mild bibasilar fibrotic interstitial lung disease so that her lung doc can sleep better at night is not very helpful for our patients. If the patient is doing well on methotrexate and the interstitial lung disease is mild, I continue [the methotrexate],” Dr. Fischer said.

He reported receiving research grants from Boehringer Ingelheim and Corbus Pharmaceuticals and serving as a consultant to Boehringer Ingelheim and other pharmaceutical companies.

bjancin@mdedge.com

MAUI, HAWAII – The incidence of methotrexate pneumonitis has been reported as ranging from 3.5% to 7.6% among patients taking the disease-modifying antirheumatic drug. It’s an estimate that Aryeh Fischer, MD, counters with a one-word response: “Nonsense!”

Bruce Jancin/MDedge News

“There’s just no way that methotrexate is causing that much lung disease,” he declared at the 2019 Rheumatology Winter Clinical Symposium.

Dr. Fischer, a rheumatologist with joint appointments to the divisions of rheumatology and pulmonary sciences and critical care medicine at the University of Colorado at Denver, Aurora, noted that his opinion is considered controversial in the pulmonology world.

“I’m not allowed to talk about methotrexate at lung conferences. They stop you at the gate. They’re convinced in lung circles that methotrexate is the worst drug known to mankind,” he said.

Methotrexate pneumonitis is greatly overdiagnosed, Dr. Fischer explained, because it can be extremely difficult to distinguish from an acute flare of interstitial lung disease.

“My take home on methotrexate lung toxicity is this: I would just say, yes, it can occur, but it’s super rare and most often we’re not really sure that it was methotrexate pneumonitis. The diagnosis is not definitive, it’s exclusionary. We know that patients with interstitial lung disease of all types get acute exacerbations, and in idiopathic pulmonary fibrosis it’s actually the leading cause of mortality,” the rheumatologist said.

He highlighted a meta-analysis of 22 randomized, double-blind clinical trials published in 1990-2013 of methotrexate versus placebo or active comparators in 8,584 RA patients. The Irish investigators of that meta-analysis found that methotrexate was associated with a small albeit statistically significant 10% increase in the risk of all adverse respiratory events and an 11% increase in the risk of respiratory infection. However, patients on methotrexate were not at increased risk of mortality because of lung disease. And not a single case of methotrexate pneumonitis was reported after 2002 (Arthritis Rheumatol. 2014 Apr;66[4]:803-12).

Methotrexate pneumonitis is not dose dependent, nor is it related to treatment duration.

“Just because your patient has been on methotrexate for years does not mean they won’t get methotrexate lung toxicity,” he cautioned. “But this is not a chronic fibrotic interstitial lung disease, this is an acute onset of peripheral infiltrates and ground glass opacifications on chest imaging.”

Bronchoalveolar lavage classically shows a hypersensitivity pneumonitis with lymphocytosis. Transbronchial or surgical lung biopsy may show an organizing pneumonia or airway-based nonnecrotizing granulomas, again indicative of a hypersensitivity reaction.

Because the diagnostic picture is so often cloudy, Dr. Fischer generally tries to avoid methotrexate in patients with moderate or severe interstitial lung disease. “I have the luxury of avoiding it because we have so many great arthritis drugs these days,” he noted.

“That being said, the notion that we’re going to stop methotrexate in an 80-year-old who’s been on it for years and has mild bibasilar fibrotic interstitial lung disease so that her lung doc can sleep better at night is not very helpful for our patients. If the patient is doing well on methotrexate and the interstitial lung disease is mild, I continue [the methotrexate],” Dr. Fischer said.

He reported receiving research grants from Boehringer Ingelheim and Corbus Pharmaceuticals and serving as a consultant to Boehringer Ingelheim and other pharmaceutical companies.

bjancin@mdedge.com

MAUI, HAWAII – The incidence of methotrexate pneumonitis has been reported as ranging from 3.5% to 7.6% among patients taking the disease-modifying antirheumatic drug. It’s an estimate that Aryeh Fischer, MD, counters with a one-word response: “Nonsense!”

Bruce Jancin/MDedge News

“There’s just no way that methotrexate is causing that much lung disease,” he declared at the 2019 Rheumatology Winter Clinical Symposium.

Dr. Fischer, a rheumatologist with joint appointments to the divisions of rheumatology and pulmonary sciences and critical care medicine at the University of Colorado at Denver, Aurora, noted that his opinion is considered controversial in the pulmonology world.

