Pulmonary Health Hub

SAN FRANCISCO – Most group A streptococcus tests performed in pediatric outpatients at a major children’s hospital were indicated based on current guidelines, but a significantly higher than expected proportion of children were treated with antibiotics, according to findings from a chart review.

Furthermore, 11.1% of the antibiotics prescribed to those patients were nonrecommended agents, Dr. Thea Brennan-Krohn reported in a poster at an annual scientific meeting on infectious diseases.

Included in the study were 234 patients, aged 3-18 years, who had a streptococcal rapid antigen detection test and/or a throat culture performed between Aug. 1, 2011, and July 31, 2013. The tests were indicated – based on a McIsaac score of 2 or greater as recommended by Infectious Diseases Society of America (IDSA) guidelines – in 95.7% of cases. If the patients had been managed according to guidelines, 8.1% would have received antibiotics, but 11.5% actually received antibiotics, reported Dr. Brennan-Krohn of Boston Children’s Hospital.

Children whose charts were reviewed as part of this study presented with pharyngitis to a clinic or emergency department at the hospital. According to the IDSA guidelines, testing is not recommended for those with acute pharyngitis with features that strongly suggest viral etiology, such as cough, rhinorrhea, hoarseness, or oral ulcers. Recommended antimicrobial agents in those who have group A streptococcus include penicillin V, amoxicillin, or intramuscular benzathine penicillin G in those without penicillin allergy, and cephalexin/cefadroxil, clindamycin, or azithromycin/clarithromycin in those who do have penicillin allergy.

Prior studies have demonstrated that guidelines are not consistently followed in adults. The current study is among the first to use individual patient data to assess guideline adherence in the pediatric population. The findings suggest that "there remains a role for targeted antimicrobial stewardship education regarding pharyngitis management in pediatric outpatient settings," Dr. Brennan-Krohn said.

Plans are underway to repeat the study in a large community-based practice setting to evaluate management of pharyngitis beyond the academic medical center setting, she noted at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

"Further investigation may help to clarify why pediatric providers appear to adhere more closely to pharyngitis management guidelines than adult providers," she concluded.

This study was supported by the Fred Lovejoy Housestaff Research and Education fund.

SAN FRANCISCO – Most group A streptococcus tests performed in pediatric outpatients at a major children’s hospital were indicated based on current guidelines, but a significantly higher than expected proportion of children were treated with antibiotics, according to findings from a chart review.

Furthermore, 11.1% of the antibiotics prescribed to those patients were nonrecommended agents, Dr. Thea Brennan-Krohn reported in a poster at an annual scientific meeting on infectious diseases.

Included in the study were 234 patients, aged 3-18 years, who had a streptococcal rapid antigen detection test and/or a throat culture performed between Aug. 1, 2011, and July 31, 2013. The tests were indicated – based on a McIsaac score of 2 or greater as recommended by Infectious Diseases Society of America (IDSA) guidelines – in 95.7% of cases. If the patients had been managed according to guidelines, 8.1% would have received antibiotics, but 11.5% actually received antibiotics, reported Dr. Brennan-Krohn of Boston Children’s Hospital.

Children whose charts were reviewed as part of this study presented with pharyngitis to a clinic or emergency department at the hospital. According to the IDSA guidelines, testing is not recommended for those with acute pharyngitis with features that strongly suggest viral etiology, such as cough, rhinorrhea, hoarseness, or oral ulcers. Recommended antimicrobial agents in those who have group A streptococcus include penicillin V, amoxicillin, or intramuscular benzathine penicillin G in those without penicillin allergy, and cephalexin/cefadroxil, clindamycin, or azithromycin/clarithromycin in those who do have penicillin allergy.

Prior studies have demonstrated that guidelines are not consistently followed in adults. The current study is among the first to use individual patient data to assess guideline adherence in the pediatric population. The findings suggest that "there remains a role for targeted antimicrobial stewardship education regarding pharyngitis management in pediatric outpatient settings," Dr. Brennan-Krohn said.

Plans are underway to repeat the study in a large community-based practice setting to evaluate management of pharyngitis beyond the academic medical center setting, she noted at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

"Further investigation may help to clarify why pediatric providers appear to adhere more closely to pharyngitis management guidelines than adult providers," she concluded.

This study was supported by the Fred Lovejoy Housestaff Research and Education fund.

SAN FRANCISCO – Most group A streptococcus tests performed in pediatric outpatients at a major children’s hospital were indicated based on current guidelines, but a significantly higher than expected proportion of children were treated with antibiotics, according to findings from a chart review.

Furthermore, 11.1% of the antibiotics prescribed to those patients were nonrecommended agents, Dr. Thea Brennan-Krohn reported in a poster at an annual scientific meeting on infectious diseases.

Included in the study were 234 patients, aged 3-18 years, who had a streptococcal rapid antigen detection test and/or a throat culture performed between Aug. 1, 2011, and July 31, 2013. The tests were indicated – based on a McIsaac score of 2 or greater as recommended by Infectious Diseases Society of America (IDSA) guidelines – in 95.7% of cases. If the patients had been managed according to guidelines, 8.1% would have received antibiotics, but 11.5% actually received antibiotics, reported Dr. Brennan-Krohn of Boston Children’s Hospital.

Children whose charts were reviewed as part of this study presented with pharyngitis to a clinic or emergency department at the hospital. According to the IDSA guidelines, testing is not recommended for those with acute pharyngitis with features that strongly suggest viral etiology, such as cough, rhinorrhea, hoarseness, or oral ulcers. Recommended antimicrobial agents in those who have group A streptococcus include penicillin V, amoxicillin, or intramuscular benzathine penicillin G in those without penicillin allergy, and cephalexin/cefadroxil, clindamycin, or azithromycin/clarithromycin in those who do have penicillin allergy.

Prior studies have demonstrated that guidelines are not consistently followed in adults. The current study is among the first to use individual patient data to assess guideline adherence in the pediatric population. The findings suggest that "there remains a role for targeted antimicrobial stewardship education regarding pharyngitis management in pediatric outpatient settings," Dr. Brennan-Krohn said.

Plans are underway to repeat the study in a large community-based practice setting to evaluate management of pharyngitis beyond the academic medical center setting, she noted at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

"Further investigation may help to clarify why pediatric providers appear to adhere more closely to pharyngitis management guidelines than adult providers," she concluded.

This study was supported by the Fred Lovejoy Housestaff Research and Education fund.

SAN FRANCISCO – Symptoms of acute respiratory infections occur in 22% of health care providers during the respiratory viral season, and almost as many have asymptomatic infection, according to findings from the Respiratory Protection Effectiveness Clinical Trial.

Mandatory influenza vaccination may help reduce absenteeism resulting from flulike symptoms, according to a separate report from the same study.

© mik38/Fotolia.com

The Respiratory Protection Effectiveness Clinical Trial (ResPECT) is an ongoing cluster randomized trial taking place at 99 outpatient departments and emergency departments in seven locations across the United States. The current analyses are based on data collected during 12 weeks of the 2011-12 and 2012-13 respiratory seasons.

For one analysis, 1,686 health care providers were surveyed for signs and symptoms of acute respiratory infection (ARI). Cultures from swabs obtained from those with symptoms, as well as paired blood samples obtained at the start of the intervention and 2 weeks later, revealed that the most common viral isolates were for coronavirus (34%), followed by influenza A and B (32% combined), and rhinovirus (17%), Dr. Trish M. Perl of Johns Hopkins University, Baltimore, reported at an annual scientific meeting on infectious diseases.

Of the 22% of health care providers with ARI symptoms, 28% had identifiable viral causes. Nearly 20% of the providers were asymptomatic but were found to have an identifiable viral infection.

Interestingly, the same three viruses – coronavirus, influenza, and rhinovirus – topped the list of isolates in both symptomatic and asymptomatic patients, Dr. Perl noted.

Also of note, 9 of the 10 patients with influenza in the 2011-12 study period had been vaccinated. The data on influenza among vaccinated individuals were not available for the 2012-13 study period, she said.

At least some of the effect of ARI exposures among providers might be attenuated by a mandatory vaccine program, according to another report from ResPECT.

Of 1,077 health care providers included in that analysis, 64% were from private sites with mandatory vaccine policies and 36% were from Veterans Affairs sites and private sites without a mandatory vaccine policy. Those from sites with mandatory vaccination had significantly higher mean influenza vaccination rates (88% vs. 59%) and a lower mean sick day ratio, defined as symptomatic absenteeism/number of participants (0.56 vs. 0.90), said John Frederick of New York Harbor Healthcare System, New York.

Hand hygiene compliance rates did not differ significantly between the private site and VA site participants (33.1% vs. 33.8%, respectively), and facial protective equipment compliance differed only marginally during respiratory illness exposures (24.7% vs. 19.8%), despite a significantly greater exposure rate among the VA site subjects (11.1% vs. 6.7%), Mr. Frederick noted.

Furthermore, institutional impact of influenza was higher in systems with mandatory vaccine policies and lower sick day ratios.

"So this would suggest that, even in the face of increased influenza rates – an increased burden of disease – increased vaccination rates can actually provide a protective effect to health care personnel, and vaccination rates may very well be the driving differential force," he said.

Though limited by certain factors, such as the use of observational and self-reported data, and possible variability in how participants define ARI symptoms, it still is possible to draw some important conclusions from the findings, he said at the conference, part of the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

"Mandating vaccination does indeed appear to increase vaccination rates, and increasing vaccination rates does appear to decrease symptomatic absenteeism. So, combining those two, it appears that mandating vaccination does indeed decrease symptomatic absenteeism among health care personnel during viral respiratory season, even in the face of higher influenza rates," he concluded, adding that other factors, such as sick-leave policies, may certainly be in play as well, and that future studies should focus on these.

Dr. Perl and Mr. Frederick reported having no disclosures. The ResPECT trial is supported by Johns Hopkins University, the Centers for Disease Control and Prevention, the Department of Veterans Affairs, and the National Institute for Occupational Safety and Health.

SAN FRANCISCO – Symptoms of acute respiratory infections occur in 22% of health care providers during the respiratory viral season, and almost as many have asymptomatic infection, according to findings from the Respiratory Protection Effectiveness Clinical Trial.

Mandatory influenza vaccination may help reduce absenteeism resulting from flulike symptoms, according to a separate report from the same study.

© mik38/Fotolia.com

The Respiratory Protection Effectiveness Clinical Trial (ResPECT) is an ongoing cluster randomized trial taking place at 99 outpatient departments and emergency departments in seven locations across the United States. The current analyses are based on data collected during 12 weeks of the 2011-12 and 2012-13 respiratory seasons.

For one analysis, 1,686 health care providers were surveyed for signs and symptoms of acute respiratory infection (ARI). Cultures from swabs obtained from those with symptoms, as well as paired blood samples obtained at the start of the intervention and 2 weeks later, revealed that the most common viral isolates were for coronavirus (34%), followed by influenza A and B (32% combined), and rhinovirus (17%), Dr. Trish M. Perl of Johns Hopkins University, Baltimore, reported at an annual scientific meeting on infectious diseases.

Of the 22% of health care providers with ARI symptoms, 28% had identifiable viral causes. Nearly 20% of the providers were asymptomatic but were found to have an identifiable viral infection.

Interestingly, the same three viruses – coronavirus, influenza, and rhinovirus – topped the list of isolates in both symptomatic and asymptomatic patients, Dr. Perl noted.

Also of note, 9 of the 10 patients with influenza in the 2011-12 study period had been vaccinated. The data on influenza among vaccinated individuals were not available for the 2012-13 study period, she said.

At least some of the effect of ARI exposures among providers might be attenuated by a mandatory vaccine program, according to another report from ResPECT.

Of 1,077 health care providers included in that analysis, 64% were from private sites with mandatory vaccine policies and 36% were from Veterans Affairs sites and private sites without a mandatory vaccine policy. Those from sites with mandatory vaccination had significantly higher mean influenza vaccination rates (88% vs. 59%) and a lower mean sick day ratio, defined as symptomatic absenteeism/number of participants (0.56 vs. 0.90), said John Frederick of New York Harbor Healthcare System, New York.

Hand hygiene compliance rates did not differ significantly between the private site and VA site participants (33.1% vs. 33.8%, respectively), and facial protective equipment compliance differed only marginally during respiratory illness exposures (24.7% vs. 19.8%), despite a significantly greater exposure rate among the VA site subjects (11.1% vs. 6.7%), Mr. Frederick noted.

Furthermore, institutional impact of influenza was higher in systems with mandatory vaccine policies and lower sick day ratios.

"So this would suggest that, even in the face of increased influenza rates – an increased burden of disease – increased vaccination rates can actually provide a protective effect to health care personnel, and vaccination rates may very well be the driving differential force," he said.

Though limited by certain factors, such as the use of observational and self-reported data, and possible variability in how participants define ARI symptoms, it still is possible to draw some important conclusions from the findings, he said at the conference, part of the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

"Mandating vaccination does indeed appear to increase vaccination rates, and increasing vaccination rates does appear to decrease symptomatic absenteeism. So, combining those two, it appears that mandating vaccination does indeed decrease symptomatic absenteeism among health care personnel during viral respiratory season, even in the face of higher influenza rates," he concluded, adding that other factors, such as sick-leave policies, may certainly be in play as well, and that future studies should focus on these.

Dr. Perl and Mr. Frederick reported having no disclosures. The ResPECT trial is supported by Johns Hopkins University, the Centers for Disease Control and Prevention, the Department of Veterans Affairs, and the National Institute for Occupational Safety and Health.

SAN FRANCISCO – Symptoms of acute respiratory infections occur in 22% of health care providers during the respiratory viral season, and almost as many have asymptomatic infection, according to findings from the Respiratory Protection Effectiveness Clinical Trial.

Mandatory influenza vaccination may help reduce absenteeism resulting from flulike symptoms, according to a separate report from the same study.

© mik38/Fotolia.com

The Respiratory Protection Effectiveness Clinical Trial (ResPECT) is an ongoing cluster randomized trial taking place at 99 outpatient departments and emergency departments in seven locations across the United States. The current analyses are based on data collected during 12 weeks of the 2011-12 and 2012-13 respiratory seasons.

For one analysis, 1,686 health care providers were surveyed for signs and symptoms of acute respiratory infection (ARI). Cultures from swabs obtained from those with symptoms, as well as paired blood samples obtained at the start of the intervention and 2 weeks later, revealed that the most common viral isolates were for coronavirus (34%), followed by influenza A and B (32% combined), and rhinovirus (17%), Dr. Trish M. Perl of Johns Hopkins University, Baltimore, reported at an annual scientific meeting on infectious diseases.

Of the 22% of health care providers with ARI symptoms, 28% had identifiable viral causes. Nearly 20% of the providers were asymptomatic but were found to have an identifiable viral infection.

Interestingly, the same three viruses – coronavirus, influenza, and rhinovirus – topped the list of isolates in both symptomatic and asymptomatic patients, Dr. Perl noted.

Also of note, 9 of the 10 patients with influenza in the 2011-12 study period had been vaccinated. The data on influenza among vaccinated individuals were not available for the 2012-13 study period, she said.

At least some of the effect of ARI exposures among providers might be attenuated by a mandatory vaccine program, according to another report from ResPECT.

Of 1,077 health care providers included in that analysis, 64% were from private sites with mandatory vaccine policies and 36% were from Veterans Affairs sites and private sites without a mandatory vaccine policy. Those from sites with mandatory vaccination had significantly higher mean influenza vaccination rates (88% vs. 59%) and a lower mean sick day ratio, defined as symptomatic absenteeism/number of participants (0.56 vs. 0.90), said John Frederick of New York Harbor Healthcare System, New York.

Hand hygiene compliance rates did not differ significantly between the private site and VA site participants (33.1% vs. 33.8%, respectively), and facial protective equipment compliance differed only marginally during respiratory illness exposures (24.7% vs. 19.8%), despite a significantly greater exposure rate among the VA site subjects (11.1% vs. 6.7%), Mr. Frederick noted.

Furthermore, institutional impact of influenza was higher in systems with mandatory vaccine policies and lower sick day ratios.

"So this would suggest that, even in the face of increased influenza rates – an increased burden of disease – increased vaccination rates can actually provide a protective effect to health care personnel, and vaccination rates may very well be the driving differential force," he said.

Though limited by certain factors, such as the use of observational and self-reported data, and possible variability in how participants define ARI symptoms, it still is possible to draw some important conclusions from the findings, he said at the conference, part of the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

"Mandating vaccination does indeed appear to increase vaccination rates, and increasing vaccination rates does appear to decrease symptomatic absenteeism. So, combining those two, it appears that mandating vaccination does indeed decrease symptomatic absenteeism among health care personnel during viral respiratory season, even in the face of higher influenza rates," he concluded, adding that other factors, such as sick-leave policies, may certainly be in play as well, and that future studies should focus on these.

Dr. Perl and Mr. Frederick reported having no disclosures. The ResPECT trial is supported by Johns Hopkins University, the Centers for Disease Control and Prevention, the Department of Veterans Affairs, and the National Institute for Occupational Safety and Health.

AMSTERDAM – Almost a quarter of patients with advanced and heavily pretreated lung cancer responded to treatment with the novel immunotherapy MPDL3280A in an ongoing phase I study.

The objective response rate was 23% in 53 patients with non–small cell lung cancer (NSCLC) evaluated for clinical activity, with 17% of patients achieving stable disease for 24 weeks or longer, and a progression-free survival rate of 45%. The best responses were seen in patients with the highest expression of the targeted protein, PD-L1; current or past smokers seemed to gain the greatest benefit from the novel immunotherapy.

Sara Freeman/IMNG Medical Media

MPDL3280A was well tolerated by the 85 patients with NSCLC who were evaluated for safety, which was the main aim of the early clinical study.

"Most adverse events seen in the trial were grade 1 or 2 and did not require intervention," Dr. Jean-Charles Soria said at the multidisciplinary European cancer congresses.

Dr. Soria, director of the Institut Gustave Roussy’s integrated cancer research center in Villejuif, France, noted that were no dose-limiting toxicities with doses of up to 20 mg/kg, and no cases of grade 3-5 pneumonitis. There was, however, a single, severe grade 3-4 adverse event in a patient with large-cell neuroendocrine NSCLC, and one death due to cardiac arrest in a patient with sinus thrombosis and a large tumor mass invading the heart at baseline.

Dr. Soria explained that MPDL3280A inhibits PD-L1 in such a way that it leaves some immune homeostatic functions intact, which could potentially prevent the development of autoimmunity.

The phase I trial he presented included patients with nonsquamous (76%) and squamous (24%) histology who were treated with an intravenous (10, 15, or 20 mg/kg) infusion of MPDL3280A every 3 weeks for up to 1 year. The patients’ median age was 60 years; 56% were male. Most (81%) were current or former smokers, and more than half (55%) of the patients had received three or more systemic regimens. Almost all (95%) patients had metastases involving the central nervous system, and 60% had EGFR wild-type.

Objective response rates (ORRs) were 21% and 27%, respectively, in patients with nonsquamous and squamous histology. Interestingly, the ORR increased with PD-L1 expression, which was determined using immunohistochemistry (IHC), suggesting this might be a potential biomarker for response. The ORR was 83% when 10% or more of the tumor cells were positive for PD-L1 (IHC 3), 46% when 5% or more of the tumor cells were PD-L1 positive (IHC 2 and 3), and 31% when 1% or more of tumor cells were PD-L1 positive (IHC 1/2/3). The respective rates of progressive disease by IHC status were 17%, 23%, and 38%.

Responses to the investigational drug were "outstandingly" durable, and all but one of the 12 patients who had responded to the drug continued to respond at the time of the data cutoff, Dr. Soria said. The longest duration of treatment response seen at this time point was 84 weeks, he added.

As it had been recently suggested that there might be a relationship between the mutational tumor load and the immunogenicity of the tumor (Clin. Cancer Res. 2012;18:6580-7), Dr. Soria and his associates decided to determine if there was any difference in the response to MPDL3280A according to patients’ smoking status. The results were striking: ORRs in smokers versus never-smokers were 26% and 10%, respectively.

"This is extremely important because most advances achieved over the past 10 years with molecularly targeted agents have benefited never-smokers," he said.

"It is very good to now have something for patients who were former smokers," said Dr. Paul Baas of the Netherlands Cancer Institute, Amsterdam. "It works in adenocarcinoma and squamous cell carcinomas, and I think the importance of this [study] is that [MPDL3280A] is already very active in phase I."

Roche is now pushing ahead with its clinical development program for MPDL3280A in a larger population of patients with NSCLC to see if the novel immunotherapeutic fulfills this early promise.

"Based on these data, we are moving quickly into late-stage clinical studies that will also include a Roche companion diagnostic to potentially identify those who are more likely to respond to treatment," Dr. Hal Barron, Roche’s chief medical officer and head of global product development, said in a statement.

Phase II studies of MPDL3280A in patients with NSCLC (NCT01846416 and NCT01903993) have already been initiated, and further studies are planned. The investigational drug is also being tested in combination with vemurafenib (Zelboraf) in the treatment of BRAFV600-mutation positive melanoma (NCT01656642), in combination with bevacizumab (Avastin) in patients with advanced solid tumors (NCT01633970), and as a single agent in patients with locally advanced or metastatic solid tumors or hematologic malignancies (NCT01375842).

Genentech, a member of the Roche Group, supported the study. Dr. Soria received research funding and advised the company. Dr. Baas received research grants from Pfizer and Roche and advised MSD and Verastem.

AMSTERDAM – Almost a quarter of patients with advanced and heavily pretreated lung cancer responded to treatment with the novel immunotherapy MPDL3280A in an ongoing phase I study.

The objective response rate was 23% in 53 patients with non–small cell lung cancer (NSCLC) evaluated for clinical activity, with 17% of patients achieving stable disease for 24 weeks or longer, and a progression-free survival rate of 45%. The best responses were seen in patients with the highest expression of the targeted protein, PD-L1; current or past smokers seemed to gain the greatest benefit from the novel immunotherapy.

Sara Freeman/IMNG Medical Media

MPDL3280A was well tolerated by the 85 patients with NSCLC who were evaluated for safety, which was the main aim of the early clinical study.

"Most adverse events seen in the trial were grade 1 or 2 and did not require intervention," Dr. Jean-Charles Soria said at the multidisciplinary European cancer congresses.

Dr. Soria, director of the Institut Gustave Roussy’s integrated cancer research center in Villejuif, France, noted that were no dose-limiting toxicities with doses of up to 20 mg/kg, and no cases of grade 3-5 pneumonitis. There was, however, a single, severe grade 3-4 adverse event in a patient with large-cell neuroendocrine NSCLC, and one death due to cardiac arrest in a patient with sinus thrombosis and a large tumor mass invading the heart at baseline.

Dr. Soria explained that MPDL3280A inhibits PD-L1 in such a way that it leaves some immune homeostatic functions intact, which could potentially prevent the development of autoimmunity.

The phase I trial he presented included patients with nonsquamous (76%) and squamous (24%) histology who were treated with an intravenous (10, 15, or 20 mg/kg) infusion of MPDL3280A every 3 weeks for up to 1 year. The patients’ median age was 60 years; 56% were male. Most (81%) were current or former smokers, and more than half (55%) of the patients had received three or more systemic regimens. Almost all (95%) patients had metastases involving the central nervous system, and 60% had EGFR wild-type.

Objective response rates (ORRs) were 21% and 27%, respectively, in patients with nonsquamous and squamous histology. Interestingly, the ORR increased with PD-L1 expression, which was determined using immunohistochemistry (IHC), suggesting this might be a potential biomarker for response. The ORR was 83% when 10% or more of the tumor cells were positive for PD-L1 (IHC 3), 46% when 5% or more of the tumor cells were PD-L1 positive (IHC 2 and 3), and 31% when 1% or more of tumor cells were PD-L1 positive (IHC 1/2/3). The respective rates of progressive disease by IHC status were 17%, 23%, and 38%.

Responses to the investigational drug were "outstandingly" durable, and all but one of the 12 patients who had responded to the drug continued to respond at the time of the data cutoff, Dr. Soria said. The longest duration of treatment response seen at this time point was 84 weeks, he added.

As it had been recently suggested that there might be a relationship between the mutational tumor load and the immunogenicity of the tumor (Clin. Cancer Res. 2012;18:6580-7), Dr. Soria and his associates decided to determine if there was any difference in the response to MPDL3280A according to patients’ smoking status. The results were striking: ORRs in smokers versus never-smokers were 26% and 10%, respectively.

"This is extremely important because most advances achieved over the past 10 years with molecularly targeted agents have benefited never-smokers," he said.

"It is very good to now have something for patients who were former smokers," said Dr. Paul Baas of the Netherlands Cancer Institute, Amsterdam. "It works in adenocarcinoma and squamous cell carcinomas, and I think the importance of this [study] is that [MPDL3280A] is already very active in phase I."

Roche is now pushing ahead with its clinical development program for MPDL3280A in a larger population of patients with NSCLC to see if the novel immunotherapeutic fulfills this early promise.

"Based on these data, we are moving quickly into late-stage clinical studies that will also include a Roche companion diagnostic to potentially identify those who are more likely to respond to treatment," Dr. Hal Barron, Roche’s chief medical officer and head of global product development, said in a statement.

Phase II studies of MPDL3280A in patients with NSCLC (NCT01846416 and NCT01903993) have already been initiated, and further studies are planned. The investigational drug is also being tested in combination with vemurafenib (Zelboraf) in the treatment of BRAFV600-mutation positive melanoma (NCT01656642), in combination with bevacizumab (Avastin) in patients with advanced solid tumors (NCT01633970), and as a single agent in patients with locally advanced or metastatic solid tumors or hematologic malignancies (NCT01375842).

Genentech, a member of the Roche Group, supported the study. Dr. Soria received research funding and advised the company. Dr. Baas received research grants from Pfizer and Roche and advised MSD and Verastem.