“I’m not allowed to talk about methotrexate at lung conferences. They stop you at the gate. They’re convinced in lung circles that methotrexate is the worst drug known to mankind,” he said.

Methotrexate pneumonitis is greatly overdiagnosed, Dr. Fischer explained, because it can be extremely difficult to distinguish from an acute flare of interstitial lung disease.

“My take home on methotrexate lung toxicity is this: I would just say, yes, it can occur, but it’s super rare and most often we’re not really sure that it was methotrexate pneumonitis. The diagnosis is not definitive, it’s exclusionary. We know that patients with interstitial lung disease of all types get acute exacerbations, and in idiopathic pulmonary fibrosis it’s actually the leading cause of mortality,” the rheumatologist said.

He highlighted a meta-analysis of 22 randomized, double-blind clinical trials published in 1990-2013 of methotrexate versus placebo or active comparators in 8,584 RA patients. The Irish investigators of that meta-analysis found that methotrexate was associated with a small albeit statistically significant 10% increase in the risk of all adverse respiratory events and an 11% increase in the risk of respiratory infection. However, patients on methotrexate were not at increased risk of mortality because of lung disease. And not a single case of methotrexate pneumonitis was reported after 2002 (Arthritis Rheumatol. 2014 Apr;66[4]:803-12).

Methotrexate pneumonitis is not dose dependent, nor is it related to treatment duration.

“Just because your patient has been on methotrexate for years does not mean they won’t get methotrexate lung toxicity,” he cautioned. “But this is not a chronic fibrotic interstitial lung disease, this is an acute onset of peripheral infiltrates and ground glass opacifications on chest imaging.”

Bronchoalveolar lavage classically shows a hypersensitivity pneumonitis with lymphocytosis. Transbronchial or surgical lung biopsy may show an organizing pneumonia or airway-based nonnecrotizing granulomas, again indicative of a hypersensitivity reaction.

Because the diagnostic picture is so often cloudy, Dr. Fischer generally tries to avoid methotrexate in patients with moderate or severe interstitial lung disease. “I have the luxury of avoiding it because we have so many great arthritis drugs these days,” he noted.

“That being said, the notion that we’re going to stop methotrexate in an 80-year-old who’s been on it for years and has mild bibasilar fibrotic interstitial lung disease so that her lung doc can sleep better at night is not very helpful for our patients. If the patient is doing well on methotrexate and the interstitial lung disease is mild, I continue [the methotrexate],” Dr. Fischer said.

He reported receiving research grants from Boehringer Ingelheim and Corbus Pharmaceuticals and serving as a consultant to Boehringer Ingelheim and other pharmaceutical companies.

bjancin@mdedge.com

There have been 704 measles cases in the United States in 2019 as of April 26, the Centers for Disease Control and Prevention reported.

The updated figure adds 9 cases to the previous tally of 695 cases as of April 24, when the CDC announced that the number of cases in 2019 had surpassed the total for any year since the disease was considered effectively eliminated from the country in 2000.

Cases have been reported in 22 states, with the largest outbreaks in Washington and New York. The outbreak in Washington, which included 72 cases, was declared over last week. Two outbreaks in New York, however, are the largest and longest-lasting measles outbreaks since the disease was considered eliminated, said Nancy Messonnier, MD, director of the CDC’s National Center for Immunization and Respiratory Diseases. The longer they continue, the “greater the chance that measles will again gain a foothold in the United States,” she said at CDC telebriefing on measles.

The outbreaks are linked to travelers who are exposed to measles abroad and bring it to the United States. The disease then may spread, especially in communities with high rates of unvaccinated people. “A significant factor contributing to the outbreaks in New York is misinformation in the communities about the safety of the measles/mumps/rubella vaccine,” according to the CDC.
 

National Infant Immunization Week

Until last week, 2014 – with 667 measles cases – had been the year with the most cases since the disease was effectively eliminated. The last time the United States had more measles cases was in 1994, when there were 963 cases for the year.

Health and Human Services Secretary Alex Azar, also at the telebriefing, pointed out that 1994 also was the year that the United States first observed National Infant Immunization Week, which is April 27–May 4 this year. The CDC is marking the 25th anniversary of the annual observance, which highlights “the importance of protecting infants from vaccine-preventable diseases” and celebrates “the achievements of immunization programs in promoting healthy communities,” Secretary Azar said.
 

Message to health care providers

CDC director Robert Redfield Jr., MD, noted that measles has “no treatment, no cure, and no way to predict how bad a case will be.”