AMSTERDAM – Almost a quarter of patients with advanced and heavily pretreated lung cancer responded to treatment with the novel immunotherapy MPDL3280A in an ongoing phase I study.

The objective response rate was 23% in 53 patients with non–small cell lung cancer (NSCLC) evaluated for clinical activity, with 17% of patients achieving stable disease for 24 weeks or longer, and a progression-free survival rate of 45%. The best responses were seen in patients with the highest expression of the targeted protein, PD-L1; current or past smokers seemed to gain the greatest benefit from the novel immunotherapy.

Sara Freeman/IMNG Medical Media

MPDL3280A was well tolerated by the 85 patients with NSCLC who were evaluated for safety, which was the main aim of the early clinical study.

"Most adverse events seen in the trial were grade 1 or 2 and did not require intervention," Dr. Jean-Charles Soria said at the multidisciplinary European cancer congresses.

Dr. Soria, director of the Institut Gustave Roussy’s integrated cancer research center in Villejuif, France, noted that were no dose-limiting toxicities with doses of up to 20 mg/kg, and no cases of grade 3-5 pneumonitis. There was, however, a single, severe grade 3-4 adverse event in a patient with large-cell neuroendocrine NSCLC, and one death due to cardiac arrest in a patient with sinus thrombosis and a large tumor mass invading the heart at baseline.

Dr. Soria explained that MPDL3280A inhibits PD-L1 in such a way that it leaves some immune homeostatic functions intact, which could potentially prevent the development of autoimmunity.

The phase I trial he presented included patients with nonsquamous (76%) and squamous (24%) histology who were treated with an intravenous (10, 15, or 20 mg/kg) infusion of MPDL3280A every 3 weeks for up to 1 year. The patients’ median age was 60 years; 56% were male. Most (81%) were current or former smokers, and more than half (55%) of the patients had received three or more systemic regimens. Almost all (95%) patients had metastases involving the central nervous system, and 60% had EGFR wild-type.

Objective response rates (ORRs) were 21% and 27%, respectively, in patients with nonsquamous and squamous histology. Interestingly, the ORR increased with PD-L1 expression, which was determined using immunohistochemistry (IHC), suggesting this might be a potential biomarker for response. The ORR was 83% when 10% or more of the tumor cells were positive for PD-L1 (IHC 3), 46% when 5% or more of the tumor cells were PD-L1 positive (IHC 2 and 3), and 31% when 1% or more of tumor cells were PD-L1 positive (IHC 1/2/3). The respective rates of progressive disease by IHC status were 17%, 23%, and 38%.

Responses to the investigational drug were "outstandingly" durable, and all but one of the 12 patients who had responded to the drug continued to respond at the time of the data cutoff, Dr. Soria said. The longest duration of treatment response seen at this time point was 84 weeks, he added.

As it had been recently suggested that there might be a relationship between the mutational tumor load and the immunogenicity of the tumor (Clin. Cancer Res. 2012;18:6580-7), Dr. Soria and his associates decided to determine if there was any difference in the response to MPDL3280A according to patients’ smoking status. The results were striking: ORRs in smokers versus never-smokers were 26% and 10%, respectively.

"This is extremely important because most advances achieved over the past 10 years with molecularly targeted agents have benefited never-smokers," he said.

"It is very good to now have something for patients who were former smokers," said Dr. Paul Baas of the Netherlands Cancer Institute, Amsterdam. "It works in adenocarcinoma and squamous cell carcinomas, and I think the importance of this [study] is that [MPDL3280A] is already very active in phase I."

Roche is now pushing ahead with its clinical development program for MPDL3280A in a larger population of patients with NSCLC to see if the novel immunotherapeutic fulfills this early promise.

"Based on these data, we are moving quickly into late-stage clinical studies that will also include a Roche companion diagnostic to potentially identify those who are more likely to respond to treatment," Dr. Hal Barron, Roche’s chief medical officer and head of global product development, said in a statement.

Phase II studies of MPDL3280A in patients with NSCLC (NCT01846416 and NCT01903993) have already been initiated, and further studies are planned. The investigational drug is also being tested in combination with vemurafenib (Zelboraf) in the treatment of BRAFV600-mutation positive melanoma (NCT01656642), in combination with bevacizumab (Avastin) in patients with advanced solid tumors (NCT01633970), and as a single agent in patients with locally advanced or metastatic solid tumors or hematologic malignancies (NCT01375842).

Genentech, a member of the Roche Group, supported the study. Dr. Soria received research funding and advised the company. Dr. Baas received research grants from Pfizer and Roche and advised MSD and Verastem.

Riociguat, a potent vasodilator that is the first in a new class of drugs, has been approved by the Food and Drug Administration for treating two types of pulmonary hypertension in adults.

The drug, which will be marketed as Adempas, was approved Oct. 8 to treat chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH), the agency said in a statement.

Orally administered in tablet form, riociguat is a soluble guanylate cyclase (sGC) stimulator, the first drug in this class to be approved for pulmonary hypertension. It is also "the first drug of any class to be shown to be effective for patients with CTEPH," Dr. Norman Stockbridge, director of the Division of Cardiovascular and Renal Drug Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.

Riociguat is a pregnancy category X drug and is available to women only through a Risk Evaluation and Mitigation Strategy (REMS) program.

The approved indications for the drug, which will be marketed by Bayer HealthCare Pharmaceuticals, are for persistent/recurrent CTEPH (WHO group 4) "after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class" or PAH (WHO group 1) "to improve exercise capacity, improve WHO functional class, and to delay clinical worsening."

Approval was based on the results of two international studies that found treatment resulted in significant improvements over placebo in the 6 minute walk test. Side effects of treatment include headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea, and vomiting, according to the FDA. Based on these results, an FDA advisory panel unanimously recommended approval of the two indications in August.

In the study of 380 patients with PAH, the change from baseline in the 6-minute walk test at 12 weeks improved by a mean of 30 m among those treated with riociguat, vs. a mean drop of 6 m in the placebo group. The WHO functional class improved in 21% of those on riociguat, compared with 14% in the placebo group, deteriorating in 4% and 14%, respectively.

In the study of 261 patients with CTEPH, the change from baseline in the 6-minute walk test at 16 weeks improved by a mean of 39 m among treated patients vs. a mean 6 m reduction in the placebo group at 16 weeks. WHO functional class improved in 33% of those on riociguat and 15% of those on placebo, deteriorating in 5% and 7%, respectively.

The two studies were published in the July 25 issue of the New England Journal of Medicine (2013;369:330-40; 2013;369:319-29).

The prescribing information includes a boxed warning about embryo-fetal toxicity. Women can receive the drug only through the REMS program.

Because of the risk of hypotension, the drug is contraindicated for use with nitrates or nitric oxide donors, such as amyl nitrate, and with phosphodiesterase inhibitors or nonspecific PDE inhibitors.

The wholesale cost of the drug is $7,500 for 30 days of treatment, with one tablet taken three times a day, according to a Bayer spokesperson. The company has set up a patient assistance program to help with coverage.

To date, riociguat has been approved in Canada for the treatment of inoperable or persistent/recurrent CTEPH after surgery in adults with WHO functional class II or III pulmonary hypertension, and it is under review in the European Union, according to the company spokesperson.

emechcatie@frontlinemedcom.com

Riociguat, a potent vasodilator that is the first in a new class of drugs, has been approved by the Food and Drug Administration for treating two types of pulmonary hypertension in adults.

The drug, which will be marketed as Adempas, was approved Oct. 8 to treat chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH), the agency said in a statement.

Orally administered in tablet form, riociguat is a soluble guanylate cyclase (sGC) stimulator, the first drug in this class to be approved for pulmonary hypertension. It is also "the first drug of any class to be shown to be effective for patients with CTEPH," Dr. Norman Stockbridge, director of the Division of Cardiovascular and Renal Drug Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.

Riociguat is a pregnancy category X drug and is available to women only through a Risk Evaluation and Mitigation Strategy (REMS) program.

The approved indications for the drug, which will be marketed by Bayer HealthCare Pharmaceuticals, are for persistent/recurrent CTEPH (WHO group 4) "after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class" or PAH (WHO group 1) "to improve exercise capacity, improve WHO functional class, and to delay clinical worsening."

Approval was based on the results of two international studies that found treatment resulted in significant improvements over placebo in the 6 minute walk test. Side effects of treatment include headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea, and vomiting, according to the FDA. Based on these results, an FDA advisory panel unanimously recommended approval of the two indications in August.

In the study of 380 patients with PAH, the change from baseline in the 6-minute walk test at 12 weeks improved by a mean of 30 m among those treated with riociguat, vs. a mean drop of 6 m in the placebo group. The WHO functional class improved in 21% of those on riociguat, compared with 14% in the placebo group, deteriorating in 4% and 14%, respectively.

In the study of 261 patients with CTEPH, the change from baseline in the 6-minute walk test at 16 weeks improved by a mean of 39 m among treated patients vs. a mean 6 m reduction in the placebo group at 16 weeks. WHO functional class improved in 33% of those on riociguat and 15% of those on placebo, deteriorating in 5% and 7%, respectively.

The two studies were published in the July 25 issue of the New England Journal of Medicine (2013;369:330-40; 2013;369:319-29).

The prescribing information includes a boxed warning about embryo-fetal toxicity. Women can receive the drug only through the REMS program.

Because of the risk of hypotension, the drug is contraindicated for use with nitrates or nitric oxide donors, such as amyl nitrate, and with phosphodiesterase inhibitors or nonspecific PDE inhibitors.

The wholesale cost of the drug is $7,500 for 30 days of treatment, with one tablet taken three times a day, according to a Bayer spokesperson. The company has set up a patient assistance program to help with coverage.

To date, riociguat has been approved in Canada for the treatment of inoperable or persistent/recurrent CTEPH after surgery in adults with WHO functional class II or III pulmonary hypertension, and it is under review in the European Union, according to the company spokesperson.

emechcatie@frontlinemedcom.com

Riociguat, a potent vasodilator that is the first in a new class of drugs, has been approved by the Food and Drug Administration for treating two types of pulmonary hypertension in adults.

The drug, which will be marketed as Adempas, was approved Oct. 8 to treat chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH), the agency said in a statement.

Orally administered in tablet form, riociguat is a soluble guanylate cyclase (sGC) stimulator, the first drug in this class to be approved for pulmonary hypertension. It is also "the first drug of any class to be shown to be effective for patients with CTEPH," Dr. Norman Stockbridge, director of the Division of Cardiovascular and Renal Drug Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.

Riociguat is a pregnancy category X drug and is available to women only through a Risk Evaluation and Mitigation Strategy (REMS) program.

The approved indications for the drug, which will be marketed by Bayer HealthCare Pharmaceuticals, are for persistent/recurrent CTEPH (WHO group 4) "after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class" or PAH (WHO group 1) "to improve exercise capacity, improve WHO functional class, and to delay clinical worsening."

Approval was based on the results of two international studies that found treatment resulted in significant improvements over placebo in the 6 minute walk test. Side effects of treatment include headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea, and vomiting, according to the FDA. Based on these results, an FDA advisory panel unanimously recommended approval of the two indications in August.

In the study of 380 patients with PAH, the change from baseline in the 6-minute walk test at 12 weeks improved by a mean of 30 m among those treated with riociguat, vs. a mean drop of 6 m in the placebo group. The WHO functional class improved in 21% of those on riociguat, compared with 14% in the placebo group, deteriorating in 4% and 14%, respectively.

In the study of 261 patients with CTEPH, the change from baseline in the 6-minute walk test at 16 weeks improved by a mean of 39 m among treated patients vs. a mean 6 m reduction in the placebo group at 16 weeks. WHO functional class improved in 33% of those on riociguat and 15% of those on placebo, deteriorating in 5% and 7%, respectively.

The two studies were published in the July 25 issue of the New England Journal of Medicine (2013;369:330-40; 2013;369:319-29).

The prescribing information includes a boxed warning about embryo-fetal toxicity. Women can receive the drug only through the REMS program.

Because of the risk of hypotension, the drug is contraindicated for use with nitrates or nitric oxide donors, such as amyl nitrate, and with phosphodiesterase inhibitors or nonspecific PDE inhibitors.

The wholesale cost of the drug is $7,500 for 30 days of treatment, with one tablet taken three times a day, according to a Bayer spokesperson. The company has set up a patient assistance program to help with coverage.

To date, riociguat has been approved in Canada for the treatment of inoperable or persistent/recurrent CTEPH after surgery in adults with WHO functional class II or III pulmonary hypertension, and it is under review in the European Union, according to the company spokesperson.

emechcatie@frontlinemedcom.com

SAN FRANCISCO – Physicians continue to inappropriately prescribe antibiotics for sore throat and bronchitis, according to analyses of data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey.

Doctors prescribed antibiotics in 60% of office visits for sore throats and 73% of visits for acute bronchitis. However, the antibiotic prescribing rate should be about 10% for sore throats – based on the prevalence of group A Streptococcus (GAS), the only common cause of sore throat for which antibiotics are indicated – and the rate should be almost zero for acute bronchitis, which is almost always caused by a virus, Dr. Jeffrey A. Linder reported during a press conference at an annual scientific meeting on infectious diseases.

The findings are based on cross-sectional analyses of the nationally representative surveys on visits by adults for either a sore throat or for acute bronchitis. The sore throat findings were based on 8,191 visits between 1997 and 2010.

The overall national antibiotic prescribing rate for sore throats did not change from 1997-1998 to 2009-2010, nor did the prescribing rate among office-based physicians or emergency departments during that time period.

Physicians reported increased prescribing of broad-spectrum, expensive, or nonrecommended antibiotics. However, prescriptions for penicillin – the antibiotic of choice for GAS – remained stable at 9% across the study period.

The bronchitis findings are based on surveys for 3,667 visits by adults with a diagnosis of acute bronchitis to primary care physicians and emergency departments between 1996 and 2010. The overall national antibiotic prescribing rate did not change during the study period, but the prescribing rate in emergency departments increased from 69% in 1996 to 73% in 2010, said Dr. Linder* of Harvard Medical School and Brigham and Women’s Hospital, Boston.

Also, physicians increasingly prescribed extended-spectrum macrolides across the study period, with such prescriptions provided at 25% of visits in 1996 and at 41% of visits in 2010, he noted.

Fluoroquinolones were prescribed at 11% of visits, aminopenicillins were prescribed at 7% of visits, and cephalosporins were prescribed at 7% of visits.

The findings were reported in posters at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society. The sore throat findings were also reported concurrently online in the Oct. 4 issue of JAMA Internal Medicine (2013 [doi:10.1001/jamainternmed.2013.11673]).

"The really bad news here is that (the antibiotic prescribing) hasn’t changed at all across the course of the study ... looking back into how we’ve done over past 20 years or so, there’s a little improvement, but it’s painfully slow, and we’re still very far away from the appropriate rate of antibiotic prescribing," he said, noting that this is despite years of effort to promote antibiotic stewardship.

Based on a prior analysis, the antibiotic prescribing rate for sore throat dropped from about 80% to 70% around 1993, and dropped again to 60% by 2000. The current findings show that the prescribing rate remains stable at the 60% level.

Although there was some indication in the survey data that patients are being a little more selective in seeking care for these conditions – perhaps because they are beginning to understand that antibiotics aren’t effective for viral illness – the findings regarding prescribing are troubling, the investigators noted.

Recently, the Centers for Disease Control and Prevention reported that 2 million people are infected with antibiotic-resistant bacteria each year, and 25,000 of those patients die as a result. Antibiotic resistance also causes a great deal of "collateral damage," such as increasing rates of Clostridium difficile infection, said Dr. Ed Septimus, who moderated the press conference.

That results in huge societal costs, estimated at about $35 billion, said Dr. Septimus of Texas A&M Health Science Center, Houston.

Education and improved communication between doctors and patients are needed to address the problem, Dr. Linder and Dr. Septimus agreed.

"Patients and doctors need to have a conversation about the illness ... some of our research suggests that patients don’t want antibiotics as much as doctors think they do," Dr. Septimus said. Doctors often prescribe out of fear that patients will walk away unsatisfied if they don’t get a prescription, he added, but frequently patients just want reassurance that they don’t need an antibiotic.

Accountability is another factor lacking in the outpatient setting, he said.

"We as physicians need to take accountability for our actions ... we need to be reminded that antibiotics, for many of these conditions, are not indicated," he said.

Dr. Linder and Dr. Septimus reported having no disclosures.

*Correction, 10/9/2013: An earlier version of this story misspelled Dr. Linder's name.

SAN FRANCISCO – Physicians continue to inappropriately prescribe antibiotics for sore throat and bronchitis, according to analyses of data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey.

Doctors prescribed antibiotics in 60% of office visits for sore throats and 73% of visits for acute bronchitis. However, the antibiotic prescribing rate should be about 10% for sore throats – based on the prevalence of group A Streptococcus (GAS), the only common cause of sore throat for which antibiotics are indicated – and the rate should be almost zero for acute bronchitis, which is almost always caused by a virus, Dr. Jeffrey A. Linder reported during a press conference at an annual scientific meeting on infectious diseases.

The findings are based on cross-sectional analyses of the nationally representative surveys on visits by adults for either a sore throat or for acute bronchitis. The sore throat findings were based on 8,191 visits between 1997 and 2010.

The overall national antibiotic prescribing rate for sore throats did not change from 1997-1998 to 2009-2010, nor did the prescribing rate among office-based physicians or emergency departments during that time period.

Physicians reported increased prescribing of broad-spectrum, expensive, or nonrecommended antibiotics. However, prescriptions for penicillin – the antibiotic of choice for GAS – remained stable at 9% across the study period.

The bronchitis findings are based on surveys for 3,667 visits by adults with a diagnosis of acute bronchitis to primary care physicians and emergency departments between 1996 and 2010. The overall national antibiotic prescribing rate did not change during the study period, but the prescribing rate in emergency departments increased from 69% in 1996 to 73% in 2010, said Dr. Linder* of Harvard Medical School and Brigham and Women’s Hospital, Boston.

Also, physicians increasingly prescribed extended-spectrum macrolides across the study period, with such prescriptions provided at 25% of visits in 1996 and at 41% of visits in 2010, he noted.

Fluoroquinolones were prescribed at 11% of visits, aminopenicillins were prescribed at 7% of visits, and cephalosporins were prescribed at 7% of visits.

The findings were reported in posters at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society. The sore throat findings were also reported concurrently online in the Oct. 4 issue of JAMA Internal Medicine (2013 [doi:10.1001/jamainternmed.2013.11673]).

"The really bad news here is that (the antibiotic prescribing) hasn’t changed at all across the course of the study ... looking back into how we’ve done over past 20 years or so, there’s a little improvement, but it’s painfully slow, and we’re still very far away from the appropriate rate of antibiotic prescribing," he said, noting that this is despite years of effort to promote antibiotic stewardship.

Based on a prior analysis, the antibiotic prescribing rate for sore throat dropped from about 80% to 70% around 1993, and dropped again to 60% by 2000. The current findings show that the prescribing rate remains stable at the 60% level.

Although there was some indication in the survey data that patients are being a little more selective in seeking care for these conditions – perhaps because they are beginning to understand that antibiotics aren’t effective for viral illness – the findings regarding prescribing are troubling, the investigators noted.

Recently, the Centers for Disease Control and Prevention reported that 2 million people are infected with antibiotic-resistant bacteria each year, and 25,000 of those patients die as a result. Antibiotic resistance also causes a great deal of "collateral damage," such as increasing rates of Clostridium difficile infection, said Dr. Ed Septimus, who moderated the press conference.

That results in huge societal costs, estimated at about $35 billion, said Dr. Septimus of Texas A&M Health Science Center, Houston.

Education and improved communication between doctors and patients are needed to address the problem, Dr. Linder and Dr. Septimus agreed.

"Patients and doctors need to have a conversation about the illness ... some of our research suggests that patients don’t want antibiotics as much as doctors think they do," Dr. Septimus said. Doctors often prescribe out of fear that patients will walk away unsatisfied if they don’t get a prescription, he added, but frequently patients just want reassurance that they don’t need an antibiotic.

Accountability is another factor lacking in the outpatient setting, he said.

"We as physicians need to take accountability for our actions ... we need to be reminded that antibiotics, for many of these conditions, are not indicated," he said.

Dr. Linder and Dr. Septimus reported having no disclosures.

*Correction, 10/9/2013: An earlier version of this story misspelled Dr. Linder's name.

SAN FRANCISCO – Physicians continue to inappropriately prescribe antibiotics for sore throat and bronchitis, according to analyses of data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey.

Doctors prescribed antibiotics in 60% of office visits for sore throats and 73% of visits for acute bronchitis. However, the antibiotic prescribing rate should be about 10% for sore throats – based on the prevalence of group A Streptococcus (GAS), the only common cause of sore throat for which antibiotics are indicated – and the rate should be almost zero for acute bronchitis, which is almost always caused by a virus, Dr. Jeffrey A. Linder reported during a press conference at an annual scientific meeting on infectious diseases.

The findings are based on cross-sectional analyses of the nationally representative surveys on visits by adults for either a sore throat or for acute bronchitis. The sore throat findings were based on 8,191 visits between 1997 and 2010.

The overall national antibiotic prescribing rate for sore throats did not change from 1997-1998 to 2009-2010, nor did the prescribing rate among office-based physicians or emergency departments during that time period.

Physicians reported increased prescribing of broad-spectrum, expensive, or nonrecommended antibiotics. However, prescriptions for penicillin – the antibiotic of choice for GAS – remained stable at 9% across the study period.

The bronchitis findings are based on surveys for 3,667 visits by adults with a diagnosis of acute bronchitis to primary care physicians and emergency departments between 1996 and 2010. The overall national antibiotic prescribing rate did not change during the study period, but the prescribing rate in emergency departments increased from 69% in 1996 to 73% in 2010, said Dr. Linder* of Harvard Medical School and Brigham and Women’s Hospital, Boston.

Also, physicians increasingly prescribed extended-spectrum macrolides across the study period, with such prescriptions provided at 25% of visits in 1996 and at 41% of visits in 2010, he noted.

Fluoroquinolones were prescribed at 11% of visits, aminopenicillins were prescribed at 7% of visits, and cephalosporins were prescribed at 7% of visits.

The findings were reported in posters at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society. The sore throat findings were also reported concurrently online in the Oct. 4 issue of JAMA Internal Medicine (2013 [doi:10.1001/jamainternmed.2013.11673]).

"The really bad news here is that (the antibiotic prescribing) hasn’t changed at all across the course of the study ... looking back into how we’ve done over past 20 years or so, there’s a little improvement, but it’s painfully slow, and we’re still very far away from the appropriate rate of antibiotic prescribing," he said, noting that this is despite years of effort to promote antibiotic stewardship.

Based on a prior analysis, the antibiotic prescribing rate for sore throat dropped from about 80% to 70% around 1993, and dropped again to 60% by 2000. The current findings show that the prescribing rate remains stable at the 60% level.

Although there was some indication in the survey data that patients are being a little more selective in seeking care for these conditions – perhaps because they are beginning to understand that antibiotics aren’t effective for viral illness – the findings regarding prescribing are troubling, the investigators noted.

Recently, the Centers for Disease Control and Prevention reported that 2 million people are infected with antibiotic-resistant bacteria each year, and 25,000 of those patients die as a result. Antibiotic resistance also causes a great deal of "collateral damage," such as increasing rates of Clostridium difficile infection, said Dr. Ed Septimus, who moderated the press conference.

That results in huge societal costs, estimated at about $35 billion, said Dr. Septimus of Texas A&M Health Science Center, Houston.

Education and improved communication between doctors and patients are needed to address the problem, Dr. Linder and Dr. Septimus agreed.

"Patients and doctors need to have a conversation about the illness ... some of our research suggests that patients don’t want antibiotics as much as doctors think they do," Dr. Septimus said. Doctors often prescribe out of fear that patients will walk away unsatisfied if they don’t get a prescription, he added, but frequently patients just want reassurance that they don’t need an antibiotic.

Accountability is another factor lacking in the outpatient setting, he said.

"We as physicians need to take accountability for our actions ... we need to be reminded that antibiotics, for many of these conditions, are not indicated," he said.

Dr. Linder and Dr. Septimus reported having no disclosures.

*Correction, 10/9/2013: An earlier version of this story misspelled Dr. Linder's name.

DENVER – A four-variable risk score predicted acute kidney injury with high specificity in patients receiving vancomycin, results from a single-center study demonstrated.

During a poster session at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Joseph J. Carreno, Pharm.D., discussed findings from a study that set out to identify patients at high risk for AKI during vancomycin therapy.

Doug Brunk/IMNG Medical Media

"Vancomycin has been the standard therapy for infections with methicillin-resistant Staphylococcus aureus for many years," Dr. Carreno of Albany College of Pharmacy and Health Sciences and his associates wrote in their abstract. "Treatment with vancomycin can be limited by the onset of renal dysfunction, which has been associated with additional morbidity. Recently, numerous investigations have evaluated and identified multiple risk factors for acute kidney injury in patients receiving vancomycin. However, few have validated the predictive probability of only those risk factors readily available at bedside at the initiation of therapy."

In a study conducted during his infectious disease pharmacy fellowship at Henry Ford Hospital, Detroit, the researchers retrospectively evaluated the medical records of 112 adult patients who were prescribed intravenous vancomycin for any suspected or confirmed infection between January 2011 and January 2012. They excluded patients who were pregnant, had end-stage renal disease at baseline, or had an absolute neutrophil count of less than 1,000/mm³.

Four risk factors were evaluated: receiving at least 4 g of vancomycin daily or having a body weight of at least 110 kg; a history of renal dysfunction; concurrent use of intravenous vasopressors, and use of concurrent nephrotoxins.

The mean age of the 112 patients was 58 years, and more than half (54%) were male. The majority (84) had fewer than two risk factors while the remaining 28 had at least two risk factors. The most common indications for therapy were infections of the lower respiratory tract and/or skin and soft tissue (49% and 27%, respectively).