Some patients may have mild symptoms, whereas others may have serious complications such as pneumonia or encephalitis. In 2019, 3% of the patients with measles have developed pneumonia, he said. No patients have died.

Dr. Redfield, a virologist, noted that the CDC is recommending that children aged 6-12 months receive 1 dose of the measles vaccine if traveling abroad.

“As CDC director and as a physician, I have and continue to wholeheartedly advocate for infant immunization,” he said in a statement. “More importantly, as a father and grandfather I have ensured all of my children and grandchildren are vaccinated on the recommended schedule. Vaccines are safe. Vaccines do not cause autism. Vaccine-preventable diseases are dangerous.”

More than 94% of parents vaccinate their children, Dr. Redfield added. “CDC is working to reach the small percentage of vaccine-hesitant individuals so they too understand the importance of vaccines. It is imperative that we correct misinformation and reassure fearful parents so they protect their children from illnesses with long-lasting health impacts.”

About 1.3%, or 100,000 children, in the United States under 2 years old have not been vaccinated, he said.

“I call upon health care providers to encourage parents and expectant parents to vaccinate their children for their own protection and to avoid the spread of vaccine-preventable diseases within their families and communities,” he said. “We must join together as a nation to once again eliminate measles and prevent future disease outbreaks.”

The CDC has a complete list of clinical recommendations for health care providers on its website.
 

The president weighs in

President Donald Trump said that children should receive vaccinations – his first public comment about vaccines since his inauguration. Previously, he had questioned the safety of vaccines.

Asked by reporters about the measles outbreaks and his message for parents about having their kids vaccinated, he said: “They have to get the shot. The vaccinations are so important. This is really going around now. They have to get their shots.”

jremaly@mdedge.com

There have been 704 measles cases in the United States in 2019 as of April 26, the Centers for Disease Control and Prevention reported.

The updated figure adds 9 cases to the previous tally of 695 cases as of April 24, when the CDC announced that the number of cases in 2019 had surpassed the total for any year since the disease was considered effectively eliminated from the country in 2000.

Cases have been reported in 22 states, with the largest outbreaks in Washington and New York. The outbreak in Washington, which included 72 cases, was declared over last week. Two outbreaks in New York, however, are the largest and longest-lasting measles outbreaks since the disease was considered eliminated, said Nancy Messonnier, MD, director of the CDC’s National Center for Immunization and Respiratory Diseases. The longer they continue, the “greater the chance that measles will again gain a foothold in the United States,” she said at CDC telebriefing on measles.

The outbreaks are linked to travelers who are exposed to measles abroad and bring it to the United States. The disease then may spread, especially in communities with high rates of unvaccinated people. “A significant factor contributing to the outbreaks in New York is misinformation in the communities about the safety of the measles/mumps/rubella vaccine,” according to the CDC.
 

National Infant Immunization Week

Until last week, 2014 – with 667 measles cases – had been the year with the most cases since the disease was effectively eliminated. The last time the United States had more measles cases was in 1994, when there were 963 cases for the year.

Health and Human Services Secretary Alex Azar, also at the telebriefing, pointed out that 1994 also was the year that the United States first observed National Infant Immunization Week, which is April 27–May 4 this year. The CDC is marking the 25th anniversary of the annual observance, which highlights “the importance of protecting infants from vaccine-preventable diseases” and celebrates “the achievements of immunization programs in promoting healthy communities,” Secretary Azar said.
 

Message to health care providers

CDC director Robert Redfield Jr., MD, noted that measles has “no treatment, no cure, and no way to predict how bad a case will be.”

Some patients may have mild symptoms, whereas others may have serious complications such as pneumonia or encephalitis. In 2019, 3% of the patients with measles have developed pneumonia, he said. No patients have died.

Dr. Redfield, a virologist, noted that the CDC is recommending that children aged 6-12 months receive 1 dose of the measles vaccine if traveling abroad.

“As CDC director and as a physician, I have and continue to wholeheartedly advocate for infant immunization,” he said in a statement. “More importantly, as a father and grandfather I have ensured all of my children and grandchildren are vaccinated on the recommended schedule. Vaccines are safe. Vaccines do not cause autism. Vaccine-preventable diseases are dangerous.”

More than 94% of parents vaccinate their children, Dr. Redfield added. “CDC is working to reach the small percentage of vaccine-hesitant individuals so they too understand the importance of vaccines. It is imperative that we correct misinformation and reassure fearful parents so they protect their children from illnesses with long-lasting health impacts.”