Dr. Carreno and his associates reported that the prevalence of AKI was 46%. In logistic regression analysis adjusted for the other three risk factors, the odds for the development of AKI was greatest among patients on vasopressors (odds ratio, 5.92), followed by those with a history of AKI or preexisting chronic kidney disease (OR, 2.99), those on high dose vancomycin or with a body weight of at least 110 kg (OR, 1.68), and those on nephrotoxins (OR, 1.07).

More than two-thirds of patients (68%) with at least two risk factors at baseline developed AKI, compared with 38% of those who had fewer than two risk factors at baseline. The difference was significant with a P value of less than 0.01.

The sensitivity and specificity of the four-variable prediction model were 78% and 33%, respectively, among patients with at least one risk factor, and 37% and 85% among patients with at least two risk factors.

"This is a bedside tool you can use that condenses 20 years’ worth of research into a small, four-variable score that’s clinically applicable," Dr. Carreno said in an interview at the meeting. "It takes less than 5 minutes to apply this to a patient."

He acknowledged that the study’s retrospective design was a limitation.

Dr. Carreno said he had no relevant financial disclosures.

dbrunk@frontlinemedcom.com

DENVER – A four-variable risk score predicted acute kidney injury with high specificity in patients receiving vancomycin, results from a single-center study demonstrated.

During a poster session at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Joseph J. Carreno, Pharm.D., discussed findings from a study that set out to identify patients at high risk for AKI during vancomycin therapy.

Doug Brunk/IMNG Medical Media

"Vancomycin has been the standard therapy for infections with methicillin-resistant Staphylococcus aureus for many years," Dr. Carreno of Albany College of Pharmacy and Health Sciences and his associates wrote in their abstract. "Treatment with vancomycin can be limited by the onset of renal dysfunction, which has been associated with additional morbidity. Recently, numerous investigations have evaluated and identified multiple risk factors for acute kidney injury in patients receiving vancomycin. However, few have validated the predictive probability of only those risk factors readily available at bedside at the initiation of therapy."

In a study conducted during his infectious disease pharmacy fellowship at Henry Ford Hospital, Detroit, the researchers retrospectively evaluated the medical records of 112 adult patients who were prescribed intravenous vancomycin for any suspected or confirmed infection between January 2011 and January 2012. They excluded patients who were pregnant, had end-stage renal disease at baseline, or had an absolute neutrophil count of less than 1,000/mm³.

Four risk factors were evaluated: receiving at least 4 g of vancomycin daily or having a body weight of at least 110 kg; a history of renal dysfunction; concurrent use of intravenous vasopressors, and use of concurrent nephrotoxins.

The mean age of the 112 patients was 58 years, and more than half (54%) were male. The majority (84) had fewer than two risk factors while the remaining 28 had at least two risk factors. The most common indications for therapy were infections of the lower respiratory tract and/or skin and soft tissue (49% and 27%, respectively).

Dr. Carreno and his associates reported that the prevalence of AKI was 46%. In logistic regression analysis adjusted for the other three risk factors, the odds for the development of AKI was greatest among patients on vasopressors (odds ratio, 5.92), followed by those with a history of AKI or preexisting chronic kidney disease (OR, 2.99), those on high dose vancomycin or with a body weight of at least 110 kg (OR, 1.68), and those on nephrotoxins (OR, 1.07).

More than two-thirds of patients (68%) with at least two risk factors at baseline developed AKI, compared with 38% of those who had fewer than two risk factors at baseline. The difference was significant with a P value of less than 0.01.

The sensitivity and specificity of the four-variable prediction model were 78% and 33%, respectively, among patients with at least one risk factor, and 37% and 85% among patients with at least two risk factors.

"This is a bedside tool you can use that condenses 20 years’ worth of research into a small, four-variable score that’s clinically applicable," Dr. Carreno said in an interview at the meeting. "It takes less than 5 minutes to apply this to a patient."

He acknowledged that the study’s retrospective design was a limitation.

Dr. Carreno said he had no relevant financial disclosures.

dbrunk@frontlinemedcom.com

DENVER – A four-variable risk score predicted acute kidney injury with high specificity in patients receiving vancomycin, results from a single-center study demonstrated.

During a poster session at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Joseph J. Carreno, Pharm.D., discussed findings from a study that set out to identify patients at high risk for AKI during vancomycin therapy.

Doug Brunk/IMNG Medical Media

"Vancomycin has been the standard therapy for infections with methicillin-resistant Staphylococcus aureus for many years," Dr. Carreno of Albany College of Pharmacy and Health Sciences and his associates wrote in their abstract. "Treatment with vancomycin can be limited by the onset of renal dysfunction, which has been associated with additional morbidity. Recently, numerous investigations have evaluated and identified multiple risk factors for acute kidney injury in patients receiving vancomycin. However, few have validated the predictive probability of only those risk factors readily available at bedside at the initiation of therapy."

In a study conducted during his infectious disease pharmacy fellowship at Henry Ford Hospital, Detroit, the researchers retrospectively evaluated the medical records of 112 adult patients who were prescribed intravenous vancomycin for any suspected or confirmed infection between January 2011 and January 2012. They excluded patients who were pregnant, had end-stage renal disease at baseline, or had an absolute neutrophil count of less than 1,000/mm³.

Four risk factors were evaluated: receiving at least 4 g of vancomycin daily or having a body weight of at least 110 kg; a history of renal dysfunction; concurrent use of intravenous vasopressors, and use of concurrent nephrotoxins.

The mean age of the 112 patients was 58 years, and more than half (54%) were male. The majority (84) had fewer than two risk factors while the remaining 28 had at least two risk factors. The most common indications for therapy were infections of the lower respiratory tract and/or skin and soft tissue (49% and 27%, respectively).

Dr. Carreno and his associates reported that the prevalence of AKI was 46%. In logistic regression analysis adjusted for the other three risk factors, the odds for the development of AKI was greatest among patients on vasopressors (odds ratio, 5.92), followed by those with a history of AKI or preexisting chronic kidney disease (OR, 2.99), those on high dose vancomycin or with a body weight of at least 110 kg (OR, 1.68), and those on nephrotoxins (OR, 1.07).

More than two-thirds of patients (68%) with at least two risk factors at baseline developed AKI, compared with 38% of those who had fewer than two risk factors at baseline. The difference was significant with a P value of less than 0.01.

The sensitivity and specificity of the four-variable prediction model were 78% and 33%, respectively, among patients with at least one risk factor, and 37% and 85% among patients with at least two risk factors.

"This is a bedside tool you can use that condenses 20 years’ worth of research into a small, four-variable score that’s clinically applicable," Dr. Carreno said in an interview at the meeting. "It takes less than 5 minutes to apply this to a patient."

He acknowledged that the study’s retrospective design was a limitation.

Dr. Carreno said he had no relevant financial disclosures.

dbrunk@frontlinemedcom.com

AMSTERDAM – Another investigational lung cancer vaccine did not improve overall survival, although its use might still benefit some patients, according to results of a phase III study presented at the multidisciplinary European cancer congresses.

The therapeutic tumor cell cancer vaccine belagenpumatucel-L (Lucanix) was no better than placebo at improving the primary endpoint of overall survival after frontline, platinum-based chemotherapy in the STOP study. A total of 532 patients with stable stage III or IV non–small cell lung cancer (NSCLC) participated in the study.

Sara Freeman/IMNG Medical Media

Median overall survival was 20.3 months in the vaccinated patients and 17.8 months in those who had received placebo over a 2-year period (hazard ratio, 0.54; P = .0595).

There was an indication that overall survival might be improved, however, if patients were given the vaccine within 12 weeks of stopping their frontline chemotherapy. Indeed, overall survival was 20.7 months in 169 patients who were vaccinated within 12 weeks of stopping chemotherapy versus 13.3 months in 149 patients who did not receive the vaccine until after that time (HR, 0.77; P = .0092).

"Prospective subset data support further development of belagenpumatucel-L in NSCLC," said Dr. Giuseppe Giaccone, the presenting investigator and associate director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington.

Dr. Giaccone said that the trial was not appropriately powered to meet its primary endpoint. The trial design presumed that the placebo-treated patients would achieve a median survival of around 10.5 months, which was the norm at the time the trial was conceived.

The somewhat disappointing findings in the STOP trial follow those of the phase III START trial, which found no overall survival benefit with a different investigational lung cancer vaccine, tecemotide (Stimuvax). Development of tecemotide also continues, however, as there was an indication that the vaccine might work if given concurrently with chemoradiation rather than after it. The START2 trial will be investigating that hypothesis.

The STOP trial was a randomized, double blind, placebo-controlled investigation performed in eight countries that ran for 46 months and involved patients with late-stage NSCLC; 490 patients had stage IIIB/IV cancer and 42 had stage IIIA cancers. Patients could be enrolled in the trial if they had stable disease after up to six cycles of platinum-based chemotherapy. The aim of the study was to determine if vaccination with belagenpumatucel-L could prevent progression after successful first-line chemotherapy.

Belagenpumatucel-L consists of four allogeneic NSCLC cell lines that have been modified to express an antisense DNA molecule that binds to the gene responsible for producing transforming growth factor beta (TGF-beta), thus blocking production of the protein. TGF-beta has immunosuppressive properties and helps tumor cells evade immune defenses. During the study, the vaccine was given as 18-month intradermal injections followed by a further two injections given 3 months apart. Each dose contained 2.5 × 10⁷ cells.

"Overall, the response rate to the vaccination was low, at 2.6%," Dr. Giaccone reported. There were only one (0.4%) complete and six (2.2%) partial responses. "Progression-free survival did not correlate with overall survival, and there was a trend in some of the subgroups toward an improved PFS, but this was not statistically significant."

The most common side effects were injection-site reactions (grade 1-2), occurring in 260 of the vaccinated and 62 of the placebo-treated patients. Unexpected effects included abdominal pain, constipation, decreased appetite, nasopharyngitis, and noncardiac chest pain, all affecting more patients who received belagenpumatucel-L than those who received placebo. Five serious adverse events occurred, three of which were in patients treated with the vaccine, and only one of these, an allergic reaction, was probably due to the vaccine itself.

NovaRx sponsored the study. Dr. Giaccone said he had no conflicts of interest but noted his coinvestigators included employees of NovaRx.

AMSTERDAM – Another investigational lung cancer vaccine did not improve overall survival, although its use might still benefit some patients, according to results of a phase III study presented at the multidisciplinary European cancer congresses.

The therapeutic tumor cell cancer vaccine belagenpumatucel-L (Lucanix) was no better than placebo at improving the primary endpoint of overall survival after frontline, platinum-based chemotherapy in the STOP study. A total of 532 patients with stable stage III or IV non–small cell lung cancer (NSCLC) participated in the study.

Sara Freeman/IMNG Medical Media

Median overall survival was 20.3 months in the vaccinated patients and 17.8 months in those who had received placebo over a 2-year period (hazard ratio, 0.54; P = .0595).

There was an indication that overall survival might be improved, however, if patients were given the vaccine within 12 weeks of stopping their frontline chemotherapy. Indeed, overall survival was 20.7 months in 169 patients who were vaccinated within 12 weeks of stopping chemotherapy versus 13.3 months in 149 patients who did not receive the vaccine until after that time (HR, 0.77; P = .0092).

"Prospective subset data support further development of belagenpumatucel-L in NSCLC," said Dr. Giuseppe Giaccone, the presenting investigator and associate director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington.

Dr. Giaccone said that the trial was not appropriately powered to meet its primary endpoint. The trial design presumed that the placebo-treated patients would achieve a median survival of around 10.5 months, which was the norm at the time the trial was conceived.

The somewhat disappointing findings in the STOP trial follow those of the phase III START trial, which found no overall survival benefit with a different investigational lung cancer vaccine, tecemotide (Stimuvax). Development of tecemotide also continues, however, as there was an indication that the vaccine might work if given concurrently with chemoradiation rather than after it. The START2 trial will be investigating that hypothesis.

The STOP trial was a randomized, double blind, placebo-controlled investigation performed in eight countries that ran for 46 months and involved patients with late-stage NSCLC; 490 patients had stage IIIB/IV cancer and 42 had stage IIIA cancers. Patients could be enrolled in the trial if they had stable disease after up to six cycles of platinum-based chemotherapy. The aim of the study was to determine if vaccination with belagenpumatucel-L could prevent progression after successful first-line chemotherapy.

Belagenpumatucel-L consists of four allogeneic NSCLC cell lines that have been modified to express an antisense DNA molecule that binds to the gene responsible for producing transforming growth factor beta (TGF-beta), thus blocking production of the protein. TGF-beta has immunosuppressive properties and helps tumor cells evade immune defenses. During the study, the vaccine was given as 18-month intradermal injections followed by a further two injections given 3 months apart. Each dose contained 2.5 × 10⁷ cells.

"Overall, the response rate to the vaccination was low, at 2.6%," Dr. Giaccone reported. There were only one (0.4%) complete and six (2.2%) partial responses. "Progression-free survival did not correlate with overall survival, and there was a trend in some of the subgroups toward an improved PFS, but this was not statistically significant."

The most common side effects were injection-site reactions (grade 1-2), occurring in 260 of the vaccinated and 62 of the placebo-treated patients. Unexpected effects included abdominal pain, constipation, decreased appetite, nasopharyngitis, and noncardiac chest pain, all affecting more patients who received belagenpumatucel-L than those who received placebo. Five serious adverse events occurred, three of which were in patients treated with the vaccine, and only one of these, an allergic reaction, was probably due to the vaccine itself.

NovaRx sponsored the study. Dr. Giaccone said he had no conflicts of interest but noted his coinvestigators included employees of NovaRx.

AMSTERDAM – Another investigational lung cancer vaccine did not improve overall survival, although its use might still benefit some patients, according to results of a phase III study presented at the multidisciplinary European cancer congresses.

The therapeutic tumor cell cancer vaccine belagenpumatucel-L (Lucanix) was no better than placebo at improving the primary endpoint of overall survival after frontline, platinum-based chemotherapy in the STOP study. A total of 532 patients with stable stage III or IV non–small cell lung cancer (NSCLC) participated in the study.

Sara Freeman/IMNG Medical Media

Median overall survival was 20.3 months in the vaccinated patients and 17.8 months in those who had received placebo over a 2-year period (hazard ratio, 0.54; P = .0595).

There was an indication that overall survival might be improved, however, if patients were given the vaccine within 12 weeks of stopping their frontline chemotherapy. Indeed, overall survival was 20.7 months in 169 patients who were vaccinated within 12 weeks of stopping chemotherapy versus 13.3 months in 149 patients who did not receive the vaccine until after that time (HR, 0.77; P = .0092).

"Prospective subset data support further development of belagenpumatucel-L in NSCLC," said Dr. Giuseppe Giaccone, the presenting investigator and associate director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington.

Dr. Giaccone said that the trial was not appropriately powered to meet its primary endpoint. The trial design presumed that the placebo-treated patients would achieve a median survival of around 10.5 months, which was the norm at the time the trial was conceived.

The somewhat disappointing findings in the STOP trial follow those of the phase III START trial, which found no overall survival benefit with a different investigational lung cancer vaccine, tecemotide (Stimuvax). Development of tecemotide also continues, however, as there was an indication that the vaccine might work if given concurrently with chemoradiation rather than after it. The START2 trial will be investigating that hypothesis.

The STOP trial was a randomized, double blind, placebo-controlled investigation performed in eight countries that ran for 46 months and involved patients with late-stage NSCLC; 490 patients had stage IIIB/IV cancer and 42 had stage IIIA cancers. Patients could be enrolled in the trial if they had stable disease after up to six cycles of platinum-based chemotherapy. The aim of the study was to determine if vaccination with belagenpumatucel-L could prevent progression after successful first-line chemotherapy.

Belagenpumatucel-L consists of four allogeneic NSCLC cell lines that have been modified to express an antisense DNA molecule that binds to the gene responsible for producing transforming growth factor beta (TGF-beta), thus blocking production of the protein. TGF-beta has immunosuppressive properties and helps tumor cells evade immune defenses. During the study, the vaccine was given as 18-month intradermal injections followed by a further two injections given 3 months apart. Each dose contained 2.5 × 10⁷ cells.

"Overall, the response rate to the vaccination was low, at 2.6%," Dr. Giaccone reported. There were only one (0.4%) complete and six (2.2%) partial responses. "Progression-free survival did not correlate with overall survival, and there was a trend in some of the subgroups toward an improved PFS, but this was not statistically significant."

The most common side effects were injection-site reactions (grade 1-2), occurring in 260 of the vaccinated and 62 of the placebo-treated patients. Unexpected effects included abdominal pain, constipation, decreased appetite, nasopharyngitis, and noncardiac chest pain, all affecting more patients who received belagenpumatucel-L than those who received placebo. Five serious adverse events occurred, three of which were in patients treated with the vaccine, and only one of these, an allergic reaction, was probably due to the vaccine itself.

NovaRx sponsored the study. Dr. Giaccone said he had no conflicts of interest but noted his coinvestigators included employees of NovaRx.

ATLANTA – For older patients with marginally operable stage 1 non–small cell lung cancer, stereotactic body radiation therapy is significantly more cost effective than surgery.

For patients with clearly operable non–small cell lung cancer (NSCLS) tumors, however, lobectomy is the most cost-effective option, reported Dr. Anand Shah, a radiation oncology resident at Columbia University Medical Center in New York.

Neil Osterweil/IMNG Medical Media

The findings, based on cost-effectiveness modeling, were robust over a wide range of assumptions, including various scenarios about treatment efficacies, toxicities, costs, and health state utilities.

"The rationale behind our study was that the traditional treatment for clearly operable patients with stage 1 lung cancer is lobectomy, whereas wedge resection and SBRT [stereotactic body radiation therapy] serve as alternatives in marginally operable patients. Given an aging population and an increased prevalence of screening, it is likely more people will be diagnosed with stage I lung cancer, and thus we felt it was critical to compare the cost effectiveness of these treatments," he said at the annual meeting of the American Society for Radiation Oncology.

The researchers created a Markov model in which hypothetical patient cohorts transition from one discrete, mutually-exclusive health state to another at fixed time increments and at defined probabilities.

For a cohort with marginally operable disease, they compared SBRT with wedge resection, and for a cohort with clearly operable disease, they compared SBRT with lobectomy. Patients in the model were older than age 65

The model assumes that in both cohorts, SBRT will be similarly efficacious, but with higher toxicity for marginally operable patients, who are more likely to experience treatment-related morbidities. The authors considered both open and less-invasive visually-assisted surgical procedures for patients undergoing lobectomy and wedge resection.

They considered costs from a Medicare perspective using 2012 dollars.

For the base case, SBRT for the marginally operable cohort cost a mean of $42,084, and the mean quality-adjusted life year (QALY) gain was 8.03 years. In contrast, wedge resection cost a mean of $51,487, for a QALY gain of 7.93 years. In statistical parlance, SBRT for this cohort was the less costly and most effective strategy.

For clearly operable patients, however, SBRT was less costly than surgery. The mean cost was $40,107 vs. $49,083, but with less efficacy at 8.21 QALY compared with 8.89 for lobectomy. The investigators calculated an incremental cost-effectiveness ratio favoring lobectomy in this cohort, at a cost of $13,200 per QALY gained.

"We conducted a number of sensitivity analyses in which we varied the cost, efficacy, utility, and toxicity data, and in the marginally operable cohort SBRT was nearly always the dominant and thus cost-effective strategy. For patients who were considered clearly operable, lobectomy was the cost-effective treatment in nearly every sensitivity analysis," Dr. Shah said.

Dr. James B. Yu, the invited discussant, said that given current data, the findings of the study generally support current practice.

"However, even if you don’t agree that lobectomy is more cost effective for the clearly operable patient, at the very least this study will illuminate what we disagree about and where better data and clearer goals are needed," he said.

Dr. Yu is a therapeutic radiologist and cancer outcomes researcher at Yale School of Medicine in New Haven, Conn.

The funding source for the study was not disclosed. Dr. Shah and Dr. Yu reported having no relevant financial disclosures.

ATLANTA – For older patients with marginally operable stage 1 non–small cell lung cancer, stereotactic body radiation therapy is significantly more cost effective than surgery.

For patients with clearly operable non–small cell lung cancer (NSCLS) tumors, however, lobectomy is the most cost-effective option, reported Dr. Anand Shah, a radiation oncology resident at Columbia University Medical Center in New York.

Neil Osterweil/IMNG Medical Media

The findings, based on cost-effectiveness modeling, were robust over a wide range of assumptions, including various scenarios about treatment efficacies, toxicities, costs, and health state utilities.

"The rationale behind our study was that the traditional treatment for clearly operable patients with stage 1 lung cancer is lobectomy, whereas wedge resection and SBRT [stereotactic body radiation therapy] serve as alternatives in marginally operable patients. Given an aging population and an increased prevalence of screening, it is likely more people will be diagnosed with stage I lung cancer, and thus we felt it was critical to compare the cost effectiveness of these treatments," he said at the annual meeting of the American Society for Radiation Oncology.

The researchers created a Markov model in which hypothetical patient cohorts transition from one discrete, mutually-exclusive health state to another at fixed time increments and at defined probabilities.

For a cohort with marginally operable disease, they compared SBRT with wedge resection, and for a cohort with clearly operable disease, they compared SBRT with lobectomy. Patients in the model were older than age 65

The model assumes that in both cohorts, SBRT will be similarly efficacious, but with higher toxicity for marginally operable patients, who are more likely to experience treatment-related morbidities. The authors considered both open and less-invasive visually-assisted surgical procedures for patients undergoing lobectomy and wedge resection.

They considered costs from a Medicare perspective using 2012 dollars.

For the base case, SBRT for the marginally operable cohort cost a mean of $42,084, and the mean quality-adjusted life year (QALY) gain was 8.03 years. In contrast, wedge resection cost a mean of $51,487, for a QALY gain of 7.93 years. In statistical parlance, SBRT for this cohort was the less costly and most effective strategy.

For clearly operable patients, however, SBRT was less costly than surgery. The mean cost was $40,107 vs. $49,083, but with less efficacy at 8.21 QALY compared with 8.89 for lobectomy. The investigators calculated an incremental cost-effectiveness ratio favoring lobectomy in this cohort, at a cost of $13,200 per QALY gained.

"We conducted a number of sensitivity analyses in which we varied the cost, efficacy, utility, and toxicity data, and in the marginally operable cohort SBRT was nearly always the dominant and thus cost-effective strategy. For patients who were considered clearly operable, lobectomy was the cost-effective treatment in nearly every sensitivity analysis," Dr. Shah said.

Dr. James B. Yu, the invited discussant, said that given current data, the findings of the study generally support current practice.

"However, even if you don’t agree that lobectomy is more cost effective for the clearly operable patient, at the very least this study will illuminate what we disagree about and where better data and clearer goals are needed," he said.

Dr. Yu is a therapeutic radiologist and cancer outcomes researcher at Yale School of Medicine in New Haven, Conn.

The funding source for the study was not disclosed. Dr. Shah and Dr. Yu reported having no relevant financial disclosures.

ATLANTA – For older patients with marginally operable stage 1 non–small cell lung cancer, stereotactic body radiation therapy is significantly more cost effective than surgery.

For patients with clearly operable non–small cell lung cancer (NSCLS) tumors, however, lobectomy is the most cost-effective option, reported Dr. Anand Shah, a radiation oncology resident at Columbia University Medical Center in New York.

Neil Osterweil/IMNG Medical Media

The findings, based on cost-effectiveness modeling, were robust over a wide range of assumptions, including various scenarios about treatment efficacies, toxicities, costs, and health state utilities.

"The rationale behind our study was that the traditional treatment for clearly operable patients with stage 1 lung cancer is lobectomy, whereas wedge resection and SBRT [stereotactic body radiation therapy] serve as alternatives in marginally operable patients. Given an aging population and an increased prevalence of screening, it is likely more people will be diagnosed with stage I lung cancer, and thus we felt it was critical to compare the cost effectiveness of these treatments," he said at the annual meeting of the American Society for Radiation Oncology.

The researchers created a Markov model in which hypothetical patient cohorts transition from one discrete, mutually-exclusive health state to another at fixed time increments and at defined probabilities.

For a cohort with marginally operable disease, they compared SBRT with wedge resection, and for a cohort with clearly operable disease, they compared SBRT with lobectomy. Patients in the model were older than age 65

The model assumes that in both cohorts, SBRT will be similarly efficacious, but with higher toxicity for marginally operable patients, who are more likely to experience treatment-related morbidities. The authors considered both open and less-invasive visually-assisted surgical procedures for patients undergoing lobectomy and wedge resection.

They considered costs from a Medicare perspective using 2012 dollars.

For the base case, SBRT for the marginally operable cohort cost a mean of $42,084, and the mean quality-adjusted life year (QALY) gain was 8.03 years. In contrast, wedge resection cost a mean of $51,487, for a QALY gain of 7.93 years. In statistical parlance, SBRT for this cohort was the less costly and most effective strategy.

For clearly operable patients, however, SBRT was less costly than surgery. The mean cost was $40,107 vs. $49,083, but with less efficacy at 8.21 QALY compared with 8.89 for lobectomy. The investigators calculated an incremental cost-effectiveness ratio favoring lobectomy in this cohort, at a cost of $13,200 per QALY gained.

"We conducted a number of sensitivity analyses in which we varied the cost, efficacy, utility, and toxicity data, and in the marginally operable cohort SBRT was nearly always the dominant and thus cost-effective strategy. For patients who were considered clearly operable, lobectomy was the cost-effective treatment in nearly every sensitivity analysis," Dr. Shah said.

Dr. James B. Yu, the invited discussant, said that given current data, the findings of the study generally support current practice.

"However, even if you don’t agree that lobectomy is more cost effective for the clearly operable patient, at the very least this study will illuminate what we disagree about and where better data and clearer goals are needed," he said.

Dr. Yu is a therapeutic radiologist and cancer outcomes researcher at Yale School of Medicine in New Haven, Conn.