About 1.3%, or 100,000 children, in the United States under 2 years old have not been vaccinated, he said.

“I call upon health care providers to encourage parents and expectant parents to vaccinate their children for their own protection and to avoid the spread of vaccine-preventable diseases within their families and communities,” he said. “We must join together as a nation to once again eliminate measles and prevent future disease outbreaks.”

The CDC has a complete list of clinical recommendations for health care providers on its website.
 

The president weighs in

President Donald Trump said that children should receive vaccinations – his first public comment about vaccines since his inauguration. Previously, he had questioned the safety of vaccines.

Asked by reporters about the measles outbreaks and his message for parents about having their kids vaccinated, he said: “They have to get the shot. The vaccinations are so important. This is really going around now. They have to get their shots.”

jremaly@mdedge.com

There have been 704 measles cases in the United States in 2019 as of April 26, the Centers for Disease Control and Prevention reported.

The updated figure adds 9 cases to the previous tally of 695 cases as of April 24, when the CDC announced that the number of cases in 2019 had surpassed the total for any year since the disease was considered effectively eliminated from the country in 2000.

Cases have been reported in 22 states, with the largest outbreaks in Washington and New York. The outbreak in Washington, which included 72 cases, was declared over last week. Two outbreaks in New York, however, are the largest and longest-lasting measles outbreaks since the disease was considered eliminated, said Nancy Messonnier, MD, director of the CDC’s National Center for Immunization and Respiratory Diseases. The longer they continue, the “greater the chance that measles will again gain a foothold in the United States,” she said at CDC telebriefing on measles.

The outbreaks are linked to travelers who are exposed to measles abroad and bring it to the United States. The disease then may spread, especially in communities with high rates of unvaccinated people. “A significant factor contributing to the outbreaks in New York is misinformation in the communities about the safety of the measles/mumps/rubella vaccine,” according to the CDC.
 

National Infant Immunization Week

Until last week, 2014 – with 667 measles cases – had been the year with the most cases since the disease was effectively eliminated. The last time the United States had more measles cases was in 1994, when there were 963 cases for the year.

Health and Human Services Secretary Alex Azar, also at the telebriefing, pointed out that 1994 also was the year that the United States first observed National Infant Immunization Week, which is April 27–May 4 this year. The CDC is marking the 25th anniversary of the annual observance, which highlights “the importance of protecting infants from vaccine-preventable diseases” and celebrates “the achievements of immunization programs in promoting healthy communities,” Secretary Azar said.
 

Message to health care providers

CDC director Robert Redfield Jr., MD, noted that measles has “no treatment, no cure, and no way to predict how bad a case will be.”

Some patients may have mild symptoms, whereas others may have serious complications such as pneumonia or encephalitis. In 2019, 3% of the patients with measles have developed pneumonia, he said. No patients have died.

Dr. Redfield, a virologist, noted that the CDC is recommending that children aged 6-12 months receive 1 dose of the measles vaccine if traveling abroad.

“As CDC director and as a physician, I have and continue to wholeheartedly advocate for infant immunization,” he said in a statement. “More importantly, as a father and grandfather I have ensured all of my children and grandchildren are vaccinated on the recommended schedule. Vaccines are safe. Vaccines do not cause autism. Vaccine-preventable diseases are dangerous.”

More than 94% of parents vaccinate their children, Dr. Redfield added. “CDC is working to reach the small percentage of vaccine-hesitant individuals so they too understand the importance of vaccines. It is imperative that we correct misinformation and reassure fearful parents so they protect their children from illnesses with long-lasting health impacts.”

About 1.3%, or 100,000 children, in the United States under 2 years old have not been vaccinated, he said.

“I call upon health care providers to encourage parents and expectant parents to vaccinate their children for their own protection and to avoid the spread of vaccine-preventable diseases within their families and communities,” he said. “We must join together as a nation to once again eliminate measles and prevent future disease outbreaks.”

The CDC has a complete list of clinical recommendations for health care providers on its website.
 

The president weighs in

President Donald Trump said that children should receive vaccinations – his first public comment about vaccines since his inauguration. Previously, he had questioned the safety of vaccines.

Asked by reporters about the measles outbreaks and his message for parents about having their kids vaccinated, he said: “They have to get the shot. The vaccinations are so important. This is really going around now. They have to get their shots.”

jremaly@mdedge.com