The funding source for the study was not disclosed. Dr. Shah and Dr. Yu reported having no relevant financial disclosures.

A large prospective study of infants hospitalized for bronchiolitis has revealed a number of previously unknown risk factors associated with apnea, a potentially life-threatening complication.

While high preadmission respiratory rates were found associated with increased apnea risk, so were low respiratory rates, a surprising finding that investigators could not explain. Low room air oxygen saturation was seen as contributing to risk. And one usual-suspect risk factor in apnea – respiratory syncytial virus – turned out not to be more dangerous than other viruses in terms of apnea risk.

Clinicians should not be reassured by either a low respiratory rate or infection with an organism other than RSV in assessing apnea risk, said Dr. Alan R. Schroeder of the Santa Clara Medical Center in San Jose, Calif., and his colleagues.

At 16 study sites nationwide starting in 2007, the researchers collected enrollment and outcome data on 2,156 children under age 2 (median age 4 months, with age corrected for birth at less than 37 weeks). The patients were admitted with bronchiolitis over three consecutive winter seasons. Of these children, 108 (5%) developed apnea while hospitalized, according to the study, which was published online Oct. 7 in Pediatrics (2013;132:1-8 [doi: 10.1542/peds.2013-1501]). The study was part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network.

The study confirmed the known risk factors of young corrected age, low birth weight, and previous apnea during the same bronchiolitis episode. Dr. Schroeder and his colleagues found that the statistically significant predictors of apnea included age of less than 2 weeks (odds ratio, 9.67) and 2-8 weeks (OR, 4.72), compared with age 6 months or older; birth weight of less than 2.3 kg (OR, 2.15), compared with birth weight of 3.2 kg or more; and previous apnea during the same bronchiolitis episode (OR, 3.63).

There also was risk associated with preadmission respiratory rates of less than 30 (OR, 4.05) and 30-39 (OR, 2.35), compared with 40-49, as well as a preadmission respiratory rate of 70 or more (OR, 2.26). Risk of apnea was also associated with having a preadmission room air oxygen saturation of less than 90% (OR, 1.60).

Apnea risk was shown to be similar across the major viral infections seen in the cohort. While more infants presented with RSV than with other viruses, there was roughly equal apnea risk seen among children infected with human rhinovirus, adenovirus, human metapneumovirus, enterovirus, coronavirus, and parainfluenza virus.

"These data suggest that using RSV status to drive admission decisions and admission locations (e.g., ward, step-down unit, ICU) due to apnea concerns may be misguided," Dr. Schroeder and his colleagues wrote in their analysis.

The study contained a number of other novel findings. While a recent, smaller study of 42 patients had suggested a possible protective effect associated with acetaminophen administered the week before hospitalization (Resuscitation 2012;83:440-46), the study by Dr. Schroeder and his colleagues found no such effect.

It also shed light on the timing of apnea during the course of bronchiolitis. While previous studies had shown apnea occurring early in the course of RSV infection, "our results challenge this notion," the authors wrote. One-third of the infants with apnea in the study began having difficulty breathing 4 or more days before the preadmission visit. "Furthermore, the time from the beginning of the ‘difficulty breathing’ to the preadmission visit was not different between children with and without apnea. Therefore, using the duration of symptoms to predict future risk of apnea or need for hospitalization may be problematic."

The investigators acknowledged as limitations of their study the possibility that the reported incidence of apnea may have been biased by oversampling of sicker patients, as the investigators recruited 20% of patients from intensive care. Some infants may have been included based on chart data that did not meet strict criteria for apnea, allowing for overreporting, they said, and apnea may have been harder to detect in intubated patients, leading to underreporting in this population.

The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.

A large prospective study of infants hospitalized for bronchiolitis has revealed a number of previously unknown risk factors associated with apnea, a potentially life-threatening complication.

While high preadmission respiratory rates were found associated with increased apnea risk, so were low respiratory rates, a surprising finding that investigators could not explain. Low room air oxygen saturation was seen as contributing to risk. And one usual-suspect risk factor in apnea – respiratory syncytial virus – turned out not to be more dangerous than other viruses in terms of apnea risk.

Clinicians should not be reassured by either a low respiratory rate or infection with an organism other than RSV in assessing apnea risk, said Dr. Alan R. Schroeder of the Santa Clara Medical Center in San Jose, Calif., and his colleagues.

At 16 study sites nationwide starting in 2007, the researchers collected enrollment and outcome data on 2,156 children under age 2 (median age 4 months, with age corrected for birth at less than 37 weeks). The patients were admitted with bronchiolitis over three consecutive winter seasons. Of these children, 108 (5%) developed apnea while hospitalized, according to the study, which was published online Oct. 7 in Pediatrics (2013;132:1-8 [doi: 10.1542/peds.2013-1501]). The study was part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network.

The study confirmed the known risk factors of young corrected age, low birth weight, and previous apnea during the same bronchiolitis episode. Dr. Schroeder and his colleagues found that the statistically significant predictors of apnea included age of less than 2 weeks (odds ratio, 9.67) and 2-8 weeks (OR, 4.72), compared with age 6 months or older; birth weight of less than 2.3 kg (OR, 2.15), compared with birth weight of 3.2 kg or more; and previous apnea during the same bronchiolitis episode (OR, 3.63).

There also was risk associated with preadmission respiratory rates of less than 30 (OR, 4.05) and 30-39 (OR, 2.35), compared with 40-49, as well as a preadmission respiratory rate of 70 or more (OR, 2.26). Risk of apnea was also associated with having a preadmission room air oxygen saturation of less than 90% (OR, 1.60).

Apnea risk was shown to be similar across the major viral infections seen in the cohort. While more infants presented with RSV than with other viruses, there was roughly equal apnea risk seen among children infected with human rhinovirus, adenovirus, human metapneumovirus, enterovirus, coronavirus, and parainfluenza virus.

"These data suggest that using RSV status to drive admission decisions and admission locations (e.g., ward, step-down unit, ICU) due to apnea concerns may be misguided," Dr. Schroeder and his colleagues wrote in their analysis.

The study contained a number of other novel findings. While a recent, smaller study of 42 patients had suggested a possible protective effect associated with acetaminophen administered the week before hospitalization (Resuscitation 2012;83:440-46), the study by Dr. Schroeder and his colleagues found no such effect.

It also shed light on the timing of apnea during the course of bronchiolitis. While previous studies had shown apnea occurring early in the course of RSV infection, "our results challenge this notion," the authors wrote. One-third of the infants with apnea in the study began having difficulty breathing 4 or more days before the preadmission visit. "Furthermore, the time from the beginning of the ‘difficulty breathing’ to the preadmission visit was not different between children with and without apnea. Therefore, using the duration of symptoms to predict future risk of apnea or need for hospitalization may be problematic."

The investigators acknowledged as limitations of their study the possibility that the reported incidence of apnea may have been biased by oversampling of sicker patients, as the investigators recruited 20% of patients from intensive care. Some infants may have been included based on chart data that did not meet strict criteria for apnea, allowing for overreporting, they said, and apnea may have been harder to detect in intubated patients, leading to underreporting in this population.

The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.

A large prospective study of infants hospitalized for bronchiolitis has revealed a number of previously unknown risk factors associated with apnea, a potentially life-threatening complication.

While high preadmission respiratory rates were found associated with increased apnea risk, so were low respiratory rates, a surprising finding that investigators could not explain. Low room air oxygen saturation was seen as contributing to risk. And one usual-suspect risk factor in apnea – respiratory syncytial virus – turned out not to be more dangerous than other viruses in terms of apnea risk.

Clinicians should not be reassured by either a low respiratory rate or infection with an organism other than RSV in assessing apnea risk, said Dr. Alan R. Schroeder of the Santa Clara Medical Center in San Jose, Calif., and his colleagues.

At 16 study sites nationwide starting in 2007, the researchers collected enrollment and outcome data on 2,156 children under age 2 (median age 4 months, with age corrected for birth at less than 37 weeks). The patients were admitted with bronchiolitis over three consecutive winter seasons. Of these children, 108 (5%) developed apnea while hospitalized, according to the study, which was published online Oct. 7 in Pediatrics (2013;132:1-8 [doi: 10.1542/peds.2013-1501]). The study was part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network.

The study confirmed the known risk factors of young corrected age, low birth weight, and previous apnea during the same bronchiolitis episode. Dr. Schroeder and his colleagues found that the statistically significant predictors of apnea included age of less than 2 weeks (odds ratio, 9.67) and 2-8 weeks (OR, 4.72), compared with age 6 months or older; birth weight of less than 2.3 kg (OR, 2.15), compared with birth weight of 3.2 kg or more; and previous apnea during the same bronchiolitis episode (OR, 3.63).

There also was risk associated with preadmission respiratory rates of less than 30 (OR, 4.05) and 30-39 (OR, 2.35), compared with 40-49, as well as a preadmission respiratory rate of 70 or more (OR, 2.26). Risk of apnea was also associated with having a preadmission room air oxygen saturation of less than 90% (OR, 1.60).

Apnea risk was shown to be similar across the major viral infections seen in the cohort. While more infants presented with RSV than with other viruses, there was roughly equal apnea risk seen among children infected with human rhinovirus, adenovirus, human metapneumovirus, enterovirus, coronavirus, and parainfluenza virus.

"These data suggest that using RSV status to drive admission decisions and admission locations (e.g., ward, step-down unit, ICU) due to apnea concerns may be misguided," Dr. Schroeder and his colleagues wrote in their analysis.

The study contained a number of other novel findings. While a recent, smaller study of 42 patients had suggested a possible protective effect associated with acetaminophen administered the week before hospitalization (Resuscitation 2012;83:440-46), the study by Dr. Schroeder and his colleagues found no such effect.

It also shed light on the timing of apnea during the course of bronchiolitis. While previous studies had shown apnea occurring early in the course of RSV infection, "our results challenge this notion," the authors wrote. One-third of the infants with apnea in the study began having difficulty breathing 4 or more days before the preadmission visit. "Furthermore, the time from the beginning of the ‘difficulty breathing’ to the preadmission visit was not different between children with and without apnea. Therefore, using the duration of symptoms to predict future risk of apnea or need for hospitalization may be problematic."

The investigators acknowledged as limitations of their study the possibility that the reported incidence of apnea may have been biased by oversampling of sicker patients, as the investigators recruited 20% of patients from intensive care. Some infants may have been included based on chart data that did not meet strict criteria for apnea, allowing for overreporting, they said, and apnea may have been harder to detect in intubated patients, leading to underreporting in this population.

The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.

Could recurrent acute otitis media be related to a neonate-like antibody response in children as old as 24 months? Dr. Michael E.* Pichichero believes so.

He and his colleagues have found data indicating the existence of what may be a new immunodeficiency that they are calling prolonged neonatal immune deficiency, Dr. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute, said in an interview.

Dr. Pichichero and his team started tracking children from his suburban Rochester, N.Y., private practice and collected blood samples from 600 patients who had not experienced acute otitis media by the age of 6 months. Between the ages of 6 and 30 months, 34 of those children (5.7%) experienced recurrent AOM and were classified as "stringently otitis prone," defined as having had three AOM episodes within 6 months, or four within 12 months, despite optimal diagnosis and treatment. These children were age-matched with 34 children from the same cohort, who experienced few or no episodes of AOM.**

Children in both groups received primary vaccinations according to the approved immunization schedule; each had blood drawn at 6, 9, 12, 15, 18, and 24 months of age.

Among samples from the stringently otitis-prone children, the investigators noted weak immune responses, including poor B and T cell memory after natural exposure to nontypeable Haemophilus influenzae and Streptococcus pneumoniae nasal colonization and AOM.

They measured antibody levels for diphtheria, tetanus, pertussis, pertussis filamentous hemagglutinin, polio, hepatitis B, H. influenzae type b, and S. pneumoniae pneumococcal polysaccharides.

When compared with children in the control group, stringently otitis-prone children at all ages had nonprotective levels of antibody for diphtheria (odds ratio, 8.59), tetanus (OR greater than 1), pertussis pertactin (OR, 5.09), and hepatitis B (OR greater than 10*). While these children more often had nonprotective levels of antibody for pertussis filamentous hemagglutinin, polio 3, and S. pneumoniae 23, the group effect varied with age (Pediatr. Infect. Dis. J. 2013 June 18; published ahead of print [doi: 10.1097/INF.0b013e31829e887e]).

Antibody responses also were measured in both groups at age 15 months, before the children received booster shots. Stringently otitis-prone children had "nondetectable or below protection titers," the investigators found. Specifically, 74% of the children had 1 or more antibodies below protection; 56% had 2 or more; 44% had 3 or more; and 27% had 5 or more. Among the age-matched controls, 47% had 1 or more; 27% had 2 or more; 12% had 3 or more; and 0% had 5 or more.

Stringently otitis-prone children may "have immune responses to otopathogens ... resembling a neonatal-like immune profile during at least the first 18-24 years of life," Dr. Pichichero said. Based on these findings, "a child with recurrent AOM should be considered a possible low vaccine responder, and vaccine-induced antibody levels may need to be evaluated."

The findings aren’t without controversy. "Not everyone has accepted the results as meaningful," Dr. Stephen I. Pelton, an epidemiologist at Boston Medical Center, said in an interview. "I think the issue relates to the fact that most children – virtually all – who have recurrent AOM do not have any other infectious diseases. Vaccine failures for PCV7 have been few, and as far as I am aware, pertussis is not more common in children with [recurrent AOM]."

Dr. Pelton also said that "children with AOM are more likely to be colonized with otopathogens early in life, and develop disease early in life as well."

"There is not that much pertussis or tetanus or diphtheria or polio around in the United States, so we did not see an increase in those diseases among otitis-prone kids," Dr. Pichichero noted. "However, we show in a paper that is forthcoming, that [stringently otitis-prone children] don’t respond to influenza vaccine, and correspondingly the kids do get flu more often. They don’t make good immunity to [respiratory syncytial virus] infections, and they get RSV more often. They also get pneumococcal infections more often."

Dr. Mark Sawyer, a pediatric infectious disease specialist at Rady Children’s Hospital in San Diego, pointed out that the question is, why don’t these children respond well to vaccines? "What is it about their immune system? That needs to be uncovered, and then if they identify those kids with some kind of simple questions, then maybe you would immunize them differently."

Dr. Pichichero said that he aims to next investigate the question of whether or not at some point otitis-prone children ever reach antibody parity with non–otitis-prone children. "We will be studying dendritic cells, B cells, and T cells further in the future. What is the mechanism? That will be the key to unlock what we can do about it."

If the data in the current study are confirmed, Dr. Pichichero said, "at 9 months when we take a blood sample for anemia and lead, we may also take a sample for vaccine responses. We could give a booster if needed."

"I think it’s a long way from leading to a change in the vaccine schedule. I think the immediate next step is to get this reproduced in a larger number of kids that are more equally balanced, so we can find out if this is purely an immune problem, or does this relate to allergy or other things that set aside one group from another," said Dr. Sawyer, who previously served on the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.

For now, Dr. Pichichero said the take-away for practicing pediatricians treating children with recurrent otitis media is that "you can explain to the parent that it may be the kid isn’t making immunity to the infection germ. We have strong hints that the ... immune system is immature."

Dr. Pichichero and his colleagues reported no relevant disclosures. The studies received funding from the Thrasher Foundation and the National Institute for Deafness and Communication Disorders.

wmcknight@frontlinemedcom.com

*Correction, 10/3/2013: An earlier version of this story misstated the odds ratio for nonprotective levels of antibody in otitis-prone children with hepatitis B. In addition, the article misstated the name of Dr. Michael E. Pichichero.

**Updated, 10/5/2013.

Could recurrent acute otitis media be related to a neonate-like antibody response in children as old as 24 months? Dr. Michael E.* Pichichero believes so.

He and his colleagues have found data indicating the existence of what may be a new immunodeficiency that they are calling prolonged neonatal immune deficiency, Dr. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute, said in an interview.

Dr. Pichichero and his team started tracking children from his suburban Rochester, N.Y., private practice and collected blood samples from 600 patients who had not experienced acute otitis media by the age of 6 months. Between the ages of 6 and 30 months, 34 of those children (5.7%) experienced recurrent AOM and were classified as "stringently otitis prone," defined as having had three AOM episodes within 6 months, or four within 12 months, despite optimal diagnosis and treatment. These children were age-matched with 34 children from the same cohort, who experienced few or no episodes of AOM.**

Children in both groups received primary vaccinations according to the approved immunization schedule; each had blood drawn at 6, 9, 12, 15, 18, and 24 months of age.

Among samples from the stringently otitis-prone children, the investigators noted weak immune responses, including poor B and T cell memory after natural exposure to nontypeable Haemophilus influenzae and Streptococcus pneumoniae nasal colonization and AOM.

They measured antibody levels for diphtheria, tetanus, pertussis, pertussis filamentous hemagglutinin, polio, hepatitis B, H. influenzae type b, and S. pneumoniae pneumococcal polysaccharides.

When compared with children in the control group, stringently otitis-prone children at all ages had nonprotective levels of antibody for diphtheria (odds ratio, 8.59), tetanus (OR greater than 1), pertussis pertactin (OR, 5.09), and hepatitis B (OR greater than 10*). While these children more often had nonprotective levels of antibody for pertussis filamentous hemagglutinin, polio 3, and S. pneumoniae 23, the group effect varied with age (Pediatr. Infect. Dis. J. 2013 June 18; published ahead of print [doi: 10.1097/INF.0b013e31829e887e]).

Antibody responses also were measured in both groups at age 15 months, before the children received booster shots. Stringently otitis-prone children had "nondetectable or below protection titers," the investigators found. Specifically, 74% of the children had 1 or more antibodies below protection; 56% had 2 or more; 44% had 3 or more; and 27% had 5 or more. Among the age-matched controls, 47% had 1 or more; 27% had 2 or more; 12% had 3 or more; and 0% had 5 or more.

Stringently otitis-prone children may "have immune responses to otopathogens ... resembling a neonatal-like immune profile during at least the first 18-24 years of life," Dr. Pichichero said. Based on these findings, "a child with recurrent AOM should be considered a possible low vaccine responder, and vaccine-induced antibody levels may need to be evaluated."

The findings aren’t without controversy. "Not everyone has accepted the results as meaningful," Dr. Stephen I. Pelton, an epidemiologist at Boston Medical Center, said in an interview. "I think the issue relates to the fact that most children – virtually all – who have recurrent AOM do not have any other infectious diseases. Vaccine failures for PCV7 have been few, and as far as I am aware, pertussis is not more common in children with [recurrent AOM]."

Dr. Pelton also said that "children with AOM are more likely to be colonized with otopathogens early in life, and develop disease early in life as well."

"There is not that much pertussis or tetanus or diphtheria or polio around in the United States, so we did not see an increase in those diseases among otitis-prone kids," Dr. Pichichero noted. "However, we show in a paper that is forthcoming, that [stringently otitis-prone children] don’t respond to influenza vaccine, and correspondingly the kids do get flu more often. They don’t make good immunity to [respiratory syncytial virus] infections, and they get RSV more often. They also get pneumococcal infections more often."

Dr. Mark Sawyer, a pediatric infectious disease specialist at Rady Children’s Hospital in San Diego, pointed out that the question is, why don’t these children respond well to vaccines? "What is it about their immune system? That needs to be uncovered, and then if they identify those kids with some kind of simple questions, then maybe you would immunize them differently."

Dr. Pichichero said that he aims to next investigate the question of whether or not at some point otitis-prone children ever reach antibody parity with non–otitis-prone children. "We will be studying dendritic cells, B cells, and T cells further in the future. What is the mechanism? That will be the key to unlock what we can do about it."

If the data in the current study are confirmed, Dr. Pichichero said, "at 9 months when we take a blood sample for anemia and lead, we may also take a sample for vaccine responses. We could give a booster if needed."

"I think it’s a long way from leading to a change in the vaccine schedule. I think the immediate next step is to get this reproduced in a larger number of kids that are more equally balanced, so we can find out if this is purely an immune problem, or does this relate to allergy or other things that set aside one group from another," said Dr. Sawyer, who previously served on the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.

For now, Dr. Pichichero said the take-away for practicing pediatricians treating children with recurrent otitis media is that "you can explain to the parent that it may be the kid isn’t making immunity to the infection germ. We have strong hints that the ... immune system is immature."

Dr. Pichichero and his colleagues reported no relevant disclosures. The studies received funding from the Thrasher Foundation and the National Institute for Deafness and Communication Disorders.

wmcknight@frontlinemedcom.com

*Correction, 10/3/2013: An earlier version of this story misstated the odds ratio for nonprotective levels of antibody in otitis-prone children with hepatitis B. In addition, the article misstated the name of Dr. Michael E. Pichichero.

**Updated, 10/5/2013.

Could recurrent acute otitis media be related to a neonate-like antibody response in children as old as 24 months? Dr. Michael E.* Pichichero believes so.

He and his colleagues have found data indicating the existence of what may be a new immunodeficiency that they are calling prolonged neonatal immune deficiency, Dr. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute, said in an interview.

Dr. Pichichero and his team started tracking children from his suburban Rochester, N.Y., private practice and collected blood samples from 600 patients who had not experienced acute otitis media by the age of 6 months. Between the ages of 6 and 30 months, 34 of those children (5.7%) experienced recurrent AOM and were classified as "stringently otitis prone," defined as having had three AOM episodes within 6 months, or four within 12 months, despite optimal diagnosis and treatment. These children were age-matched with 34 children from the same cohort, who experienced few or no episodes of AOM.**

Children in both groups received primary vaccinations according to the approved immunization schedule; each had blood drawn at 6, 9, 12, 15, 18, and 24 months of age.

Among samples from the stringently otitis-prone children, the investigators noted weak immune responses, including poor B and T cell memory after natural exposure to nontypeable Haemophilus influenzae and Streptococcus pneumoniae nasal colonization and AOM.

They measured antibody levels for diphtheria, tetanus, pertussis, pertussis filamentous hemagglutinin, polio, hepatitis B, H. influenzae type b, and S. pneumoniae pneumococcal polysaccharides.

When compared with children in the control group, stringently otitis-prone children at all ages had nonprotective levels of antibody for diphtheria (odds ratio, 8.59), tetanus (OR greater than 1), pertussis pertactin (OR, 5.09), and hepatitis B (OR greater than 10*). While these children more often had nonprotective levels of antibody for pertussis filamentous hemagglutinin, polio 3, and S. pneumoniae 23, the group effect varied with age (Pediatr. Infect. Dis. J. 2013 June 18; published ahead of print [doi: 10.1097/INF.0b013e31829e887e]).

Antibody responses also were measured in both groups at age 15 months, before the children received booster shots. Stringently otitis-prone children had "nondetectable or below protection titers," the investigators found. Specifically, 74% of the children had 1 or more antibodies below protection; 56% had 2 or more; 44% had 3 or more; and 27% had 5 or more. Among the age-matched controls, 47% had 1 or more; 27% had 2 or more; 12% had 3 or more; and 0% had 5 or more.

Stringently otitis-prone children may "have immune responses to otopathogens ... resembling a neonatal-like immune profile during at least the first 18-24 years of life," Dr. Pichichero said. Based on these findings, "a child with recurrent AOM should be considered a possible low vaccine responder, and vaccine-induced antibody levels may need to be evaluated."

The findings aren’t without controversy. "Not everyone has accepted the results as meaningful," Dr. Stephen I. Pelton, an epidemiologist at Boston Medical Center, said in an interview. "I think the issue relates to the fact that most children – virtually all – who have recurrent AOM do not have any other infectious diseases. Vaccine failures for PCV7 have been few, and as far as I am aware, pertussis is not more common in children with [recurrent AOM]."

Dr. Pelton also said that "children with AOM are more likely to be colonized with otopathogens early in life, and develop disease early in life as well."

"There is not that much pertussis or tetanus or diphtheria or polio around in the United States, so we did not see an increase in those diseases among otitis-prone kids," Dr. Pichichero noted. "However, we show in a paper that is forthcoming, that [stringently otitis-prone children] don’t respond to influenza vaccine, and correspondingly the kids do get flu more often. They don’t make good immunity to [respiratory syncytial virus] infections, and they get RSV more often. They also get pneumococcal infections more often."

Dr. Mark Sawyer, a pediatric infectious disease specialist at Rady Children’s Hospital in San Diego, pointed out that the question is, why don’t these children respond well to vaccines? "What is it about their immune system? That needs to be uncovered, and then if they identify those kids with some kind of simple questions, then maybe you would immunize them differently."

Dr. Pichichero said that he aims to next investigate the question of whether or not at some point otitis-prone children ever reach antibody parity with non–otitis-prone children. "We will be studying dendritic cells, B cells, and T cells further in the future. What is the mechanism? That will be the key to unlock what we can do about it."

If the data in the current study are confirmed, Dr. Pichichero said, "at 9 months when we take a blood sample for anemia and lead, we may also take a sample for vaccine responses. We could give a booster if needed."

"I think it’s a long way from leading to a change in the vaccine schedule. I think the immediate next step is to get this reproduced in a larger number of kids that are more equally balanced, so we can find out if this is purely an immune problem, or does this relate to allergy or other things that set aside one group from another," said Dr. Sawyer, who previously served on the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.

For now, Dr. Pichichero said the take-away for practicing pediatricians treating children with recurrent otitis media is that "you can explain to the parent that it may be the kid isn’t making immunity to the infection germ. We have strong hints that the ... immune system is immature."

Dr. Pichichero and his colleagues reported no relevant disclosures. The studies received funding from the Thrasher Foundation and the National Institute for Deafness and Communication Disorders.

wmcknight@frontlinemedcom.com

*Correction, 10/3/2013: An earlier version of this story misstated the odds ratio for nonprotective levels of antibody in otitis-prone children with hepatitis B. In addition, the article misstated the name of Dr. Michael E. Pichichero.

**Updated, 10/5/2013.